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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study with an Open-Label Phase 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)

    Summary
    EudraCT number
    2014-005630-60
    Trial protocol
    DE   CZ   ES   AT   IT  
    Global end of trial date
    12 Jan 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    23 Feb 2019
    First version publication date
    23 Feb 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TOZ-CL05
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02453386
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Acorda Therapeutics
    Sponsor organisation address
    420 Saw Mill River Road, Ardsley, United States, 10502
    Public contact
    Christopher Kenney, Senior Vice President - Medical Affairs, Acorda Therapeutics, +914 326-5775, ckenney@acorda.com
    Scientific contact
    Christopher Kenney, Senior Vice President - Medical Affairs, Acorda Therapeutics, +914 326-5775, ckenney@acorda.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Jan 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Jan 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jan 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary efficacy objective of this study is to demonstrate the efficacy of the A2a receptor antagonist tozadenant in the treatment of levodopa-treated PD patients experiencing end-of-dose “wearing-off”, based on the change from Baseline to Week 24 in the number of hours per day spent in the OFF state.
    Protection of trial subjects
    Conduct of the study must be approved by an appropriately constituted IRB or IEC. Approval is required for the study protocol, investigational drug brochure, protocol amendments, informed consent forms, patient information sheets, and advertising materials. For each study patient, written informed consent will be obtained prior to any protocol-related activities. As part of this procedure, the principal investigator or one of his/her associates must explain orally and in writing the nature, duration, and purpose of the study, and the action of the drug in such a manner that the patient is aware of the potential risks, inconveniences, or adverse effects that may occur. The patient should be informed that he/she may withdraw from the study at any time, and the patient will receive all information that is required by local regulations and ICH guidelines. The principal investigator will provide the Sponsor or its representative with a copy of the IRB/IEC-approved informed consent form prior to the start of the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Jul 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 37
    Country: Number of subjects enrolled
    Austria: 8
    Country: Number of subjects enrolled
    Czech Republic: 66
    Country: Number of subjects enrolled
    Germany: 57
    Country: Number of subjects enrolled
    Canada: 15
    Country: Number of subjects enrolled
    Italy: 59
    Country: Number of subjects enrolled
    United States: 207
    Worldwide total number of subjects
    449
    EEA total number of subjects
    227
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    200
    From 65 to 84 years
    249
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted at 80 sites in 7 countries (United States, Canada, Italy, Austria, Spain, Germany, Czech Republic). Planned patient enrollment numbers were achieved, but the study and the tozadenant development program were terminated prior to study completion by all patients, based on an unexpected emerging safety signal.

    Pre-assignment
    Screening details
    Of the 616 patients screened in the study, a total of 449 were randomized: 149 to receive placebo, 151 to receive 60 mg BID tozadenant, and 149 to receive 120 mg BID tozadenant.

    Period 1
    Period 1 title
    24 Weeks (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    -
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The patients will take two tablets by mouth BID.

    Arm title
    60 mg BID Tozadenant
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Tozadenant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The patients take 60 mg BID.

    Arm title
    120 mg BID Tozadenant
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Tozadenant
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One or two doses of 60 mg or 120 mg BID.

    Number of subjects in period 1
    Placebo 60 mg BID Tozadenant 120 mg BID Tozadenant
    Started
    149
    151
    149
    Completed
    108
    102
    100
    Not completed
    41
    49
    49
         Protocol deviation
    1
    1
    -
         Other
    1
    1
    -
         Sponsor Terminated the Study
    11
    14
    8
         Consent withdrawn by subject
    9
    10
    9
         Adverse Events
    15
    22
    30
         Subject Terminated by Investigator
    2
    -
    1
         Lost to follow-up
    1
    -
    -
         Subject Terminated by Sponsor
    1
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    24 Weeks
    Reporting group description
    -

    Reporting group values
    24 Weeks Total
    Number of subjects
    449 449
    Age categorical
    Overall, the majority of patients were male (67.0%) and Caucasian (97.6%), and the average age was 64.7 years (range: 35 to 81 years), characteristic of the general PD population. The treatment groups were well balanced with regard to these demographic variables.
    Units: Subjects
        Adults (18-64 years)
    200 200
        From 65-84 years
    249 249
        85 years and over
    0 0
    Gender categorical
    Units: Subjects
        Female
    148 148
        Male
    301 301

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group title
    60 mg BID Tozadenant
    Reporting group description
    -

    Reporting group title
    120 mg BID Tozadenant
    Reporting group description
    -

    Primary: Change from Baseline to Week 24 in the number of hours per day spent in OFF time

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    End point title
    Change from Baseline to Week 24 in the number of hours per day spent in OFF time
    End point description
    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.
    End point type
    Primary
    End point timeframe
    Baseline to 24 Weeks
    End point values
    Placebo 60 mg BID Tozadenant 120 mg BID Tozadenant
    Number of subjects analysed
    108
    104
    104
    Units: Hours
        arithmetic mean (standard deviation)
    -0.958 ± 2.2725
    -0.835 ± 2.9730
    -1.789 ± 2.4802
    Statistical analysis title
    Change from Baseline to Week 24 in OFF time Hours
    Statistical analysis description
    The change from baseline OFF hours was analyzed by a mixed model repeated measures ANCOVA that included country/region, treatment group, week, interaction between treatment group and week as fixed terms, baseline number of OFF hours as covariate and subject as random effect.
    Comparison groups
    Placebo v 120 mg BID Tozadenant
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.026
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.724
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.362
         upper limit
    -0.087
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3242

    Secondary: Change in Good ON time from baseline to Week 24

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    End point title
    Change in Good ON time from baseline to Week 24
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Baseline to 24 Weeks
    End point values
    Placebo 60 mg BID Tozadenant 120 mg BID Tozadenant
    Number of subjects analysed
    108
    104
    104
    Units: Hours
        arithmetic mean (standard deviation)
    1.011 ± 2.5470
    0.705 ± 3.1219
    1.689 ± 2.7335
    No statistical analyses for this end point

    Secondary: Change in Unified Parkinson's Disease Rating Scale (UPDRS) Part II Activities of Daily Living (ADL) subscale + Part III Motor Function

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    End point title
    Change in Unified Parkinson's Disease Rating Scale (UPDRS) Part II Activities of Daily Living (ADL) subscale + Part III Motor Function
    End point description
    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,(Part I, Mentation, Behavior and Mood; Part II, Activities of Daily Living; Part III, Motor Examination; Part IV, Complications of Therapy). Points are assigned to every item based on the person’s response, as well as observation and physical examination. Each part has multiple points that are individually scored, using zero for normal or no problems, 1 for minimal problems, 2 for mild problems, 3 for moderate problems, and 4 for severe problems. These scores are tallied to indicate the severity of the disease, with 199 points being the worst and total disability and 0 meaning no disability. For patients with missing baseline or baseline was measured post-dose, screening was used as baseline in the calculation of change from baseline. Total scores are calculated only when all Part II & III questions.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    Placebo 60 mg BID Tozadenant 120 mg BID Tozadenant
    Number of subjects analysed
    108
    103
    106
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -2.80 ± 8.183
    -2.54 ± 8.584
    -3.68 ± 7.853
    No statistical analyses for this end point

    Secondary: Change From Baseline to Week 24 in the ON state in Unified Parkinson's Disease Rating Scale (UPDRS) Part IIl

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    End point title
    Change From Baseline to Week 24 in the ON state in Unified Parkinson's Disease Rating Scale (UPDRS) Part IIl
    End point description
    Change from Baseline to Week 24 in the Unified Parkinson's Disease Rating Scale (UPDRS) Parts III Motor Function (motor subscale) total scores. Score Range of 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. For Patients with missing baseline or baseline was measured post-dose, screening was used as baseline in the calculation of change from baseline. Total scores are calculated only when all Part III questions are answered.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    Placebo 60 mg BID Tozadenant 120 mg BID Tozadenant
    Number of subjects analysed
    108
    103
    106
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -2.15 ± 6.363
    -2.13 ± 6.822
    -2.93 ± 6.048
    No statistical analyses for this end point

    Other pre-specified: Global Assessments of Improvement: Clinical Global Impression of Improvement (CGI-I) Week 24

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    End point title
    Global Assessments of Improvement: Clinical Global Impression of Improvement (CGI-I) Week 24
    End point description
    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.
    End point type
    Other pre-specified
    End point timeframe
    At Week 24
    End point values
    Placebo 60 mg BID Tozadenant 120 mg BID Tozadenant
    Number of subjects analysed
    111
    106
    107
    Units: Score on a scale
        arithmetic mean (standard deviation)
    3.5 ± 0.92
    3.5 ± 1.07
    3.2 ± 0.98
    No statistical analyses for this end point

    Other pre-specified: Patient Global Impression of Improvement (PGI-I) Week 24

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    End point title
    Patient Global Impression of Improvement (PGI-I) Week 24
    End point description
    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.
    End point type
    Other pre-specified
    End point timeframe
    At Week24
    End point values
    Placebo 60 mg BID Tozadenant 120 mg BID Tozadenant
    Number of subjects analysed
    111
    106
    107
    Units: Score on a scale
        arithmetic mean (standard deviation)
    3.6 ± 1.14
    3.6 ± 1.21
    3.4 ± 1.14
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    24 Weeks
    Adverse event reporting additional description
    Safety evaluation was based on the Safety Set (SS) population who took at least 1 dose of IMP. In Part A, the SS included 447 of the total of 449 randomized patients.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group title
    60 mg BID Tozadenant
    Reporting group description
    -

    Reporting group title
    120 mg BID Tozadenant
    Reporting group description
    -

    Serious adverse events
    Placebo 60 mg BID Tozadenant 120 mg BID Tozadenant
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 148 (10.14%)
    13 / 150 (8.67%)
    12 / 149 (8.05%)
         number of deaths (all causes)
    1
    1
    1
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Accelerated hypertension
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 148 (0.00%)
    0 / 150 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Thyroid adenoma
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 148 (0.00%)
    0 / 150 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 148 (0.00%)
    0 / 150 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hallucination, visual
         subjects affected / exposed
    0 / 148 (0.00%)
    0 / 150 (0.00%)
    2 / 149 (1.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Burns third degree
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Face injury
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fractured sacrum
         subjects affected / exposed
    0 / 148 (0.00%)
    0 / 150 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory fume inhalation disorder
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 148 (0.00%)
    0 / 150 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 148 (0.00%)
    0 / 150 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Torsade de pointes
         subjects affected / exposed
    0 / 148 (0.00%)
    0 / 150 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 148 (0.00%)
    0 / 150 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carotid artery occlusion
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 148 (0.00%)
    0 / 150 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 148 (0.00%)
    0 / 150 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyskinesia
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parkinson's disease
         subjects affected / exposed
    1 / 148 (0.68%)
    2 / 150 (1.33%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis ischaemic
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 148 (0.00%)
    0 / 150 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Anuria
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calculus ureteric
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Cervical spinal stenosis
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    2 / 148 (1.35%)
    0 / 150 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 148 (0.00%)
    1 / 150 (0.67%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 148 (0.00%)
    0 / 150 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    Placebo 60 mg BID Tozadenant 120 mg BID Tozadenant
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    111 / 148 (75.00%)
    115 / 150 (76.67%)
    111 / 149 (74.50%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 148 (0.68%)
    1 / 150 (0.67%)
    4 / 149 (2.68%)
         occurrences all number
    1
    1
    4
    Hypertension
         subjects affected / exposed
    3 / 148 (2.03%)
    5 / 150 (3.33%)
    3 / 149 (2.01%)
         occurrences all number
    111
    115
    111
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 150 (0.00%)
    5 / 149 (3.36%)
         occurrences all number
    1
    0
    5
    Fall
         subjects affected / exposed
    9 / 148 (6.08%)
    22 / 150 (14.67%)
    13 / 149 (8.72%)
         occurrences all number
    9
    22
    13
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    3 / 148 (2.03%)
    4 / 150 (2.67%)
    6 / 149 (4.03%)
         occurrences all number
    3
    4
    6
    Weight decreased
         subjects affected / exposed
    0 / 148 (0.00%)
    4 / 150 (2.67%)
    2 / 149 (1.34%)
         occurrences all number
    0
    4
    2
    White blood cell count decreased
         subjects affected / exposed
    4 / 148 (2.70%)
    2 / 150 (1.33%)
    0 / 149 (0.00%)
         occurrences all number
    4
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 148 (1.35%)
    1 / 150 (0.67%)
    4 / 149 (2.68%)
         occurrences all number
    2
    1
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    9 / 148 (6.08%)
    7 / 150 (4.67%)
    7 / 149 (4.70%)
         occurrences all number
    9
    7
    7
    Dyskinesia
         subjects affected / exposed
    13 / 148 (8.78%)
    22 / 150 (14.67%)
    22 / 149 (14.77%)
         occurrences all number
    13
    22
    22
    Parkinson's disease
         subjects affected / exposed
    7 / 148 (4.73%)
    11 / 150 (7.33%)
    3 / 149 (2.01%)
         occurrences all number
    7
    11
    3
    Somnolence
         subjects affected / exposed
    5 / 148 (3.38%)
    5 / 150 (3.33%)
    8 / 149 (5.37%)
         occurrences all number
    5
    5
    8
    Sudden onset of sleep
         subjects affected / exposed
    4 / 148 (2.70%)
    7 / 150 (4.67%)
    7 / 149 (4.70%)
         occurrences all number
    4
    7
    7
    Headache
         subjects affected / exposed
    5 / 148 (3.38%)
    3 / 150 (2.00%)
    2 / 149 (1.34%)
         occurrences all number
    5
    3
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 148 (1.35%)
    7 / 150 (4.67%)
    4 / 149 (2.68%)
         occurrences all number
    2
    7
    4
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    3 / 148 (2.03%)
    5 / 150 (3.33%)
    2 / 149 (1.34%)
         occurrences all number
    3
    5
    2
    Confusional state
         subjects affected / exposed
    1 / 148 (0.68%)
    2 / 150 (1.33%)
    4 / 149 (2.68%)
         occurrences all number
    1
    2
    4
    Hallucination, visual
         subjects affected / exposed
    2 / 148 (1.35%)
    8 / 150 (5.33%)
    8 / 149 (5.37%)
         occurrences all number
    2
    8
    8
    Insomnia
         subjects affected / exposed
    9 / 148 (6.08%)
    9 / 150 (6.00%)
    9 / 149 (6.04%)
         occurrences all number
    9
    9
    9
    Disorientation
         subjects affected / exposed
    0 / 148 (0.00%)
    4 / 150 (2.67%)
    0 / 149 (0.00%)
         occurrences all number
    0
    4
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 148 (1.35%)
    15 / 150 (10.00%)
    8 / 149 (5.37%)
         occurrences all number
    2
    15
    8
    Dry mouth
         subjects affected / exposed
    0 / 148 (0.00%)
    2 / 150 (1.33%)
    4 / 149 (2.68%)
         occurrences all number
    0
    2
    4
    Nausea
         subjects affected / exposed
    6 / 148 (4.05%)
    8 / 150 (5.33%)
    13 / 149 (8.72%)
         occurrences all number
    6
    8
    13
    Renal and urinary disorders
    Micturition urgency
         subjects affected / exposed
    0 / 148 (0.00%)
    3 / 150 (2.00%)
    4 / 149 (2.68%)
         occurrences all number
    0
    3
    4
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    8 / 148 (5.41%)
    4 / 150 (2.67%)
    7 / 149 (4.70%)
         occurrences all number
    8
    4
    7
    Myalgia
         subjects affected / exposed
    0 / 148 (0.00%)
    4 / 150 (2.67%)
    2 / 149 (1.34%)
         occurrences all number
    0
    4
    2
    Pain in extremity
         subjects affected / exposed
    6 / 148 (4.05%)
    5 / 150 (3.33%)
    3 / 149 (2.01%)
         occurrences all number
    6
    5
    3
    Arthralgia
         subjects affected / exposed
    6 / 148 (4.05%)
    3 / 150 (2.00%)
    2 / 149 (1.34%)
         occurrences all number
    6
    3
    2
    Musculoskeletal pain
         subjects affected / exposed
    1 / 148 (0.68%)
    4 / 150 (2.67%)
    0 / 149 (0.00%)
         occurrences all number
    1
    4
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    10 / 148 (6.76%)
    7 / 150 (4.67%)
    5 / 149 (3.36%)
         occurrences all number
    10
    7
    5
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 148 (4.73%)
    6 / 150 (4.00%)
    1 / 149 (0.67%)
         occurrences all number
    7
    6
    1
    Urinary tract infection
         subjects affected / exposed
    4 / 148 (2.70%)
    4 / 150 (2.67%)
    9 / 149 (6.04%)
         occurrences all number
    4
    4
    9

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 May 2015
    Amendment 1 Revisions: 1. Updated List of Abbreviations (p. 8-9). 2. Corrected typographical errors in Table 1: Part A - Schedule of Events/Evaluations (p. 30). 3. Revised Section 11.6, Unblinding Upon Completion of Part A (p. 131) to clarify that primary and secondary efficacy analyses will be conducted after the Part A data base is locked and will not be modified; and to clarify that exploratory analyses that do not involve the primary or secondary efficacy analyses are subject to modification. 4. Added the following exploratory endpoints to Parts A and B: Part A 15. EuroQol 5D-5L Health Questionnaire (EQ-5D-5L). 16. Treatment Satisfaction Questionnaire for Medication (TSQM 9) (evaluated at Weeks 6 and 24). Part B 11. EQ-5D-5L. 12. TSQM 9 (evaluated at Week 76).
    10 Jun 2015
    Amendment 2 Revisions: 1. Revised Exclusion Criteria (EC) #24 to delete “including any history of hepatic or renal failure” (p. 22; p. 55). 2. Added EC #27: “Patients with moderate to severe hepatic or renal impairment.” (p. 22; p. 55). 3. Added EC #28: “Patients who have taken strong CYP3A4 inhibitors or inducers within 4 weeks prior to Baseline (Visit 2) or who anticipate requiring the use of strong CYP3A4 inhibitors or inducers during the duration of the trial (see Section 5.9.2 and Appendix 15.15)” (p. 22; p. 55). 4. Added EC #29: “Patients with pacemakers or implantable cardioverter defibrillators” (p. 22; p. 55). 5. Added to Section 4.3.2, Definite Criteria for Withdrawal from Study: “9. Patients noted to have an elevated BP post-baseline, with a systolic BP ≥ 160 mmHg and/or a diastolic BP≥ 100 mmHg that is present at 2 consecutive post-baseline study visits” (p. 57). 6. Added to Section 5.9.2, Prohibited Concomitant Medications/ Treatments, regarding medications prohibited throughout the study (Parts A and B): “Strong CYP3A4 inhibitors or inducers. Refer to Appendix 15.15” (p. 61). 7. Added paragraph at end of Section 9.5.1, Blood Pressure and Pulse Measurements: “Patients noted to have an elevated BP post-baseline, with a systolic BP ≥ 160 mmHg and/or a diastolic BP ≥ 100 mmHg that is present at 2 consecutive post-baseline study visits, will be discontinued from study (see Section 4.3.2)” (p. 118). 8. Added Appendix 15.15, Prohibited CYP3A4 Inhibitors and Inducers (p. 183).
    13 Oct 2017
    Amendment 3 Revisions 1. Updated company name, email addresses and telephone numbers of Study Director, and Chief Medical Officer in multiple places. 2. Updated Study Contact Information 3. Updated safety reporting fax number 4. Added to Abbreviations ANC (absolute neutrophil count), WBC (white blood cells) 5. Inserted into Parts A and B procedures additional blood draws for hematology. 6. Added Tables 1.1 (Part A – Schedule of Events/ Evaluations for Hematology Monitoring) and 2.1 Part B – Schedule of Events/ Evaluations for Hematology Monitoring. 7. Inserted into Criteria for Patient Discontinuation a lower limit for absolute neutrophils. 8. Added the following as section 6.2.6 a Visit 3.5 (Week 4). 9. Inserted section 6.2.9 a Visit 4.3 (Week 8). 10. Inserted section 6.2.10 a Visit 4.8 (Week 10) 11. Section 6.2.12: Clarified the next visit by number and differentiates next blood draw (visit 16) and telephone call (visit 18). 12. Insert section 6.2.13 a Visit 5.5 (Week 16) 13. Insert section 6.2.16 a Visit 6.5 (Week 22)

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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