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    Clinical Trial Results:
    Efficacy, Safety, and Tolerability of Fosmetpantotenate (RE-024), a Phosphopantothenate Replacement Therapy, in Patients With Pantothenate Kinase-Associated Neurodegeneration (PKAN): A Randomized, Double-Blind, Placebo-Controlled Study With an Open-Label Extension

    Summary
    EudraCT number
    2016-001955-29
    Trial protocol
    DE   ES   GB   CZ   NO   FR   PL   IT  
    Global end of trial date
    30 Dec 2019

    Results information
    Results version number
    v2(current)
    This version publication date
    01 Jan 2021
    First version publication date
    10 Sep 2020
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Correction of typographical errors

    Trial information

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    Trial identification
    Sponsor protocol code
    024PKAN15004
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03041116
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Travere Therapeutics, Inc.
    Sponsor organisation address
    3611 Valley Centre Drive, Suite 300, San Diego, United States, 92130
    Public contact
    Clinical Trial Information Desk, Travere Therapeutics, Inc., +1 877-659-5518,
    Scientific contact
    Clinical Trial Information Desk, Travere Therapeutics, Inc., +1 877-659-5518,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-002036-PIP01-16
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Feb 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Dec 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy, safety, and tolerability of fosmetpantotenate over 24 weeks in subjects with Pantothenate Kinase-associated Neurodegeneration (PKAN).
    Protection of trial subjects
    At each study site, the protocol and associated informed consent form (ICF), participant information sheet, any information provided to the subject, and the investigator’s brochure (IB), reviewed and approved by Institutional Review Board (IRB)/ Independent Ethics Committee (IEC). Amendments to the protocol and ICF were reviewed and approved in the same manner before being implemented. This study was conducted in accordance with Good Clinical Practice (GCP) as required by the International Council for Harmonisation (ICH) guidelines and in accordance with country-specific laws and regulations governing clinical studies of investigational products. Compliance with these requirements also constitutes conformity with the ethical principles of the Declaration of Helsinki (1996). The study progress in accordance with the protocol, GCP, and local regulations were monitored periodically by Sponsor representative or by its designee. During the conduct of the study, the data monitoring committee (DMC) periodically reviewed safety study results and evaluated treatment groups for excess adverse events (AEs), and the paediatric subjects were enrolled only after 8 adult subjects had been enrolled, completed 3 weeks of study treatment, and safety data from adult subjects were reviewed by the DMC. All study findings and documents were regarded as confidential. Each subject or parent or legal guardians were given full and adequate oral and written information about the nature, purpose, possible risks, and benefits of the study as well as potential treatment alternatives.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    17 Jul 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    United States: 24
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Czech Republic: 5
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Norway: 3
    Country: Number of subjects enrolled
    Poland: 5
    Worldwide total number of subjects
    84
    EEA total number of subjects
    57
    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)
    17
    Adolescents (12-17 years)
    13
    Adults (18-64 years)
    54
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted in Spain, United States, Canada, Czech Republic, France, Germany, Italy, Norway, and Poland from 17Jul2017 to 23Dec2019. In total 91 subjects were screened. Of these 84 subjects were randomised in the double blind period and 78 subjects completed the double blind period.

    Pre-assignment
    Screening details
    The study consisted of a screening period of up to 29 days. All assessments at screening were done as per the schedule of assessments.

    Period 1
    Period 1 title
    Double-blind
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    This was double-blind clinical study. The identity of the treatments were concealed by the use of study drugs that are identical in packaging, labeling, and schedule of administration, appearance, taste, and odor. During the open-label extension, subjects (including parents or legal guardians of subjects <18 years of age) and site personnel remained blinded to the subject’s randomized treatment assignment.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Each randomized subject received oral dose of placebo matched to fosmetpantotenate (RE-024) with dose escalation for Days 1 through 3, followed by the full dose three times a day (TID) from Day 4, based on the subject’s age and weight at screening for 24 Weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once on Day 1, two times a day on Days 2 and 3, TID on Day 4, then continued till Week 24. Subject’s aged 18 to 65 years and 6 to <18 years weighing >= 40 kg: received 300 mg dose on Day 1, 300 mg twice a day on Days 2 and 3, 300 mg TID on Day 4; subject’s aged 6 to <18 years weighing >=20 kg but <40 kg: received 150 mg dose on Day 1, 150 mg twice a day on Days 2 and 3, 150 mg TID on Day 4; subject’s aged 6 to <18 years weighing <20 kg: received 75 mg dose on Day 1, 75 mg twice a day on Days 2 and 3, 75 mg TID on Day 4.

    Arm title
    Fosmetpantotenate
    Arm description
    Each randomized subject received oral dose of fosmetpantotenate with dose escalation for Days 1 through 3, followed by the full dose three times a day (TID) from Day 4, based on the subject’s age and weight at screening for 24 Weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Fosmetpantotenate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once on Day 1, two times a day on Days 2 and 3, TID on Day 4, then continued till Week 24. Subject’s aged 18 to 65 years and 6 to <18 years weighing >= 40 kg: received 300 mg dose on Day 1, 300 mg twice a day on Days 2 and 3, 300 mg TID on Day 4; subject’s aged 6 to <18 years weighing >=20 kg but <40 kg: received 150 mg dose on Day 1, 150 mg twice a day on Days 2 and 3, 150 mg TID on Day 4; subject’s aged 6 to <18 years weighing <20 kg: received 75 mg dose on Day 1, 75 mg twice a day on Days 2 and 3, 75 mg TID on Day 4.

    Number of subjects in period 1
    Placebo Fosmetpantotenate
    Started
    43
    41
    Completed
    37
    41
    Not completed
    6
    0
         Death
    2
    -
         Withdrawal of Subject/Guardian Assent/Consent
    4
    -
    Period 2
    Period 2 title
    Open-label
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Each randomized subject received oral dose of placebo matched to fosmetpantotenate with dose escalation for Days 1 through 3, followed by the full dose TID from Day 4, based on the subject’s age and weight at screening for 24 Weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once on Day 1, two times a day on Days 2 and 3, TID on Day 4, then continued till Week 24. Subject’s aged 18 to 65 years and 6 to <18 years weighing >= 40 kg: received 300 mg dose on Day 1, 300 mg twice a day on Days 2 and 3, 300 mg TID on Day 4; subject’s aged 6 to <18 years weighing >=20 kg but <40 kg: received 150 mg dose on Day 1, 150 mg twice a day on Days 2 and 3, 150 mg TID on Day 4; subject’s aged 6 to <18 years weighing <20 kg: received 75 mg dose on Day 1, 75 mg twice a day on Days 2 and 3, 75 mg TID on Day 4.

    Arm title
    Fosmetpantotenate
    Arm description
    Each randomized subject received oral dose of fosmetpantotenate with dose escalation for Days 1 through 3, followed by the full dose TID from Day 4, based on the subject’s age and weight at screening for 24 Weeks. No dose escalation was required for the open-label period. All subjects (including placebo group subjects from the double-blind period initiating fosmetpantotenate treatment) started treatment with fosmetpantotenate in the open-label period according to the dose of study medication they were receiving at the end of the double-blind period.
    Arm type
    Experimental

    Investigational medicinal product name
    Fosmetpantotenate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally once on Day 1, two times a day on Days 2 and 3, TID on Day 4, then continued till Week 24. Subject’s aged 18 to 65 years and 6 to <18 years weighing >= 40 kg: received 300 mg dose on Day 1, 300 mg twice a day on Days 2 and 3, 300 mg TID on Day 4; subject’s aged 6 to <18 years weighing >=20 kg but <40 kg: received 150 mg dose on Day 1, 150 mg twice a day on Days 2 and 3, 150 mg TID on Day 4; subject’s aged 6 to <18 years weighing <20 kg: received 75 mg dose on Day 1, 75 mg twice a day on Days 2 and 3, 75 mg TID on Day 4.

    Number of subjects in period 2
    Placebo Fosmetpantotenate
    Started
    37
    41
    Completed
    0
    0
    Not completed
    37
    41
         Death
    -
    1
         Termination of the Study by Sponsor
    37
    39
         Withdrawal of Subject/Guardian Assent/Consent
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Each randomized subject received oral dose of placebo matched to fosmetpantotenate (RE-024) with dose escalation for Days 1 through 3, followed by the full dose three times a day (TID) from Day 4, based on the subject’s age and weight at screening for 24 Weeks.

    Reporting group title
    Fosmetpantotenate
    Reporting group description
    Each randomized subject received oral dose of fosmetpantotenate with dose escalation for Days 1 through 3, followed by the full dose three times a day (TID) from Day 4, based on the subject’s age and weight at screening for 24 Weeks.

    Reporting group values
    Placebo Fosmetpantotenate Total
    Number of subjects
    43 41 84
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    9 8 17
        Adolescents (12-17 years)
    7 6 13
        Adults (18-64 years)
    27 27 54
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    23.1 ± 13.56 22.6 ± 10.61 -
    Gender categorical
    Units: Subjects
        Female
    19 20 39
        Male
    24 21 45

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Each randomized subject received oral dose of placebo matched to fosmetpantotenate (RE-024) with dose escalation for Days 1 through 3, followed by the full dose three times a day (TID) from Day 4, based on the subject’s age and weight at screening for 24 Weeks.

    Reporting group title
    Fosmetpantotenate
    Reporting group description
    Each randomized subject received oral dose of fosmetpantotenate with dose escalation for Days 1 through 3, followed by the full dose three times a day (TID) from Day 4, based on the subject’s age and weight at screening for 24 Weeks.
    Reporting group title
    Placebo
    Reporting group description
    Each randomized subject received oral dose of placebo matched to fosmetpantotenate with dose escalation for Days 1 through 3, followed by the full dose TID from Day 4, based on the subject’s age and weight at screening for 24 Weeks.

    Reporting group title
    Fosmetpantotenate
    Reporting group description
    Each randomized subject received oral dose of fosmetpantotenate with dose escalation for Days 1 through 3, followed by the full dose TID from Day 4, based on the subject’s age and weight at screening for 24 Weeks. No dose escalation was required for the open-label period. All subjects (including placebo group subjects from the double-blind period initiating fosmetpantotenate treatment) started treatment with fosmetpantotenate in the open-label period according to the dose of study medication they were receiving at the end of the double-blind period.

    Primary: Change from baseline in the Pantothenate Kinase-Associated Neurodegeneration–Activities of Daily Living (PKAN-ADL) total score to the end of the 24-week double-blind period

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    End point title
    Change from baseline in the Pantothenate Kinase-Associated Neurodegeneration–Activities of Daily Living (PKAN-ADL) total score to the end of the 24-week double-blind period
    End point description
    Change from baseline to Week 24 activities of daily living was assessed on the PKAN-ADL scale based on the Unified Parkinson’s Disease Rating Scale (UPDRS) Part II.
    End point type
    Primary
    End point timeframe
    At Baseline (Day -1), and Week 24
    End point values
    Placebo Fosmetpantotenate
    Number of subjects analysed
    43
    41
    Units: Unit on a Scale
    least squares mean (standard error)
        Week 24
    -1.3 ± 0.58
    -1.3 ± 0.56
    Statistical analysis title
    Statistical analysis for Week 24
    Comparison groups
    Placebo v Fosmetpantotenate
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9115 [1]
    Method
    Mixed models analysis
    Parameter type
    Difference in LS Mean
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.69
         upper limit
    1.51
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.8
    Notes
    [1] - p-value is derived from test of contrast between treatment effects using LSM estimate, adjusted for baseline score and age group from Type III analysis. The test of contrast at week 24 is considered the primary comparison.

    Primary: Number of subjects with at least 1 (≥1) treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs)

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    End point title
    Number of subjects with at least 1 (≥1) treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs) [2]
    End point description
    An adverse event (AE) is any untoward medical occurrence associated with the use of the investigational product (IP; active or placebo) in a subject, without regard to possibility of causal relationship with IP. A serious adverse event (SAE) is an AE resulting in any of the following outcomes: death; initial or prolonged inpatient hospitalization ; life threatening experience (immediate risk of death from AE); persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious medical events. The TEAEs in double-blind period are defined as AEs that are new or are a worsening of an existing condition that begins from day of first dose of IP until day after last dose for double-blind treatment period.
    End point type
    Primary
    End point timeframe
    From Screening until end of treatment (Approximately 29 Months)
    Notes
    [2] - 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: Statistical Analysis was not performed on the safety data.
    End point values
    Placebo Fosmetpantotenate
    Number of subjects analysed
    43
    41
    Units: Count of Subjects
    number (not applicable)
        ≥1 AE
    36
    34
        ≥1 TEAE
    35
    34
        ≥1 TESAE
    6
    8
        ≥1 TEAE leading to IP discontinuation
    2
    0
        Mild TEAE
    15
    15
        Moderate TEAE
    12
    16
        Severe TEAE
    8
    3
        TEAE not related to IP
    11
    12
        TEAE unlikely related to IP
    5
    7
        Possibly related to IP
    14
    10
        Related to IP
    5
    5
        TEAE with outcome of death
    2
    0
    No statistical analyses for this end point

    Secondary: Absolute change from baseline in the Unified Parkinson’s Disease Rating Scale Part 3 (UPDRS-III) total score to the end of the 24-week double-blind period

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    End point title
    Absolute change from baseline in the Unified Parkinson’s Disease Rating Scale Part 3 (UPDRS-III) total score to the end of the 24-week double-blind period
    End point description
    The UPDRS is a comprehensive assessment of the burden and severity of signs and symptoms of parkinsonism captured via systematic interview and neurological examination.
    End point type
    Secondary
    End point timeframe
    At Baseline (Day -1), and Week 24
    End point values
    Placebo Fosmetpantotenate
    Number of subjects analysed
    43
    41
    Units: Unit on a Scale
    arithmetic mean (standard deviation)
        Week 24 (n= 35, 40)
    -1.0 ± 6.81
    0.7 ± 5.25
    Statistical analysis title
    Statistical analysis for Week 24
    Comparison groups
    Placebo v Fosmetpantotenate
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1421 [3]
    Method
    Mixed models analysis
    Parameter type
    Difference in LS Mean
    Point estimate
    2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    4.78
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.38
    Notes
    [3] - p-value is derived from the test of contrast between treatment effects using the LSM estimate, adjusted for baseline score and age group from the Type III analysis. The test of contrast at week 24 is considered the primary comparison.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Screening until end of treatment (Approximately 29 Months)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Fosmetpantotenate Treatment-Placebo
    Reporting group description
    -

    Reporting group title
    Fosmetpantotenate Treatment-Fosmetpantotenate
    Reporting group description
    -

    Reporting group title
    Double-Blind- Placebo
    Reporting group description
    Each randomized subject received an oral dose of placebo matched to fosmetpantotenate with dose escalation for Days 1 through 3, followed by the full dose TID from Day 4, based on the subjec’s age and weight at screening, for 24 weeks.

    Reporting group title
    Double-Blind- Fosmetpantotenate
    Reporting group description
    Each randomized subject received an oral dose of fosmetpantotenate with dose escalation for Days 1 through 3, followed by the full dose 3 times daily (TID) from Day 4, based on the subject’s age and weight at screening, for 24 weeks

    Reporting group title
    Open-label-Placebo
    Reporting group description
    All subjects continued treatment with fosmetpantotenate according to the dose they were receiving at the end of the double-blind period. No dose escalation was required.

    Reporting group title
    Open-label-Fosmetpantotenate
    Reporting group description
    All subjects started treatment with fosmetpantotenate according to the placebo dose they were receiving at the end of the double-blind period. No dose escalation was required.

    Serious adverse events
    Fosmetpantotenate Treatment-Placebo Fosmetpantotenate Treatment-Fosmetpantotenate Double-Blind- Placebo Double-Blind- Fosmetpantotenate Open-label-Placebo Open-label-Fosmetpantotenate
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 37 (24.32%)
    9 / 41 (21.95%)
    6 / 43 (13.95%)
    8 / 41 (19.51%)
    9 / 37 (24.32%)
    4 / 41 (9.76%)
         number of deaths (all causes)
    0
    1
    2
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    2
    0
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shunt malfunction
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Fracture treatment
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    1 / 43 (2.33%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Dystonia
         subjects affected / exposed
    4 / 37 (10.81%)
    4 / 41 (9.76%)
    1 / 43 (2.33%)
    2 / 41 (4.88%)
    4 / 37 (10.81%)
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 6
    0 / 1
    1 / 3
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple sclerosis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotonia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 41 (4.88%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    1 / 37 (2.70%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
    1 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin lesion
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Skin Infections
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 41 (4.88%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis streptococcal
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Fosmetpantotenate Treatment-Placebo Fosmetpantotenate Treatment-Fosmetpantotenate Double-Blind- Placebo Double-Blind- Fosmetpantotenate Open-label-Placebo Open-label-Fosmetpantotenate
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 37 (67.57%)
    35 / 41 (85.37%)
    35 / 43 (81.40%)
    34 / 41 (82.93%)
    26 / 37 (70.27%)
    25 / 41 (60.98%)
    Immune system disorders
    Hypersensitivity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Drug hypersensitivity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Seasonal allergy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 37 (2.70%)
    7 / 41 (17.07%)
    4 / 43 (9.30%)
    5 / 41 (12.20%)
    1 / 37 (2.70%)
    2 / 41 (4.88%)
         occurrences all number
    1
    8
    4
    6
    1
    2
    Discomfort
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Fatigue
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    1 / 43 (2.33%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Feeling cold
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Gait disturbance
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    1
    0
    1
    1
    0
    General physical health deterioration
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Generalised oedema
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Medical device site inflammation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Medical device site rash
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Chest pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    2
    0
    0
    0
    2
    0
    Influenza like illness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Oedema peripheral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Psychiatric disorders
    Anxiety
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 41 (4.88%)
    1 / 43 (2.33%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    2
    1
    1
    0
    1
    Insomnia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 41 (4.88%)
    1 / 43 (2.33%)
    2 / 41 (4.88%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    2
    1
    2
    0
    0
    Sleep disorder
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 41 (4.88%)
    0 / 43 (0.00%)
    2 / 41 (4.88%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    2
    0
    2
    0
    0
    Adjustment disorder with depressed mood
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Restlessness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Affect lability
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Gastrostomy tube site complication
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 41 (7.32%)
    0 / 43 (0.00%)
    2 / 41 (4.88%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    3
    0
    2
    0
    1
    Laceration
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 41 (2.44%)
    2 / 43 (4.65%)
    0 / 41 (0.00%)
    2 / 37 (5.41%)
    1 / 41 (2.44%)
         occurrences all number
    2
    1
    4
    0
    2
    1
    Fall
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 41 (4.88%)
    0 / 43 (0.00%)
    2 / 41 (4.88%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    2
    0
    2
    1
    0
    Hand fracture
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 41 (4.88%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    1 / 37 (2.70%)
    1 / 41 (2.44%)
         occurrences all number
    1
    2
    0
    1
    1
    1
    Skin abrasion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 41 (4.88%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    2
    0
    1
    0
    1
    Arthropod bite
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Contusion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Face injury
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    2
    0
    2
    1
    0
    Foetal exposure during pregnancy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Limb injury
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Traumatic haemorrhage
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Wound
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    1
    0
    1
    1
    0
    Animal scratch
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Eyelid contusion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Post-traumatic pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Rib fracture
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Scar
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Traumatic fracture
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Joint dislocation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 41 (2.44%)
    1 / 43 (2.33%)
    1 / 41 (2.44%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    1
    1
    1
    1
    0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 37 (2.70%)
    4 / 41 (9.76%)
    2 / 43 (4.65%)
    4 / 41 (9.76%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    4
    4
    4
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 37 (8.11%)
    1 / 41 (2.44%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    3 / 37 (8.11%)
    1 / 41 (2.44%)
         occurrences all number
    3
    1
    2
    0
    3
    1
    Weight decreased
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    2 / 37 (5.41%)
    0 / 41 (0.00%)
         occurrences all number
    2
    0
    1
    0
    2
    0
    Haemoglobin decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 41 (4.88%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    2
    1
    0
    0
    2
    Activated partial thromboplastin time prolonged
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    2 / 43 (4.65%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    2
    0
    0
    1
    Alanine aminotransferase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 41 (2.44%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    1 / 41 (2.44%)
         occurrences all number
    1
    1
    1
    0
    1
    1
    Bacterial test positive
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    2
    0
    1
    0
    1
    Blood cholesterol increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Blood glucose decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Cardiac murmur
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Coagulation time prolonged
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Crystal urine present
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    2 / 43 (4.65%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    3
    1
    0
    0
    Culture throat positive
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Haemoglobin urine present
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 41 (2.44%)
    2 / 43 (4.65%)
    1 / 41 (2.44%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    1
    2
    1
    1
    0
    Lymphocyte count decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Monocyte count increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Monocyte percentage increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Neutrophil count decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    2
    0
    2
    0
    0
    Neutrophil count increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Nitrite urine present
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    1 / 43 (2.33%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    2
    1
    1
    0
    1
    Platelet count increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Urine leukocyte esterase positive
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 41 (2.44%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    1 / 41 (2.44%)
         occurrences all number
    1
    1
    1
    0
    1
    1
    White blood cell count decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    2
    0
    2
    0
    0
    White blood cell count increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Blood lactate dehydrogenase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Blood urea increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Cortisol decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    1
    0
    1
    0
    Platelet count decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    White blood cells urine positive
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    2
    0
    1
    0
    2
    0
    Prothrombin time prolonged
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    2 / 43 (4.65%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Urine leukocyte esterase
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Cardiac disorders
    Left ventricular hypertrophy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Leukopenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    1 / 43 (2.33%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    2
    1
    0
    0
    Normochromic normocytic anaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Lymphadenopathy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 41 (4.88%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    2
    0
    1
    0
    1
    Apnoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Bronchial secretion retention
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Epistaxis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    3
    0
    2
    0
    1
    Nasal congestion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Oropharyngeal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Productive cough
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Rhinorrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Choking
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Obstructive airways disorder
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pharyngeal erythema
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Nervous system disorders
    Dystonia
         subjects affected / exposed
    3 / 37 (8.11%)
    7 / 41 (17.07%)
    8 / 43 (18.60%)
    6 / 41 (14.63%)
    3 / 37 (8.11%)
    1 / 41 (2.44%)
         occurrences all number
    3
    11
    9
    10
    3
    1
    Headache
         subjects affected / exposed
    3 / 37 (8.11%)
    4 / 41 (9.76%)
    5 / 43 (11.63%)
    2 / 41 (4.88%)
    3 / 37 (8.11%)
    2 / 41 (4.88%)
         occurrences all number
    3
    4
    9
    2
    3
    2
    Oromandibular dystonia
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 41 (2.44%)
    1 / 43 (2.33%)
    1 / 41 (2.44%)
    2 / 37 (5.41%)
    0 / 41 (0.00%)
         occurrences all number
    2
    1
    1
    1
    2
    0
    Dizziness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 41 (4.88%)
    2 / 43 (4.65%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    2
    3
    1
    0
    1
    Paraesthesia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 41 (4.88%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    2
    0
    0
    0
    2
    Drooling
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    2
    0
    2
    0
    0
    Dyskinesia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Muscle spasticity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Neuralgia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Migraine
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Nystagmus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Sciatica
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Seizure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    2
    0
    0
    0
    2
    Somnolence
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    2 / 43 (4.65%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    2
    1
    0
    0
    Multiple sclerosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Nerve compression
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Epilepsy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Opisthotonus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Parkinsonism
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Restless legs syndrome
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Hyperkinesia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    1 / 43 (2.33%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Eye disorders
    Dark circles under eyes
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Eczema eyelids
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Optic atrophy
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Visual acuity reduced
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Dry eye
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Ear and labyrinth disorders
    Hypoacusis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 37 (5.41%)
    8 / 41 (19.51%)
    4 / 43 (9.30%)
    5 / 41 (12.20%)
    2 / 37 (5.41%)
    3 / 41 (7.32%)
         occurrences all number
    2
    11
    6
    5
    2
    6
    Abdominal pain upper
         subjects affected / exposed
    1 / 37 (2.70%)
    5 / 41 (12.20%)
    0 / 43 (0.00%)
    4 / 41 (9.76%)
    1 / 37 (2.70%)
    1 / 41 (2.44%)
         occurrences all number
    1
    5
    0
    4
    1
    1
    Vomiting
         subjects affected / exposed
    2 / 37 (5.41%)
    8 / 41 (19.51%)
    5 / 43 (11.63%)
    4 / 41 (9.76%)
    2 / 37 (5.41%)
    4 / 41 (9.76%)
         occurrences all number
    2
    12
    6
    8
    2
    4
    Constipation
         subjects affected / exposed
    2 / 37 (5.41%)
    4 / 41 (9.76%)
    2 / 43 (4.65%)
    3 / 41 (7.32%)
    2 / 37 (5.41%)
    2 / 41 (4.88%)
         occurrences all number
    2
    5
    2
    3
    2
    2
    Nausea
         subjects affected / exposed
    0 / 37 (0.00%)
    4 / 41 (9.76%)
    7 / 43 (16.28%)
    2 / 41 (4.88%)
    0 / 37 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    4
    13
    2
    0
    2
    Dyspepsia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 41 (4.88%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    2
    0
    1
    0
    1
    Abdominal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 41 (4.88%)
    2 / 43 (4.65%)
    1 / 41 (2.44%)
    1 / 37 (2.70%)
    1 / 41 (2.44%)
         occurrences all number
    1
    2
    3
    1
    1
    1
    Dry mouth
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    1 / 43 (2.33%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Faecaloma
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    1
    0
    1
    1
    0
    Faeces soft
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    2
    0
    2
    0
    0
    Gastrointestinal haemorrhage
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Haematemesis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Haematochezia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Hyperchlorhydria
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Parotid gland enlargement
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Salivary hypersecretion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    1
    0
    1
    1
    0
    Tongue disorder
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Toothache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    1 / 43 (2.33%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Abdominal pain lower
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Abdominal discomfort
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Dysphagia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Flatulence
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Gastrointestinal hypermotility
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Gastrooesophageal reflux disease
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Renal and urinary disorders
    Chromaturia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Urine odour abnormal
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 41 (4.88%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    4
    0
    3
    0
    1
    Dermal cyst
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Dermatitis diaper
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Ingrowing nail
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Pruritus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    1
    0
    1
    1
    0
    Rash generalised
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Skin lesion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Urticaria
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    1 / 43 (2.33%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Acne
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Hyperhidrosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    2 / 43 (4.65%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Rash pruritic
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Product issues
    Product taste abnormal
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 41 (4.88%)
    2 / 43 (4.65%)
    2 / 41 (4.88%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    2
    2
    2
    0
    0
    Device failure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Device occlusion
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 41 (4.88%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    2
    0
    1
    0
    1
    Arthralgia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Back pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Knee deformity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Muscle spasms
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    1 / 43 (2.33%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Osteopenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Joint swelling
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Muscle tightness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Posture abnormal
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Endocrine disorders
    Secondary adrenocortical insufficiency
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 41 (7.32%)
    0 / 43 (0.00%)
    2 / 41 (4.88%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    3
    0
    2
    0
    1
    Iron deficiency
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Vitamin D deficiency
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Hypoglycaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Infections and infestations
    Ear infection
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 41 (7.32%)
    0 / 43 (0.00%)
    3 / 41 (7.32%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    3
    0
    3
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 41 (7.32%)
    0 / 43 (0.00%)
    3 / 41 (7.32%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    4
    0
    4
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 37 (2.70%)
    5 / 41 (12.20%)
    2 / 43 (4.65%)
    3 / 41 (7.32%)
    1 / 37 (2.70%)
    2 / 41 (4.88%)
         occurrences all number
    1
    7
    2
    4
    1
    3
    Urinary tract infection
         subjects affected / exposed
    2 / 37 (5.41%)
    6 / 41 (14.63%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    2 / 37 (5.41%)
    5 / 41 (12.20%)
         occurrences all number
    2
    6
    0
    1
    2
    5
    Bronchitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 41 (4.88%)
    0 / 43 (0.00%)
    2 / 41 (4.88%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    2
    0
    2
    1
    0
    Genital candidiasis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 41 (4.88%)
    0 / 43 (0.00%)
    2 / 41 (4.88%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    2
    0
    2
    0
    0
    Respiratory tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 41 (4.88%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    3
    0
    0
    0
    3
    Skin infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 41 (4.88%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    2 / 41 (4.88%)
         occurrences all number
    0
    3
    0
    0
    0
    3
    Clostridium difficile infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Gastroenteritis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Gastroenteritis viral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    1
    0
    0
    1
    Gastrointestinal infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    1
    0
    1
    1
    0
    Helminthic infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Influenza
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    1
    0
    0
    1
    Oral candidiasis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Oropharyngeal candidiasis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Pharyngitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    1 / 43 (2.33%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    Stoma site infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    1 / 41 (2.44%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Tooth infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Viral infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Vulvovaginal candidiasis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 41 (2.44%)
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Cellulitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Herpes zoster
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Pneumonia influenzal
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Rhinitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Tonsillitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    1 / 37 (2.70%)
    0 / 41 (0.00%)
         occurrences all number
    2
    0
    1
    0
    2
    0
    Ear lobe infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 41 (0.00%)
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 37 (0.00%)
    0 / 41 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Apr 2018
    Amendment 1 (Version 2): The following changes were made to the protocol- Changed lower age limit for classification as an adult from 19 to 18 years of age. Excluded subjects with history of metastasized or ongoing malignancy. Prohibited changing deep brain stimulation (DBS) settings during the study. Clarified that a dose escalation was not required for subjects once they rolled over from the double-blind period and that all subjects should start the open-label period according to the dose of study medication they were receiving at the end of the double-blind period. Clarified that, for subjects 6 to <18 years of age, in the open-label extension period, the initial dose may be adjusted, if needed, based on the subject’s weight at the end of the double-blind period. In addition, the reasons for permanent discontinuation of study medication were updated to be Clinical Data Interchange Standards Consortium (CDISC)-compliant and text was added to clarify that subjects who discontinue study medication early should be encouraged to continue study visits through Week 120. An additional visit, End of Treatment, was added. Added guidance for follow-up management of subjects who presented with suicidality on the Columbia Suicide Severity Rating Scale (C-SSRS). Provided option for subjects to have some study visits performed at home at the discretion of the Investigator. Added text to clarify that the bitter taste of the study medication was not to be captured as an AE, although reactions to the taste such as vomiting, and gagging could be reported as AEs. Added elevations in liver enzymes as an AE of interest. Clarified that male subjects were to report if their female partner became pregnant and that female subjects would be discontinued from study medication (not the study) if they became pregnant.
    06 Feb 2019
    Amendment 2 (Version 3: US version only): Extended open-label extension period from 96 weeks to 276 weeks. Added an exploratory assessment for research.
    23 May 2019
    Amendment 3 (Global Version 4): Clarified that the open-label extension period should have been 278 weeks (instead of 276). Clarified circumstances for which routine electrocardiograms may be waived for subjects using DBS devices. Added flexibility to waive the C-SSRS assessment based on the Polish’s principal investigator, judgement. Reduced the number of blood draws for exploratory assessment for research. Added analysis of PKAN-ADL at Week 3 to align with the statistical analysis plan.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    30 Dec 2019
    The sponsor made the decision to terminate the open label extension of the study after the results of the double blind period were analyzed and did not show efficacy. The primary efficacy endpoint was neither statistically significant nor clinically different between treatment and placebo.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    In the double-blind period, fosmetpantotenate did not show statistically significant effects or clinical benefits; hence, the open-label period of the study was terminated. So, only endpoints for double-blind period are presented.
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