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    Clinical Trial Results:
    Long-term Safety and Efficacy Study of Deferiprone in Patients with Pantothenate Kinase-Associated Neurodegeneration (PKAN)

    Summary
    EudraCT number
    		 2014-001427-79
    Trial protocol
    		 DE   GB   IT  
    Global end of trial date
    16 Mar 2018

    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-EXT
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02174848
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ApoPharma Inc.
    Sponsor organisation address
    200 Barmac Drive, Toronto, 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
    16 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Mar 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the long-term safety and tolerability of deferiprone in patients with PKAN.
    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. During treatment with deferiprone, patients were not to receive any other investigational product or any drugs that are known to cause neutropenia or agranulocytosis.
    Evidence for comparator
    		 This was a single-arm study in which all participants received deferiprone.
    Actual start date of recruitment
    01 Jul 2014
    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
    United States: 27
    Country: Number of subjects enrolled
    Germany: 32
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Italy: 4
    Worldwide total number of subjects
    68
    EEA total number of subjects
    41
    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)
    14
    Adolescents (12-17 years)
    14
    Adults (18-64 years)
    40
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All patients who had completed the placebo-controlled study TIRCON2012V1 were invited to enroll in the extension study.

    Pre-assignment
    Screening details
    		 To be eligible, patients had to have completed TIRCON2012V1 and to have no current contraindications to being in the trial.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable. All participants in this trial received deferiprone.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 DFP-DFP
    Arm description
    		 Patients in this group had been randomized to deferiprone treatment in the TIRCON2012V1 study and continued on deferiprone in the extension study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Deferiprone oral solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    The dosage was up to 15 milligrams of deferiprone per kilogram of body weight (mg/kg) twice daily, for a total dosage of up to 30 mg/kg per day.

    Arm title
    		 Placebo-DFP
    Arm description
    		 Patients in this group had been randomized to placebo treatment in the TIRCON2012V1 study and were then switched to deferiprone in the extension study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Deferiprone oral solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    The dosage was up to 15 milligrams of deferiprone per kilogram of body weight (mg/kg) twice daily, for a total dosage of up to 30 mg/kg per day.

    Arm title
    		 Placebo-DFP in initial study
    Arm description
    		 These are the same patients as those included in the Placebo-DFP group. During the initial study, they received 18 months of placebo treatment.
    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
    The volume of placebo was matched to the volume prescribed for deferiprone.

    Arm title
    		 DFP-DFP in initial study
    Arm description
    		 These are the same patients as those included in the DFP-DFP group. During the initial study, they received 18 months of deferiprone treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Deferiprone oral solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    The dosage was up to 15 milligrams of deferiprone per kilogram of body weight (mg/kg) twice daily, for a total dosage of up to 30 mg/kg per day.

    Number of subjects in period 1
    		DFP-DFP Placebo-DFP Placebo-DFP in initial study DFP-DFP in initial study
    Started
    44
    24
    24
    44
    Completed
    38
    17
    24
    44
    Not completed
    6
    7
    0
    0
         Adverse event, serious fatal
    1
    1
    -
    -
         Consent withdrawn by subject
    3
    3
    -
    -
         Adverse event, non-fatal
    -
    1
    -
    -
         Worsening of disease
    1
    1
    -
    -
         Inability to comply with study requirements
    -
    1
    -
    -
         Lost to follow-up
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    DFP-DFP
    Reporting group description
    		 Patients in this group had been randomized to deferiprone treatment in the TIRCON2012V1 study and continued on deferiprone in the extension study.

    Reporting group title
    Placebo-DFP
    Reporting group description
    		 Patients in this group had been randomized to placebo treatment in the TIRCON2012V1 study and were then switched to deferiprone in the extension study.

    Reporting group title
    Placebo-DFP in initial study
    Reporting group description
    		 These are the same patients as those included in the Placebo-DFP group. During the initial study, they received 18 months of placebo treatment.

    Reporting group title
    DFP-DFP in initial study
    Reporting group description
    		 These are the same patients as those included in the DFP-DFP group. During the initial study, they received 18 months of deferiprone treatment.

    Reporting group values
    		 DFP-DFP Placebo-DFP Placebo-DFP in initial study DFP-DFP in initial study Total
    Number of subjects
    		 44 24 24 44
    Age categorical
    Units: Subjects
    Age continuous
    For the main study, whose duration was 18 months, subjects had to be at least 4 years old. Therefore, in this extension study, the minimum age was 5.5 years.
    Units: years
        arithmetic mean (standard deviation)
    		 22.4 ( 9.6 ) 19.9 ( 13.0 ) 19.9 ( 13.0 ) 22.4 ( 9.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 16 14 14 16 30
        Male
    		 28 10 10 28 38

    End points

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    End points reporting groups
    Reporting group title
    DFP-DFP
    Reporting group description
    		 Patients in this group had been randomized to deferiprone treatment in the TIRCON2012V1 study and continued on deferiprone in the extension study.

    Reporting group title
    Placebo-DFP
    Reporting group description
    		 Patients in this group had been randomized to placebo treatment in the TIRCON2012V1 study and were then switched to deferiprone in the extension study.

    Reporting group title
    Placebo-DFP in initial study
    Reporting group description
    		 These are the same patients as those included in the Placebo-DFP group. During the initial study, they received 18 months of placebo treatment.

    Reporting group title
    DFP-DFP in initial study
    Reporting group description
    		 These are the same patients as those included in the DFP-DFP group. During the initial study, they received 18 months of deferiprone treatment.

    Primary: Number of participants with adverse events

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    End point title
    		 Number of participants with adverse events [1] [2]
    End point description
    Safety and tolerability were assessed based on changes in frequency of adverse events (AEs), frequency of serious adverse events (SAEs), and discontinuation due to AEs. No statistical comparison between the groups was conducted as all participants received the same study product.
    End point type
    Primary
    End point timeframe
    Baseline to end of study
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This was a single-arm study in which all patients received the same product. Unlike the efficacy analyses, which were based on which product patients had been taking in an earlier randomized study, in the case of safety, the data were consolidated into a single reporting group. Hence, despite this being a primary endpoint, no statistical analyses were possible.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The safety analyses were concerned only with data obtained in the current study, so only the groups "DFP-DFP" and "Placebo-DFP" were applicable. The arms "Placebo-DFP in initial study" and "DFP-DFP in initial study", which applied to data that had been obtained in the initial study, were used for the efficacy analyses but were not part of the safety analyses.
    End point values
    		 DFP-DFP Placebo-DFP
    Number of subjects analysed
    44
    24
    Units: Participants
        Number of patients with at least one AE
    42
    22
        Number of patients with at least one serious AE
    14
    12
        Number of patients who withdrew due to an AE
    1
    2
    No statistical analyses for this end point

    Secondary: Change in Score on the BAD Scale -- Comparison of Treatment Groups Over Each Study

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    End point title
    		 Change in Score on the BAD Scale -- Comparison of Treatment Groups Over Each Study [3]
    End point description
    The Barry-Albright Dystonia (BAD) scale is an instrument for rating the severity of dystonia in eight body regions. The individual scores are summed to provide a total score that ranges from 0 to 32; the higher the score, the more severe the dystonia. Patients were assessed for the change in total BAD score over the course of both the initial study (during which one group received placebo and the other received deferiprone) and the extension study (during which both groups received deferiprone).
    End point type
    Secondary
    End point timeframe
    Baseline and Month 18 of each study
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This between-groups analysis is comparing the results of the DFP-DFP patients vs. those of the Placebo-DFP patients, so uses only the arms "DFP-DFP" and "Placebo-DFP". The arms "DFP-DFP in initial study" and "Placebo-DFP in initial study" are used only for the within-group analyses, and are not applicable here.
    End point values
    		 DFP-DFP Placebo-DFP
    Number of subjects analysed
    43
    19
    Units: Points on the BAD scale
    arithmetic mean (standard deviation)
        Change in BAD score over initial study
    1.9 ( 3.2 )
    4.4 ( 4.8 )
        Change in BAD score over extension study
    1.4 ( 2.4 )
    1.4 ( 3.7 )
    Statistical analysis title
    		 T-test
    Statistical analysis description
    Comparison between the treatment groups in the change from baseline to Month 18 in total BAD score during the placebo-controlled study
    Comparison groups
    DFP-DFP v Placebo-DFP
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05 [4]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [4] - During the controlled trial, in which the two groups received different treatments, the difference between them fell just short of statistical significance (defined as p < 0.05)
    Statistical analysis title
    		 T-test
    Statistical analysis description
    Comparison between the treatment groups in the change from baseline to Month 18 in total BAD score during the extension study
    Comparison groups
    DFP-DFP v Placebo-DFP
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9781 [5]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [5] - During the extension study, in which both groups received deferiprone, there was no difference in progression of dystonia, based on change in BAD score.

    Secondary: Change in Score on the BAD Scale -- Comparison of Placebo-DFP Patients Across Studies

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    End point title
    		 Change in Score on the BAD Scale -- Comparison of Placebo-DFP Patients Across Studies [6]
    End point description
    The Barry-Albright Dystonia (BAD) scale is an instrument for rating the severity of dystonia in eight body regions. The individual scores are summed to provide a total score that ranges from 0 to 32; the higher the score, the more severe the dystonia. Patients were assessed for the change in total BAD score over the course of each study.
    End point type
    Secondary
    End point timeframe
    Baseline to Visit 4, where Visit 4 is Month 18 in the initial study and the final visit (Month 18 or earlier) in the extension study.
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was concerned with comparing the results of the 24 Placebo-DFP patients across studies: i.e., the change in BAD score during placebo treatment in the initial study vs. the change in BAD score during deferiprone treatment in the current study. The results of the 44 patients who received deferiprone in both studies were not part of this analysis, so the arms "DFP-DFP in initial study" and "DFP-DFP" are not applicable here.
    End point values
    		 Placebo-DFP Placebo-DFP in initial study
    Number of subjects analysed
    19
    19
    Units: Points on the BAD scale
        arithmetic mean (standard deviation)
    1.4 ( 3.7 )
    4.4 ( 4.8 )
    Statistical analysis title
    		 Paired t-test
    Statistical analysis description
    Comparison between the change in total BAD score during the controlled study and during the extension study, for the placebo-DFP group
    Comparison groups
    Placebo-DFP v Placebo-DFP in initial study
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0206 [7]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [7] - Patients showed significantly slower progress in dystonia during deferiprone treatment than during placebo treatment

    Secondary: Change in score on the BAD scale - Comparison of DFP-DFP Patients Across Studies

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    End point title
    		 Change in score on the BAD scale - Comparison of DFP-DFP Patients Across Studies [8]
    End point description
    The Barry-Albright Dystonia (BAD) scale is an instrument for rating the severity of dystonia in eight body regions. The individual scores are summed to provide a total score that ranges from 0 to 32; the higher the score, the more severe the dystonia. Patients were assessed for the change in total BAD score over the course of each study.
    End point type
    Secondary
    End point timeframe
    Baseline to Visit 4, where Visit 4 is Month 18 in the initial study and the final visit (Month 18 or earlier) in the extension study.
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was concerned with comparing the results of the 44 DFP-DFP patients across studies: i.e., the change in BAD score during deferiprone treatment in the initial study vs. the change in BAD score during deferiprone treatment in the current study. The results of the 24 patients who received placebo in the first study and deferiprone in the second were not part of this analysis, so the arms "Placebo-DFP in initial study" and "Placebo-DFP" are not applicable here.
    End point values
    		 DFP-DFP DFP-DFP in initial study
    Number of subjects analysed
    43
    43
    Units: Points on the BAD scale
        arithmetic mean (standard deviation)
    1.4 ( 2.4 )
    1.9 ( 3.2 )
    Statistical analysis title
    		 Paired t-test
    Statistical analysis description
    Comparison between the change in total BAD score during the controlled study and during the extension study, for the DFP-DFP group
    Comparison groups
    DFP-DFP v DFP-DFP in initial study
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2684 [9]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [9] - For patients who received deferiprone in both studies, was no difference between the progression in dystonia seen during the two studies.

    Secondary: Patient Global Impression of Improvement (PGI-I) Comparison of Placebo-DFP Patients Across Studies

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    End point title
    		 Patient Global Impression of Improvement (PGI-I) Comparison of Placebo-DFP Patients Across Studies [10]
    End point description
    The Patient Global Impression of Improvement (PGI-I) is a global index used to rate the response of a condition to a therapy. Patients were asked at each post-baseline visit to rate their overall condition since the start of the extension study on a 7-point rating scale: 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
    Secondary
    End point timeframe
    End of each study
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was concerned with comparing the results of the Placebo-DFP patients across studies: i.e., the PGI-I score following placebo treatment in the initial study vs. the PGI-I score following deferiprone treatment in the current study. The results of the patients who received deferiprone in both studies were not part of this analysis, so the arms "DFP-DFP in initial study" and "DFP-DFP" are not applicable here.
    End point values
    		 Placebo-DFP Placebo-DFP in initial study
    Number of subjects analysed
    19
    19
    Units: Points on the PGI-I scale
        arithmetic mean (standard deviation)
    4.7 ( 1.4 )
    4.4 ( 1.5 )
    Statistical analysis title
    		 Paired t-test
    Statistical analysis description
    Comparison of the PGI-I score following 12 months of placebo treatment vs. the PGI-I score vs. 12 months of deferiprone treatment
    Comparison groups
    Placebo-DFP v Placebo-DFP in initial study
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3306 [11]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [11] - Patients did not report a difference in this measure between studies.

    Secondary: Patient Global Impression of Improvement (PGI-I) Comparison of DFP-DFP Patients Across Studies

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    End point title
    		 Patient Global Impression of Improvement (PGI-I) Comparison of DFP-DFP Patients Across Studies [12]
    End point description
    The Patient Global Impression of Improvement (PGI-I) is a global index used to rate the response of a condition to a therapy. Patients were asked at each post-baseline visit to rate their overall condition since the start of the extension study on a 7-point rating scale: 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
    Secondary
    End point timeframe
    End of each study
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was concerned with comparing the results of the 44 DFP-DFP patients across studies: i.e., the PGI-I score following deferiprone treatment in the initial study vs. the PGI-I score following deferiprone treatment in the current study. The results of the 24 patients who received placebo in the first study and deferiprone in the second were not part of this analysis, so the arms "Placebo-DFP in initial study" and "Placebo-DFP" are not applicable here.
    End point values
    		 DFP-DFP DFP-DFP in initial study
    Number of subjects analysed
    43
    43
    Units: Points on the PGI-I scale
        arithmetic mean (standard deviation)
    4.1 ( 1.4 )
    4.4 ( 1.3 )
    Statistical analysis title
    		 Paired t-test
    Comparison groups
    DFP-DFP v DFP-DFP in initial study
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3079 [13]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [13] - Patients did not report a difference in this measure between studies.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Start of deferiprone treatment to end of TIRCON-EXT study. For DFP-DFP patients, this included any AEs that occurred during the 18 months of the initial study, while for placebo-DFP patients, it included only AEs that occurred during the TIRCON-EXT study.
    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
    21.0
    Reporting groups
    Reporting group title
    Safety population
    Reporting group description
    		 The safety population included all patients who took at least one dose of study drug in the extension study.

    Serious adverse events
    		 Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    33 / 68 (48.53%)
         number of deaths (all causes)
    2
         number of deaths resulting from adverse events
    2
    Vascular disorders
    Thrombosis
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Colostomy closure
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dental operation
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal tube insertion
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrostomy
         subjects affected / exposed
    4 / 68 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    Hip surgery
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intrathecal pump insertion
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Jejunostomy
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Medical device battery replacemen
         subjects affected / exposed
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Medical device change
         subjects affected / exposed
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Medical device implantation
         subjects affected / exposed
    3 / 68 (4.41%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Medical device removal
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tracheostomy
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Tracheostomy tube removal
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound treatment
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Medical device site inflammation
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Obstruction
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 68 (4.41%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Choking
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cough
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device malfunction
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device stimulation issue
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Device function test
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Physical examination
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Chemical eye injury
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Unintentional medical device removal
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cyanosis
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Dystonia
         subjects affected / exposed
    8 / 68 (11.76%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyporesponsive to stimuli
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oromandibular dystonia
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    4 / 68 (5.88%)
         occurrences causally related to treatment / all
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal dilatatio
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Salivary hypersecretion
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Urinary bladder rupture
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bursitis
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bacterial disease carrier
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infective glossitis
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Respiratory tract infection
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 68 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound infection
         subjects affected / exposed
    2 / 68 (2.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    66 / 68 (97.06%)
    Investigations
    Body temperature increased
         subjects affected / exposed
    4 / 68 (5.88%)
         occurrences all number
    4
    Neutrophil count decreased
         subjects affected / exposed
    10 / 68 (14.71%)
         occurrences all number
    26
    Serum ferritin decreased
         subjects affected / exposed
    18 / 68 (26.47%)
         occurrences all number
    25
    Iron deficiency
         subjects affected / exposed
    11 / 68 (16.18%)
         occurrences all number
    11
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    5 / 68 (7.35%)
         occurrences all number
    5
    Laceration
         subjects affected / exposed
    8 / 68 (11.76%)
         occurrences all number
    20
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    5 / 68 (7.35%)
         occurrences all number
    6
    Ataxia
         subjects affected / exposed
    4 / 68 (5.88%)
         occurrences all number
    4
    Balance disorder
         subjects affected / exposed
    5 / 68 (7.35%)
         occurrences all number
    5
    Dystonia
         subjects affected / exposed
    32 / 68 (47.06%)
         occurrences all number
    74
    Headache
         subjects affected / exposed
    19 / 68 (27.94%)
         occurrences all number
    64
    Somnolence
         subjects affected / exposed
    6 / 68 (8.82%)
         occurrences all number
    8
    Tremor
         subjects affected / exposed
    4 / 68 (5.88%)
         occurrences all number
    7
    Blood and lymphatic system disorders
    Anemias
         subjects affected / exposed
    12 / 68 (17.65%)
         occurrences all number
    27
    General disorders and administration site conditions
    Condition aggravated
         subjects affected / exposed
    17 / 68 (25.00%)
         occurrences all number
    25
    Pain
         subjects affected / exposed
    5 / 68 (7.35%)
         occurrences all number
    5
    Pyrexia
         subjects affected / exposed
    20 / 68 (29.41%)
         occurrences all number
    64
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    8 / 68 (11.76%)
         occurrences all number
    16
    Diarrhoea
         subjects affected / exposed
    4 / 68 (5.88%)
         occurrences all number
    6
    Dysphagia
         subjects affected / exposed
    8 / 68 (11.76%)
         occurrences all number
    8
    Nausea
         subjects affected / exposed
    5 / 68 (7.35%)
         occurrences all number
    5
    Vomiting
         subjects affected / exposed
    10 / 68 (14.71%)
         occurrences all number
    13
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 68 (17.65%)
         occurrences all number
    19
    Oropharyngeal pain
         subjects affected / exposed
    10 / 68 (14.71%)
         occurrences all number
    11
    Rhinorrhoea
         subjects affected / exposed
    6 / 68 (8.82%)
         occurrences all number
    8
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    5 / 68 (7.35%)
         occurrences all number
    5
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    5 / 68 (7.35%)
         occurrences all number
    13
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 68 (16.18%)
         occurrences all number
    12
    Back pain
         subjects affected / exposed
    4 / 68 (5.88%)
         occurrences all number
    4
    Muscle spasms
         subjects affected / exposed
    8 / 68 (11.76%)
         occurrences all number
    11
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    6 / 68 (8.82%)
         occurrences all number
    30
    Influenza
         subjects affected / exposed
    4 / 68 (5.88%)
         occurrences all number
    4
    Nasopharyngitis
         subjects affected / exposed
    11 / 68 (16.18%)
         occurrences all number
    22
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 68 (19.12%)
         occurrences all number
    19
    Urinary tract infection
         subjects affected / exposed
    6 / 68 (8.82%)
         occurrences all number
    8
    Metabolism and nutrition disorders
    Pain in extremity
         subjects affected / exposed
    14 / 68 (20.59%)
         occurrences all number
    26

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Aug 2014
    • The EudraCT number was corrected • An Extension Study Scientific Steering Committee was formed to clarify ownership of data and publication • The vendor for centralized evaluation of. BAD scores was changed • Paracetamol/acetaminophen was removed from the list of prohibited drugs

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31202468
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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