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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled trial of deferiprone in patients with pantothenate kinase-associated neurodegeneration (PKAN)

    Summary
    EudraCT number
    		 2012-000845-11
    Trial protocol
    		 DE   IT   GB  
    Global end of trial date
    21 Oct 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Oct 2020
    First version publication date
    02 Oct 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TIRCON2012V1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01741532
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND: 104,880
    Sponsors
    Sponsor organisation name
    ApoPharma Inc.
    Sponsor organisation address
    200 Barmac Drive, Toronto, Ontario, Canada, M9L 2Z7
    Public contact
    Fernando Tricta, MD, ApoPharma Inc., +1 416-558-6342, f.tricta@chiesi.com
    Scientific contact
    Fernando Tricta, MD, ApoPharma Inc., +1 416-558-6342 , f.tricta@chiesi.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
    21 Oct 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Oct 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Oct 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of the study were: To evaluate the change in severity of dystonia in patients with PKAN treated with deferiprone vs. placebo for 18 months To evaluate the global impression of improvement in patients with PKAN treated with deferiprone vs. placebo for 18 months
    Protection of trial subjects
    An independent Data Safety Monitoring Board (DSMB) was established to monitor the safety of patients during the course of the trial. The DSMB was responsible for overseeing the conduct of the trial, and was empowered to recommend stopping the trial if in their judgement continuation was not ethically acceptable on the grounds of safety.
    Background therapy
    		 Medications considered necessary for the patient’s welfare could be given at the discretion of the Investigator. Patients who were taking dystonia medications at baseline, whether on a regular schedule or as needed (PRN), were permitted to continue on these during the study provided that the dosage and regimen remained the same. For PRN medications, however, they had to observe a drug interruption period prior to each efficacy assessment visit, the duration of which depended on the particular drug. The use of rescue medication, defined as the introduction or dosage change of a medication that has the potential to have an effect on dystonia symptoms, was limited to circumstances judged to be absolutely necessary by the Investigator. Such medications included but were not limited to baclofen, trihexyphenidyl, clonazepam, tizanidine, tetrabenazine, and Botox. If a patient was administered rescue medications for more than two events, the investigator was to notify the sponsor to discuss that patient’s continued participation in the study.
    Evidence for comparator
    		 The study was placebo-controlled in order to detect the effect of deferiprone. Since PKAN is a progressive disorder, symptoms would be expected to worsen over time in the absence of effective treatment; thus, either an improvement, a stabilization, or a lesser decline in the deferiprone group compared to the placebo group would indicate some efficacy. The duration of 18 months was selected to allow enough time for the anticipated worsening in the placebo group to occur.
    Actual start date of recruitment
    13 Dec 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 18 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Germany: 37
    Country: Number of subjects enrolled
    Italy: 13
    Country: Number of subjects enrolled
    United States: 31
    Worldwide total number of subjects
    89
    EEA total number of subjects
    58
    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)
    24
    Adolescents (12-17 years)
    13
    Adults (18-64 years)
    52
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Starting in December 2012, patients were recruited in Germany, Italy, the United Kingdom, and the United States. Patients from neighbouring countries who were able to travel to one of the study sites were permitted to enroll as well. All appropriate regulatory and ethics committees standards were met.

    Pre-assignment
    Screening details
    		 A total of 100 prospective subjects were screened, of whom 89 were enrolled. The main criteria were a verified diagnosis of PKAN, a BAD score of at least 3, an expectation of stability in the use of concomitant medications and devices for the treatment of dystonia over the course of the trial, and no contraindications to the use of deferiprone.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Carer, Assessor, Subject
    Blinding implementation details
    The placebo product matched the active product with respect to appearance, odor, and taste, and was provided in identical bottles. The patients, the staff at the study sites, employees of ApoPharma who were involved in the trial, and the neurologists who analyzed the videotapes for determination of BAD scores were all blinded as to which product was assigned.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Deferiprone
    Arm description
    		 Patients in this arm received deferiprone oral solution (80 mg/mL) at a dosage of up to 15 mg/kg b.i.d., for a total daily dosage of up to 30 mg/kg, for up to 18 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Deferiprone oral solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    The dosage was 15 mg/kg twice daily, for a total daily dosage of 30 mg/kg.

    Arm title
    		 Placebo
    Arm description
    		 Patients in this arm received placebo solution twice daily, volume-matched to a 15 mg/kg b.i.d. dosage of deferiprone oral solution, for up to 18 months.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Volume-matched to a dosage of 15 mg/kg deferiprone oral solution

    Number of subjects in period 1
    		Deferiprone Placebo
    Started
    59
    30
    Completed
    49
    27
    Not completed
    10
    3
         Consent withdrawn by subject
    1
    1
         Adverse event, non-fatal
    4
    -
         Worsening of the disease
    3
    1
         Sponsor decision
    1
    -
         Medical event; withdrawn before dosing began
    1
    -
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Deferiprone
    Reporting group description
    		 Patients in this arm received deferiprone oral solution (80 mg/mL) at a dosage of up to 15 mg/kg b.i.d., for a total daily dosage of up to 30 mg/kg, for up to 18 months.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients in this arm received placebo solution twice daily, volume-matched to a 15 mg/kg b.i.d. dosage of deferiprone oral solution, for up to 18 months.

    Reporting group values
    		 Deferiprone Placebo Total
    Number of subjects
    		 59 30 89
    Age categorical
    Units: Subjects
    Age continuous
    Patients had to be at least 4 years of age at the time of enrollment. There was no maximum age.
    Units: years
        arithmetic mean (standard deviation)
    		 20.8 ( 10.7 ) 19.2 ( 12.5 ) -
    Gender categorical
    Both male and female subjects were enrolled.
    Units: Subjects
        Female
    		 25 17 42
        Male
    		 34 13 47
    BAD score at baseline
    The Barry-Albright Dystonia (BAD) scale is an instrument for rating dystonia. It is scored on a scale from 0 (best) to 32 (worst).
    Units: points on a scale
        arithmetic mean (standard deviation)
    		 19.6 ( 8.4 ) 16.5 ( 8.1 ) -
    UPDRS Part I score at baseline
    Part I of the Unified Parkinson’s Disease Rating Scale (UPDRS) assesses mentation, behavior, and mood, and is scored from 0 (best) to 16 (worst)
    Units: Points on a scale
        arithmetic mean (standard deviation)
    		 2.0 ( 2.0 ) 2.0 ( 2.8 ) -
    UPDRS Part II score at baseline
    Part II of the UPDRS score assesses activities of daily living. It is scored on a scale from 0 (best) to 52 (worst).
    Units: Points on a scale
        arithmetic mean (standard deviation)
    		 26.9 ( 8.5 ) 22.0 ( 11.4 ) -
    UPDRS Part III score at baseline
    Part III of the UPDRS assesses motor performance. It is scored on a scale from 0 (best) to 108 (worst).
    Units: Points on a scale
        arithmetic mean (standard deviation)
    		 42.4 ( 22.4 ) 32.5 ( 20.3 ) -
    UPDRS Part VI score at baseline
    Part VI of the UPDRS assesses the Schwab and England activities of daily living. It is scored on a scale from 0% (worst) to 100% (best).
    Units: Percentage
        arithmetic mean (standard deviation)
    		 43.2 ( 29.0 ) 51.1 ( 29.0 ) -
    FIM score at baseline
    The FIM scale is used to measure a range of functional abilities in adults. A global score is generated that ranges from 18 (worst) to 126 (best).
    Units: Points on a scale
        arithmetic mean (standard deviation)
    		 81.6 ( 32.1 ) 84.9 ( 30.2 ) -
    Global PedsQL score at baseline – child self-report
    The PedsQL questionnaire obtains information from patients and their parents on how the patient has felt over the previous month, and generates scores for physical health and psychosocial health as well as a total score. It is scored on a scale from 0 (worst) to 100 (best).
    Units: Points on a scale
        arithmetic mean (standard deviation)
    		 51.3 ( 19.1 ) 52.6 ( 16.2 ) -
    Pittsburgh Sleep Quality Index (PSQI),
    The PSQI questionnaire obtains information on quality of sleep. Scores range from 0 (worst) to 100 (best).
    Units: Points on a scale
        arithmetic mean (standard deviation)
    		 6.4 ( 4.4 ) 6.5 ( 4.3 ) -
    MRI R2*
    MRI R2* was used to measure iron levels in the globus pallidus
    Units: Hz
        arithmetic mean (standard deviation)
    		 96.6 ( 31.6 ) 93.5 ( 31.2 ) -
    WeeFIM score at baseline
    The WeeFIM scale is used to measure a range of functional abilities in children. A global score is generated that ranges from 18 (worst) to 126 (best).
    Units: Points on a scale
        arithmetic mean (standard deviation)
    		 60.0 ( 25.9 ) 72.1 ( 33.3 ) -
    Global PedsQL score at baseline - parent-proxy report
    The PedsQL questionnaire obtains information from patients and their parents on how the patient has felt over the previous month, and generates scores for physical health and psychosocial health as well as a total score. It is scored on a scale from 0 (worst) to 100 (best).
    Units: Points on a scale
        arithmetic mean (standard deviation)
    		 50.7 ( 14.4 ) 52.8 ( 15.7 ) -

    End points

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    End points reporting groups
    Reporting group title
    Deferiprone
    Reporting group description
    		 Patients in this arm received deferiprone oral solution (80 mg/mL) at a dosage of up to 15 mg/kg b.i.d., for a total daily dosage of up to 30 mg/kg, for up to 18 months.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients in this arm received placebo solution twice daily, volume-matched to a 15 mg/kg b.i.d. dosage of deferiprone oral solution, for up to 18 months.

    Primary: Change from baseline to Month 18 in total score on the Barry Albright Dystonia (BAD) scale

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    End point title
    		 Change from baseline to Month 18 in total score on the Barry Albright Dystonia (BAD) scale
    End point description
    The Barry-Albright Dystonia (BAD) scale is an instrument for rating dystonia (sustained muscle contractions causing twisting and repetitive movements or abnormal postures). It consists of a 5-point ordinal scale that rates severity of dystonia in 8 body regions. The individual scores are summed to provide a total score ranging from 0 to 32, with higher scores indicating greater severity.
    End point type
    Primary
    End point timeframe
    Baseline to Month 18
    End point values
    		 Deferiprone Placebo
    Number of subjects analysed
    58
    28
    Units: Points on the BAD scale
        least squares mean (standard error)
    2.48 ( 0.63 )
    3.99 ( 0.82 )
    Attachments
    		 Change in BAD total score
    Statistical analysis title
    		 Mixed-Effect Model Repeated Measures model
    Statistical analysis description
    This model used the baseline value of the variable and age at onset of motor symptoms (before vs. at or after 6 years) as covariates and treatment group as the main factor. The least squares estimate of the mean (LSmean) change at Month 18 was used for determining the treatment effect in the primary analysis.
    Comparison groups
    Deferiprone v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0761 [1]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [1] - The difference between the groups in the change from baseline to Month 18 in total BAD score approached but did not reach significance.

    Primary: Score on Patient Global Impression of Improvement (PGI-I) at Month 18

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    End point title
    		 Score on Patient Global Impression of Improvement (PGI-I) at Month 18
    End point description
    The Patient Global Impression of Improvement (PGI-I) is a global index that assesses the response of a condition to a therapy by asking patients to rate their current state relative to their state at baseline. It consists of a 7-point rating scale, where 1=very much improved, 2= much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse.
    End point type
    Primary
    End point timeframe
    Month 18
    End point values
    		 Deferiprone Placebo
    Number of subjects analysed
    58
    28
    Units: Score on PGI-I
        least squares mean (standard error)
    4.55 ( 0.30 )
    4.66 ( 0.38 )
    Attachments
    		 Untitled (Filename: Change in PGI-I score.docx)
    Statistical analysis title
    		 Mixed-Effect Model Repeated Measure model
    Comparison groups
    Deferiprone v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7279 [2]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [2] - There was no significant difference between the treatment groups in PGI-I score at Month 18, and neither group indicated subjective awareness of either improvement or worsening from baseline.

    Secondary: Change from baseline to Month 18 in score on the Unified Parkinson’s Disease Rating Scale (UPDRS) Part I

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    End point title
    		 Change from baseline to Month 18 in score on the Unified Parkinson’s Disease Rating Scale (UPDRS) Part I
    End point description
    Part I of the UPDRS assesses mentation, behavior, and mood, and is scored from 0 (best) to 16 (worst). Thus, an increase in score indicates worsening.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 18
    End point values
    		 Deferiprone Placebo
    Number of subjects analysed
    58
    28
    Units: Points on the UPDRS Part I scale
        least squares mean (standard error)
    -0.25 ( 0.43 )
    -0.07 ( 0.55 )
    Statistical analysis title
    		 Mixed-Effect Model Repeated Measures (MMRM) model
    Statistical analysis description
    The MMRM model used baseline value and age at onset of motor symptoms as covariates and treatment group as the main factor.
    Comparison groups
    Deferiprone v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7228 [3]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [3] - There was no significant difference between the treatment groups.

    Secondary: Change from baseline to Month 18 in score on the Unified Parkinson’s Disease Rating Scale (UPDRS) Part II

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    End point title
    		 Change from baseline to Month 18 in score on the Unified Parkinson’s Disease Rating Scale (UPDRS) Part II
    End point description
    Part II of the UPDRS assesses activities of daily living, and is scored from 0 (best) to 52 (worst). Thus, an increase in score indicates worsening.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 18
    End point values
    		 Deferiprone Placebo
    Number of subjects analysed
    58
    28
    Units: Points on the UPDRS scale Part II
        least squares mean (standard error)
    1.09 ( 1.19 )
    2.36 ( 1.52 )
    Statistical analysis title
    		 Mixed-Effect Model Repeated Measures (MMRM) model
    Statistical analysis description
    The MMRM model used baseline value and age at onset of motor symptoms as covariates and treatment group as the main factor.
    Comparison groups
    Deferiprone v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3677 [4]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [4] - There was no significant difference between the treatment groups.

    Secondary: Change from baseline to Month 18 in score on the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III

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    End point title
    		 Change from baseline to Month 18 in score on the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III
    End point description
    Part III of the UPDRS assesses motor performance, and is scored from 0 (best) to 108 (worst). Thus, an increase in score indicates worsening.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 18
    End point values
    		 Deferiprone Placebo
    Number of subjects analysed
    58
    28
    Units: Points on the UPDRS scale Part III
        least squares mean (standard error)
    5.38 ( 2.20 )
    2.06 ( 2.79 )
    Statistical analysis title
    		 Mixed-Effect Model Repeated Measures (MMRM) model
    Statistical analysis description
    The MMRM model used baseline value and age at onset of motor symptoms as covariates and treatment group as the main factor.
    Comparison groups
    Deferiprone v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2182 [5]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [5] - There was no significant difference between the treatment groups.

    Secondary: Change from baseline to Month 18 in score on the Unified Parkinson’s Disease Rating Scale (UPDRS) Part VI

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    End point title
    		 Change from baseline to Month 18 in score on the Unified Parkinson’s Disease Rating Scale (UPDRS) Part VI
    End point description
    Part VI of the UPDRS assesses the Schwab and England activities of daily living, and is scored from 0% (worst) to 100% (best). Thus, an decrease in score indicates worsening.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 18
    End point values
    		 Deferiprone Placebo
    Number of subjects analysed
    58
    28
    Units: Points on the UPDRS scale Part VI
        least squares mean (standard error)
    -2.17 ( 2.94 )
    -7.66 ( 3.85 )
    Statistical analysis title
    		 Mixed-Effect Model Repeated Measures (MMRM) model
    Statistical analysis description
    The MMRM model used baseline value and age at onset of motor symptoms as covariates and treatment group as the main factor.
    Comparison groups
    Deferiprone v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1749 [6]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [6] - There was no significant difference between the treatment groups.

    Secondary: Change from baseline to Month 18 in global score on the Functional Independence Measure (FIM)

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    End point title
    		 Change from baseline to Month 18 in global score on the Functional Independence Measure (FIM)
    End point description
    The FIM scale is used to measure a range of functional abilities in adults. Items on this scale measure abilities across the domains of self-care (eating, grooming, bathing, dressing–upper body, dressing–lower body, toileting, bladder management, bowel management), mobility (transfer: chair/wheelchair, transfer: toilet, transfer: tub/shower, walk/wheelchair, stairs; and cognition (comprehension, expression, social interaction, problem solving, memory). Each of the 18 items is scored from 1 (total assistance needed) to 7 (complete independence), and a global score is generated that ranges from 18 to 126. Thus, a decrease in score indicates worsening.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 18
    End point values
    		 Deferiprone Placebo
    Number of subjects analysed
    37
    14
    Units: Points on the FIM scale
        least squares mean (standard error)
    5.40 ( 2.36 )
    0.69 ( 3.34 )
    Statistical analysis title
    		 Mixed-Effect Model Repeated Measures (MMRM) model
    Statistical analysis description
    The MMRM model used baseline value and age at onset of motor symptoms as covariates and treatment group as the main factor.
    Comparison groups
    Deferiprone v Placebo
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1524 [7]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [7] - There was no significant difference between the treatment groups.

    Secondary: Change from baseline to Month 18 in global score on the pediatric Functional Independence Measure (WeeFIM) scale

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    End point title
    		 Change from baseline to Month 18 in global score on the pediatric Functional Independence Measure (WeeFIM) scale
    End point description
    The WeeFIM scale is used to measure a range of functional abilities in children. Items on this scale measure abilities across the domains of self-care (eating, grooming, bathing, dressing–upper body, dressing–lower body, toileting, bladder management, bowel management), mobility (transfer: chair/wheelchair, transfer: toilet, transfer: tub/shower, walk/wheelchair/crawl, stairs; and cognition (comprehension, expression, social interaction, problem solving, memory). Each of the 18 items is scored from 1 (total assistance needed) to 7 (complete independence), and a global score is generated that, and a global score is generated that ranges from 18 to 126. Thus, a decrease in score indicates worsening.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 18
    End point values
    		 Deferiprone Placebo
    Number of subjects analysed
    21
    14
    Units: Points on the WeeFIM scale
        least squares mean (standard error)
    4.91 ( 5.30 )
    -2.40 ( 5.42 )
    Statistical analysis title
    		 Mixed-Effect Model Repeated Measures (MMRM) model
    Statistical analysis description
    The MMRM model used baseline value and age at onset of motor symptoms as covariates and treatment group as the main factor.
    Comparison groups
    Deferiprone v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2026 [8]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [8] - There was no significant difference between the treatment groups.

    Secondary: Change from baseline to Month 18 in total score on the Pediatric Quality of Life (PedsQL) scale, patient self-report version

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    End point title
    		 Change from baseline to Month 18 in total score on the Pediatric Quality of Life (PedsQL) scale, patient self-report version
    End point description
    The PedsQL questionnaire obtains information from patients and their parents on how the patient has felt over the previous month, and generates scores for physical health and psychosocial health as well as a total score. Each score ranges from 0 (worst) to 100 (best); i.e., a decrease in score indicates worsening.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 18
    End point values
    		 Deferiprone Placebo
    Number of subjects analysed
    42
    25
    Units: Points on the PedsQL scale
        least squares mean (standard error)
    1.21 ( 3.68 )
    1.34 ( 4.49 )
    Statistical analysis title
    		 Mixed-Effect Model Repeated Measures (MMRM) model
    Statistical analysis description
    The MMRM model used baseline value and age at onset of motor symptoms as covariates and treatment group as the main factor.
    Comparison groups
    Deferiprone v Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9759 [9]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [9] - There was no significant difference between the treatment groups.

    Secondary: Change from baseline to Month 18 in total score on the Pediatric Quality of Life (PedsQL) scale, parent proxy report version

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    End point title
    		 Change from baseline to Month 18 in total score on the Pediatric Quality of Life (PedsQL) scale, parent proxy report version
    End point description
    The PedsQL questionnaire obtains information from patients and their parents on how the patient has felt over the previous month, and generates scores for physical health and psychosocial health as well as a total score. Each score ranges from 0 (worst) to 100 (best); i.e., a decrease in score indicates worsening. This version was completed by the parent or guardian.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 18
    End point values
    		 Deferiprone Placebo
    Number of subjects analysed
    41
    19
    Units: Points on PedsQL scale, proxy version
        least squares mean (standard error)
    -4.90 ( 3.99 )
    -2.37 ( 4.90 )
    Statistical analysis title
    		 Mixed-Effect Model Repeated Measures (MMRM) model
    Statistical analysis description
    The MMRM model used baseline value and age at onset of motor symptoms as covariates and treatment group as the main factor.
    Comparison groups
    Deferiprone v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5781 [10]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [10] - There was no significant difference between the treatment groups.

    Secondary: Change from baseline to Month 18 in the Pittsburgh Sleep Quality Index (PSQI)

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    End point title
    		 Change from baseline to Month 18 in the Pittsburgh Sleep Quality Index (PSQI)
    End point description
    The PSQI is a self-rated questionnaire that assesses sleep quality and disturbances over a 1-month time interval. A total of 19 individual items are used to generate 7 “component” scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction, and a score is generated that ranges from 0 (best) to 21 (worst).
    End point type
    Secondary
    End point timeframe
    Baseline to Month 18
    End point values
    		 Deferiprone Placebo
    Number of subjects analysed
    56
    26
    Units: Points on the PSQI
        least squares mean (standard error)
    0.48 ( 0.61 )
    0.14 ( 0.80 )
    Statistical analysis title
    		 Mixed-Effect Model Repeated Measures (MMRM) model
    Statistical analysis description
    The MMRM model used baseline value and age at onset of motor symptoms as covariates and treatment group as the main factor.
    Comparison groups
    Deferiprone v Placebo
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6323 [11]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [11] - There was no significant difference between the treatment groups.

    Secondary: Change from baseline to Month 18 in level of brain iron

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    End point title
    		 Change from baseline to Month 18 in level of brain iron
    End point description
    Neurodegeneration in patients with PKAN appears to be related to intracellular mismanagement of iron, resulting in localized brain iron accumulation, toxicity, and eventual cell death. The region of the brain with the highest amount of iron accumulation is the globus pallidus, which is one of the main areas for motor control. Patients underwent MRI R2* for the measurement of iron levels in the globus pallidus.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 18
    End point values
    		 Deferiprone Placebo
    Number of subjects analysed
    24
    16
    Units: Hz as measured by MRI R2*
        least squares mean (standard error)
    -36.1 ( 3.11 )
    -0.50 ( 3.97 )
    Statistical analysis title
    		 Mixed-Effect Model Repeated Measures (MMRM) model
    Statistical analysis description
    The MMRM model used baseline value and age at onset of motor symptoms as covariates and treatment group as the main factor.
    Comparison groups
    Deferiprone v Placebo
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [12]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [12] - There was a highly significant difference between the treatment groups in the reduction of brain iron.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from the day of screening until the end of the study. For patients who did not continue in an extension study (TIRCON2012V1-EXT), adverse events continued to be collected for 4 weeks following the last dose administration
    Adverse event reporting additional description
    Safety and tolerability of deferiprone oral solution were assessed through adverse events, clinical laboratory tests, physical examinations, vital signs, and ECG.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Deferiprone
    Reporting group description
    		 Patients in this arm received deferiprone oral solution (80 mg/mL) at a dosage of up to 15 mg/kg b.i.d., for a total daily dosage of up to 30 mg/kg, for /day, for up to 18 months.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients in this arm received placebo solution twice daily, volume-matched to a 15 mg/kg dosage of deferiprone oral solution

    Serious adverse events
    		 Deferiprone Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 58 (31.03%)
    10 / 30 (33.33%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Thrombosis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Colectomy
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal tube insertion
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal anastomosis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intrathecal pump insertion
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laparotomy
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device battery replacement
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal septal operation
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheostomy
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheostomy tube removal
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound treatment
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Choking
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Staring
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device malfunction
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Medical observation
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Chemical eye injury
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Unintentional medical device removal
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative ileus
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dystonia
         subjects affected / exposed
    3 / 58 (5.17%)
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotonia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oromandibular dystonia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    5 / 58 (8.62%)
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    6 / 7
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal dilatation
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary bladder rupture
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial disease carrier
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Deferiprone Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    56 / 58 (96.55%)
    30 / 30 (100.00%)
    General disorders and administration site conditions
    Abasia
         subjects affected / exposed
    2 / 58 (3.45%)
    2 / 30 (6.67%)
         occurrences all number
    2
    2
    Condition aggravated
         subjects affected / exposed
    10 / 58 (17.24%)
    8 / 30 (26.67%)
         occurrences all number
    12
    9
    Pain
         subjects affected / exposed
    4 / 58 (6.90%)
    0 / 30 (0.00%)
         occurrences all number
    4
    0
    Pyrexia
         subjects affected / exposed
    15 / 58 (25.86%)
    13 / 30 (43.33%)
         occurrences all number
    33
    28
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    8
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    9 / 58 (15.52%)
    5 / 30 (16.67%)
         occurrences all number
    11
    9
    Nasal congestion
         subjects affected / exposed
    1 / 58 (1.72%)
    2 / 30 (6.67%)
         occurrences all number
    1
    3
    Oropharyngeal pain
         subjects affected / exposed
    9 / 58 (15.52%)
    3 / 30 (10.00%)
         occurrences all number
    10
    3
    Rhinorrhoea
         subjects affected / exposed
    4 / 58 (6.90%)
    2 / 30 (6.67%)
         occurrences all number
    6
    2
    Investigations
    Blood iron decreased
         subjects affected / exposed
    3 / 58 (5.17%)
    2 / 30 (6.67%)
         occurrences all number
    3
    2
    Body temperature increased
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    Neutrophil count decreased
         subjects affected / exposed
    10 / 58 (17.24%)
    3 / 30 (10.00%)
         occurrences all number
    18
    20
    Serum ferritin decreased
         subjects affected / exposed
    19 / 58 (32.76%)
    5 / 30 (16.67%)
         occurrences all number
    23
    5
    White blood cell count increased
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 58 (1.72%)
    2 / 30 (6.67%)
         occurrences all number
    1
    4
    Contusion
         subjects affected / exposed
    2 / 58 (3.45%)
    2 / 30 (6.67%)
         occurrences all number
    2
    2
    Fall
         subjects affected / exposed
    2 / 58 (3.45%)
    2 / 30 (6.67%)
         occurrences all number
    3
    2
    Laceration
         subjects affected / exposed
    6 / 58 (10.34%)
    3 / 30 (10.00%)
         occurrences all number
    15
    3
    Skin abrasion
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    4
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    3 / 58 (5.17%)
    2 / 30 (6.67%)
         occurrences all number
    3
    2
    Drooling
         subjects affected / exposed
    2 / 58 (3.45%)
    2 / 30 (6.67%)
         occurrences all number
    2
    2
    Dystonia
         subjects affected / exposed
    24 / 58 (41.38%)
    13 / 30 (43.33%)
         occurrences all number
    46
    17
    Freezing phenomenon
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 30 (10.00%)
         occurrences all number
    0
    3
    Headache
         subjects affected / exposed
    13 / 58 (22.41%)
    9 / 30 (30.00%)
         occurrences all number
    43
    30
    Migraine
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 30 (0.00%)
         occurrences all number
    21
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 58 (17.24%)
    0 / 30 (0.00%)
         occurrences all number
    15
    0
    Leukocytosis
         subjects affected / exposed
    2 / 58 (3.45%)
    2 / 30 (6.67%)
         occurrences all number
    3
    2
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 58 (1.72%)
    3 / 30 (10.00%)
         occurrences all number
    1
    3
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    4 / 58 (6.90%)
    5 / 30 (16.67%)
         occurrences all number
    6
    7
    Constipation
         subjects affected / exposed
    2 / 58 (3.45%)
    4 / 30 (13.33%)
         occurrences all number
    3
    4
    Diarrhoea
         subjects affected / exposed
    4 / 58 (6.90%)
    3 / 30 (10.00%)
         occurrences all number
    7
    8
    Toothache
         subjects affected / exposed
    2 / 58 (3.45%)
    2 / 30 (6.67%)
         occurrences all number
    2
    3
    Vomiting
         subjects affected / exposed
    9 / 58 (15.52%)
    7 / 30 (23.33%)
         occurrences all number
    16
    18
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    3 / 58 (5.17%)
    1 / 30 (3.33%)
         occurrences all number
    3
    1
    Rash
         subjects affected / exposed
    4 / 58 (6.90%)
    1 / 30 (3.33%)
         occurrences all number
    4
    1
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    3 / 58 (5.17%)
    2 / 30 (6.67%)
         occurrences all number
    4
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    8 / 58 (13.79%)
    1 / 30 (3.33%)
         occurrences all number
    8
    1
    Back pain
         subjects affected / exposed
    3 / 58 (5.17%)
    2 / 30 (6.67%)
         occurrences all number
    3
    8
    Muscle spasms
         subjects affected / exposed
    3 / 58 (5.17%)
    2 / 30 (6.67%)
         occurrences all number
    4
    2
    Pain in extremity
         subjects affected / exposed
    10 / 58 (17.24%)
    4 / 30 (13.33%)
         occurrences all number
    13
    7
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    5 / 58 (8.62%)
    2 / 30 (6.67%)
         occurrences all number
    13
    2
    Ear infection
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Gastrointestinal infection
         subjects affected / exposed
    3 / 58 (5.17%)
    3 / 30 (10.00%)
         occurrences all number
    3
    4
    Influenza
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 30 (0.00%)
         occurrences all number
    4
    0
    Localised infection
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    11 / 58 (18.97%)
    6 / 30 (20.00%)
         occurrences all number
    20
    10
    Rhinitis
         subjects affected / exposed
    4 / 58 (6.90%)
    1 / 30 (3.33%)
         occurrences all number
    6
    1
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 58 (13.79%)
    4 / 30 (13.33%)
         occurrences all number
    9
    5
    Urinary tract infection
         subjects affected / exposed
    2 / 58 (3.45%)
    2 / 30 (6.67%)
         occurrences all number
    2
    2
    Viral infection
         subjects affected / exposed
    4 / 58 (6.90%)
    1 / 30 (3.33%)
         occurrences all number
    5
    1
    Metabolism and nutrition disorders
    Iron deficiency
         subjects affected / exposed
    9 / 58 (15.52%)
    3 / 30 (10.00%)
         occurrences all number
    9
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Aug 2012
    • As per FDA recommendation, a statement was added that the study would be considered positive if both primary endpoints reached statistical significance • Analytical methods were modified to comply with FDA recommendations • Return of medication and dose dispensing were added at Month 1.5 and Month 3, to accommodate the dose escalation • The visit window was increased to allow patients more flexibility
    31 Aug 2012
    • Addition of accountability of returned study medication at Month 1.5 and Month 3, in order to check patient compliance • Updated to refer to licensed versions of the FIM and WeeFIM questionnaires and removal of incorrect versions
    06 Dec 2012
    • Sponsorship of study switched from the TIRCON group to ApoPharma Inc. • Addition of Dr. Elliott Vichinsky as principal investigator • Clarification that MRI would be done only in patients where the investigator had no safety concerns • Likert scale for patient’s assessment of PKAN symptoms added • Exclusion criteria #5 and #6 were modified/added to clarify and better define the illnesses for exclusion in the study. • List of rescue medications added in an appendix • Clarifications added for definition and management of neutropenia
    18 Jan 2013
    • Wording changes to ensure that the protocol was in line with the TIRCON FP7 Grant Agreement and Consortium Agreement
    27 Feb 2013
    • Clarification in exclusion criteria of the use of medications that may have an effect on dystonia symptoms • Addition of instructions and reminders for patients on the use of medications that might impact the study results due to the effect on dystonia symptoms
    31 Jul 2013
    • Exclusion criteria modified to permit a change in DBS parameters or baclofen pump settings in limited circumstances, to ensure that patients were appropriately treated and that patient safety took precedence over study protocol. • Reasons for discontinuation modified to permit use of rescue medication, limited to circumstances judged as absolutely necessary by the Investigator. At screening, patients currently taking a medication that might have an effect on dystonia could be enrolled provided they had been taking it for at least the period specified, to ensure that the baseline assessments were not associated with the use of a new medication. • Change in the name of the CRO used for the Bioanalytical/Pharmacokinetic analysis • Specification that AEs were to be collected for up to 14 days after the last dose of study medication

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31202468
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