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    Clinical Trial Results:
    A Phase III, Multicentre, Single-arm, Open-label Study to Evaluate the Long-term Safety of Z-338 in Subjects with Functional Dyspepsia

    Summary
    EudraCT number
    		 2013-003342-16
    Trial protocol
    		 BE   SK   GB   LV   LT   BG  
    Global end of trial date
    30 Sep 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Oct 2017
    First version publication date
    14 Oct 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    Z338-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01973790
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Zeria Pharmaceutical Co., Ltd. London Office
    Sponsor organisation address
    Building 3, Chiswick Park, 566 Chiswick High Road, London, United Kingdom, W4 5YA
    Public contact
    Project Manager, Zeria Pharmaceutical Co., Ltd. London Office, +81 336611183, tomoharu-miyagawa@zeria.co.jp
    Scientific contact
    Project Manager, Zeria Pharmaceutical Co., Ltd. London Office, +81 336611183, tomoharu-miyagawa@zeria.co.jp
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Jan 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Sep 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the long-term safety of 100 mg Z-338 three times a day (TID) in subjects with Functional Dyspepsia.
    Protection of trial subjects
    The study procedures outlined in this protocol will be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with the International Conference on Harmonisation (ICH) consolidated Guideline E6 for GCP, and applicable national/regional laws and regulatory requirement(s). In general, if a subject is injured as a direct result of the study drug, the Sponsor will pay for reasonable and necessary medical treatment for the injury, to the extent the expenses are not covered by the subject’s medical insurance, a government program, or other responsible third party. If laws or regulations of the locality in which the trial is taking place require additional payment of expenses, the Sponsor shall comply with such law or regulation. Where applicable, the Sponsor has taken specific national insurance.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Mar 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Latvia: 49
    Country: Number of subjects enrolled
    Russian Federation: 10
    Country: Number of subjects enrolled
    Ukraine: 35
    Country: Number of subjects enrolled
    Romania: 22
    Country: Number of subjects enrolled
    Slovakia: 21
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Bulgaria: 16
    Country: Number of subjects enrolled
    Lithuania: 41
    Worldwide total number of subjects
    207
    EEA total number of subjects
    162
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    196
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study Centers: Total of 62 sites initiated in 10 European countries: 1 in Belgium, 7 in Bulgaria, 8 in Latvia, 8 in Lithuania, 10 in Romania, 7 in Russia, 10 in Slovakia, 3 in Sweden, 5 in the Ukraine, and 3 in the United Kingdom. Study Period (‘First patient in’ to ‘Last patient out’): First patient in: 28-Mar-2014 Last patient out: 30-Sep-2016

    Pre-assignment
    Screening details
    		 Male and female patients who were at least 18 years old and with a diagnosis of FD (PDS) as defined by the ROME III criteria, who presented with early satiation or postprandial fullness with a severity of at least moderate and a frequency of at least 2 days a week during the run-in period

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not blinded

    Arms
    Arm title
    		 100 mg Z-338 group
    Arm description
    		 Subjects entering the open-label treatment period will receive Z-338 supplied as a white film-coated tablet containing 100 mg Z-338.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Acotiamide
    Investigational medicinal product code
    Z-338
    Other name
    Acofide
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects will take 1 tablet of 100 mg acotiamide TID before food (subjects should be encouraged to eat 3 meals a day, i.e. morning, afternoon and evening).

    Number of subjects in period 1
    		100 mg Z-338 group
    Started
    207
    Completed
    168
    Not completed
    39
         Consent withdrawn by subject
    12
         Adverse event, non-fatal
    6
         Other
    5
         Pregnancy
    1
         Lost to follow-up
    2
         Lack of efficacy
    7
         Protocol deviation
    3
         Noncompliance
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    100 mg Z-338 group
    Reporting group description
    		 Subjects entering the open-label treatment period will receive Z-338 supplied as a white film-coated tablet containing 100 mg Z-338.

    Reporting group values
    		 100 mg Z-338 group Total
    Number of subjects
    		 207 207
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 196 196
        From 65-84 years
    		 11 11
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 64 64
        Male
    		 143 143
    Subject analysis sets

    Subject analysis set title
    Safety analysis
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety Analysis Set Population: all enrolled subjects who receive at least one dose of open-label study treatment

    Subject analysis set title
    Full analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis Set Population: all enrolled subjects who receive at least one dose of open-label study treatment and have at least one post-baseline efficacy assessment.

    Subject analysis sets values
    		 Safety analysis Full analysis
    Number of subjects
    207
    207
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    196
    196
        From 65-84 years
    11
    11
        85 years and over
    0
    0
    Age continuous
    Units: years
        median (full range (min-max))
    Gender categorical
    Units: Subjects
        Female
    64
    64
        Male
    143
    143

    End points

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    End points reporting groups
    Reporting group title
    100 mg Z-338 group
    Reporting group description
    		 Subjects entering the open-label treatment period will receive Z-338 supplied as a white film-coated tablet containing 100 mg Z-338.

    Subject analysis set title
    Safety analysis
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Safety Analysis Set Population: all enrolled subjects who receive at least one dose of open-label study treatment

    Subject analysis set title
    Full analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full Analysis Set Population: all enrolled subjects who receive at least one dose of open-label study treatment and have at least one post-baseline efficacy assessment.

    Primary: Safety - number of subjects with AEs

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    End point title
    		 Safety - number of subjects with AEs [1]
    End point description
    End point type
    Primary
    End point timeframe
    Treatment-emergent Adverse events (TEAEs) will be monitored throughout the study for all subjects from the time of signing informed consent until 2 weeks after the End of Treatment (Visit 11 [Week 52]) or Early Termination visit, as applicable
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analyses not applicable due to the nature of the trial
    End point values
    		 100 mg Z-338 group
    Number of subjects analysed
    207
    Units: subjects
        Patients with at least 1 TEAE
    92
        Patients with at least 1 Treatment related TEAE
    18
        Patients with at least 1 Serious TEAE
    6
        Patients with at least 1 TEAE led to discontinue
    7
        Deaths
    0
    No statistical analyses for this end point

    Secondary: Change from baseline in Early satiation by time point

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    End point title
    		 Change from baseline in Early satiation by time point
    End point description
    Subjects will be asked to record the severity of each individual FD symptom on a daily basis during the 7-day run-in period (Visit 2 [Week -1] to Visit 3 [Week 0]) using the LPDS incorporated in an ePRO system. During the open-label treatment period, subjects will be asked to record the severity of each individual symptom on a daily basis from Visit 3 (Week 0) to Visit 6 (Week 12), Visit 7 (Week 24) to Visit 8 (Week 26), and Visit 10 (Week 50) to Visit 11 (Week 52), using the LPDS incorporated in an ePRO system. The LPDS has been developed and validated by Professor Jan Tack of the University of Leuven, Belgium.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11, Week 12, Week 25, Week 26, Week 51, Week 52, End of treatment
    End point values
    		 100 mg Z-338 group
    Number of subjects analysed
    207
    Units: Score
    arithmetic mean (standard deviation)
        Week 1
    -0.46 ( 0.649 )
        Week 2
    -0.65 ( 0.769 )
        Week 3
    -0.76 ( 0.841 )
        Week 4
    -0.85 ( 0.839 )
        Week 5
    -0.86 ( 0.839 )
        Week 6
    -0.89 ( 0.893 )
        Week 7
    -0.93 ( 0.859 )
        Week 8
    -0.99 ( 0.896 )
        Week 9
    -1.05 ( 0.896 )
        Week 10
    -1.06 ( 0.909 )
        Week 11
    -1.07 ( 0.883 )
        Week 12
    -1.16 ( 0.91 )
        Week 25
    -1.3 ( 0.912 )
        Week 26
    -1.35 ( 0.929 )
        Week 51
    -1.46 ( 0.977 )
        Week 52
    -1.48 ( 0.979 )
        End of treatment
    -1.38 ( 0.975 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Postprandial fullness by time point

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    End point title
    		 Change from baseline in Postprandial fullness by time point
    End point description
    "Subjects will be asked to record the severity of each individual FD symptom on a daily basis during the 7-day run-in period (Visit 2 [Week -1] to Visit 3 [Week 0]) using the LPDS incorporated in an ePRO system. During the open-label treatment period, subjects will be asked to record the severity of each individual symptom on a daily basis from Visit 3 (Week 0) to Visit 6 (Week 12), Visit 7 (Week 24) to Visit 8 (Week 26), and Visit 10 (Week 50) to Visit 11 (Week 52), using the LPDS incorporated in an ePRO system. The LPDS has been developed and validated by Professor Jan Tack of the University of Leuven, Belgium."
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11, Week 12, Week 25, Week 26, Week 51, Week 52, End of treatment
    End point values
    		 100 mg Z-338 group
    Number of subjects analysed
    207
    Units: Score
    arithmetic mean (standard deviation)
        Week 1
    -0.57 ( 0.666 )
        Week 2
    -0.71 ( 0.801 )
        Week 3
    -0.91 ( 0.84 )
        Week 4
    -1.04 ( 0.848 )
        Week 5
    -1.08 ( 0.849 )
        Week 6
    -1.09 ( 0.85 )
        Week 7
    -1.15 ( 0.891 )
        Week 8
    -1.22 ( 0.906 )
        Week 9
    -1.27 ( 0.903 )
        Week 10
    -1.32 ( 0.904 )
        Week 11
    -1.37 ( 0.899 )
        Week 12
    -1.4 ( 0.893 )
        Week 25
    -1.58 ( 0.867 )
        Week 26
    -1.62 ( 0.895 )
        Week 51
    -1.8 ( 0.886 )
        Week 52
    -1.81 ( 0.909 )
        End of treatment
    -1.69 ( 0.941 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Upper Abdominal Bloating by time point

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    End point title
    		 Change from baseline in Upper Abdominal Bloating by time point
    End point description
    "Subjects will be asked to record the severity of each individual FD symptom on a daily basis during the 7-day run-in period (Visit 2 [Week -1] to Visit 3 [Week 0]) using the LPDS incorporated in an ePRO system. During the open-label treatment period, subjects will be asked to record the severity of each individual symptom on a daily basis from Visit 3 (Week 0) to Visit 6 (Week 12), Visit 7 (Week 24) to Visit 8 (Week 26), and Visit 10 (Week 50) to Visit 11 (Week 52), using the LPDS incorporated in an ePRO system. The LPDS has been developed and validated by Professor Jan Tack of the University of Leuven, Belgium."
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11, Week 12, Week 25, Week 26, Week 51, Week 52, End of treatment
    End point values
    		 100 mg Z-338 group
    Number of subjects analysed
    207
    Units: Score
    arithmetic mean (standard deviation)
        Week 1
    -0.16 ( 0.612 )
        Week 2
    -0.31 ( 0.689 )
        Week 3
    -0.34 ( 0.746 )
        Week 4
    -0.39 ( 0.773 )
        Week 5
    -0.42 ( 0.781 )
        Week 6
    -0.45 ( 0.834 )
        Week 7
    -0.49 ( 0.839 )
        Week 8
    -0.5 ( 0.855 )
        Week 9
    -0.54 ( 0.778 )
        Week 10
    -0.56 ( 0.812 )
        Week 11
    -0.6 ( 0.789 )
        Week 12
    -0.59 ( 0.739 )
        Week 25
    -0.71 ( 0.855 )
        Week 26
    -0.73 ( 0.895 )
        Week 51
    -0.84 ( 0.847 )
        Week 52
    -0.85 ( 0.874 )
        End of treatment
    -0.8 ( 0.904 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Epigastric Pain by time point

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    End point title
    		 Change from baseline in Epigastric Pain by time point
    End point description
    "Subjects will be asked to record the severity of each individual FD symptom on a daily basis during the 7-day run-in period (Visit 2 [Week -1] to Visit 3 [Week 0]) using the LPDS incorporated in an ePRO system. During the open-label treatment period, subjects will be asked to record the severity of each individual symptom on a daily basis from Visit 3 (Week 0) to Visit 6 (Week 12), Visit 7 (Week 24) to Visit 8 (Week 26), and Visit 10 (Week 50) to Visit 11 (Week 52), using the LPDS incorporated in an ePRO system. The LPDS has been developed and validated by Professor Jan Tack of the University of Leuven, Belgium."
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11, Week 12, Week 25, Week 26, Week 51, Week 52, End of treatment
    End point values
    		 100 mg Z-338 group
    Number of subjects analysed
    207
    Units: Score
    arithmetic mean (standard deviation)
        Week 1
    0.13 ( 0.457 )
        Week 2
    0.11 ( 0.447 )
        Week 3
    0.1 ( 0.464 )
        Week 4
    0.09 ( 0.453 )
        Week 5
    0.1 ( 0.529 )
        Week 6
    0.11 ( 0.518 )
        Week 7
    0.06 ( 0.474 )
        Week 8
    0.08 ( 0.535 )
        Week 9
    0.03 ( 0.4 )
        Week 10
    0.02 ( 0.382 )
        Week 11
    0.02 ( 0.362 )
        Week 12
    0.01 ( 0.367 )
        Week 25
    0.02 ( 0.375 )
        Week 26
    0.02 ( 0.387 )
        Week 51
    -0.02 ( 0.352 )
        Week 52
    -0.01 ( 0.384 )
        End of treatment
    0.02 ( 0.506 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Epigastric Burning by time point

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    End point title
    		 Change from baseline in Epigastric Burning by time point
    End point description
    "Subjects will be asked to record the severity of each individual FD symptom on a daily basis during the 7-day run-in period (Visit 2 [Week -1] to Visit 3 [Week 0]) using the LPDS incorporated in an ePRO system. During the open-label treatment period, subjects will be asked to record the severity of each individual symptom on a daily basis from Visit 3 (Week 0) to Visit 6 (Week 12), Visit 7 (Week 24) to Visit 8 (Week 26), and Visit 10 (Week 50) to Visit 11 (Week 52), using the LPDS incorporated in an ePRO system. The LPDS has been developed and validated by Professor Jan Tack of the University of Leuven, Belgium."
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11, Week 12, Week 25, Week 26, Week 51, Week 52, End of treatment
    End point values
    		 100 mg Z-338 group
    Number of subjects analysed
    207
    Units: Score
    arithmetic mean (standard deviation)
        Week 1
    0.08 ( 0.349 )
        Week 2
    0.08 ( 0.349 )
        Week 3
    0.09 ( 0.375 )
        Week 4
    0.07 ( 0.322 )
        Week 5
    0.09 ( 0.374 )
        Week 6
    0.11 ( 0.419 )
        Week 7
    0.08 ( 0.384 )
        Week 8
    0.11 ( 0.406 )
        Week 9
    0.07 ( 0.258 )
        Week 10
    0.06 ( 0.249 )
        Week 11
    0.04 ( 0.237 )
        Week 12
    0.04 ( 0.231 )
        Week 25
    0.06 ( 0.233 )
        Week 26
    0.06 ( 0.262 )
        Week 51
    0.01 ( 0.21 )
        Week 52
    0.02 ( 0.286 )
        End of treatment
    0.06 ( 0.418 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Belching by time point

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    End point title
    		 Change from baseline in Belching by time point
    End point description
    "Subjects will be asked to record the severity of each individual FD symptom on a daily basis during the 7-day run-in period (Visit 2 [Week -1] to Visit 3 [Week 0]) using the LPDS incorporated in an ePRO system. During the open-label treatment period, subjects will be asked to record the severity of each individual symptom on a daily basis from Visit 3 (Week 0) to Visit 6 (Week 12), Visit 7 (Week 24) to Visit 8 (Week 26), and Visit 10 (Week 50) to Visit 11 (Week 52), using the LPDS incorporated in an ePRO system. The LPDS has been developed and validated by Professor Jan Tack of the University of Leuven, Belgium."
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11, Week 12, Week 25, Week 26, Week 51, Week 52, End of treatment
    End point values
    		 100 mg Z-338 group
    Number of subjects analysed
    207
    Units: Score
    arithmetic mean (standard deviation)
        Week 1
    0.01 ( 0.589 )
        Week 2
    -0.04 ( 0.599 )
        Week 3
    -0.07 ( 0.628 )
        Week 4
    -0.1 ( 0.616 )
        Week 5
    -0.07 ( 0.651 )
        Week 6
    -0.1 ( 0.679 )
        Week 7
    -0.12 ( 0.645 )
        Week 8
    -0.14 ( 0.644 )
        Week 9
    -0.15 ( 0.638 )
        Week 10
    -0.18 ( 0.606 )
        Week 11
    -0.2 ( 0.606 )
        Week 12
    -0.18 ( 0.621 )
        Week 25
    -0.22 ( 0.688 )
        Week 26
    -0.22 ( 0.655 )
        Week 51
    -0.29 ( 0.656 )
        Week 52
    -0.28 ( 0.665 )
        End of treatment
    -0.23 ( 0.71 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Nausea by time point

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    End point title
    		 Change from baseline in Nausea by time point
    End point description
    "Subjects will be asked to record the severity of each individual FD symptom on a daily basis during the 7-day run-in period (Visit 2 [Week -1] to Visit 3 [Week 0]) using the LPDS incorporated in an ePRO system. During the open-label treatment period, subjects will be asked to record the severity of each individual symptom on a daily basis from Visit 3 (Week 0) to Visit 6 (Week 12), Visit 7 (Week 24) to Visit 8 (Week 26), and Visit 10 (Week 50) to Visit 11 (Week 52), using the LPDS incorporated in an ePRO system. The LPDS has been developed and validated by Professor Jan Tack of the University of Leuven, Belgium."
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11, Week 12, Week 25, Week 26, Week 51, Week 52, End of treatment
    End point values
    		 100 mg Z-338 group
    Number of subjects analysed
    207
    Units: Score
    arithmetic mean (standard deviation)
        Week 1
    0 ( 0.425 )
        Week 2
    -0.02 ( 0.448 )
        Week 3
    -0.01 ( 0.435 )
        Week 4
    -0.01 ( 0.441 )
        Week 5
    0.02 ( 0.447 )
        Week 6
    0.01 ( 0.473 )
        Week 7
    0 ( 0.454 )
        Week 8
    0 ( 0.472 )
        Week 9
    -0.02 ( 0.41 )
        Week 10
    -0.06 ( 0.381 )
        Week 11
    -0.06 ( 0.38 )
        Week 12
    -0.1 ( 0.366 )
        Week 25
    -0.07 ( 0.376 )
        Week 26
    -0.06 ( 0.404 )
        Week 51
    -0.1 ( 0.365 )
        Week 52
    -0.1 ( 0.358 )
        End of treatment
    -0.05 ( 0.475 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Heartburn by time point

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    End point title
    		 Change from baseline in Heartburn by time point
    End point description
    "Subjects will be asked to record the severity of each individual FD symptom on a daily basis during the 7-day run-in period (Visit 2 [Week -1] to Visit 3 [Week 0]) using the LPDS incorporated in an ePRO system. During the open-label treatment period, subjects will be asked to record the severity of each individual symptom on a daily basis from Visit 3 (Week 0) to Visit 6 (Week 12), Visit 7 (Week 24) to Visit 8 (Week 26), and Visit 10 (Week 50) to Visit 11 (Week 52), using the LPDS incorporated in an ePRO system. The LPDS has been developed and validated by Professor Jan Tack of the University of Leuven, Belgium."
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11, Week 12, Week 25, Week 26, Week 51, Week 52, End of treatment
    End point values
    		 100 mg Z-338 group
    Number of subjects analysed
    207
    Units: Score
    arithmetic mean (standard deviation)
        Week 1
    0.08 ( 0.331 )
        Week 2
    0.1 ( 0.354 )
        Week 3
    0.08 ( 0.358 )
        Week 4
    0.07 ( 0.302 )
        Week 5
    0.09 ( 0.37 )
        Week 6
    0.12 ( 0.04 )
        Week 7
    0.09 ( 0.356 )
        Week 8
    0.09 ( 0.364 )
        Week 9
    0.06 ( 0.227 )
        Week 10
    0.07 ( 0.237 )
        Week 11
    0.06 ( 0.234 )
        Week 12
    0.04 ( 0.217 )
        Week 25
    0.05 ( 0.18 )
        Week 26
    0.04 ( 0.204 )
        Week 51
    0.04 ( 0.178 )
        Week 52
    0.05 ( 0.273 )
        End of treatment
    0.07 ( 0.383 )
    No statistical analyses for this end point

    Secondary: Overall treatment evaluation by time point

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    End point title
    		 Overall treatment evaluation by time point
    End point description
    The OTE will be used to measure subjects’ global outcome on a weekly basis, from the start of open-label treatment (Day 1 to Visit 6 [Week 12], Visit 7 [Week 24] to Visit 8 [Week 26], and Visit 10 [Week 50] to Visit 11 [Week 52]).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, Week 2, Week 3, Week 4, Week 5, Week 6, Week 7, Week 8, Week 9, Week 10, Week 11, Week 12, Week 25, Week 26, Week 51, Week 52, End of treatment
    End point values
    		 100 mg Z-338 group
    Number of subjects analysed
    207
    Units: Improvement rate
    number (confidence interval 95%)
        Week 1
    13.1 (8.6 to 18.9)
        Week 2
    18.7 (13.4 to 24.9)
        Week 3
    21 (15.5 to 27.4)
        Week 4
    26.2 (20.1 to 33)
        Week 5
    26.9 (20.6 to 34)
        Week 6
    33.3 (26.6 to 40.6)
        Week 7
    32.2 (25.5 to 39.5)
        Week 8
    39.1 (32 to 46.6)
        Week 9
    41.2 (34 to 48.7)
        Week 10
    45.7 (38.2 to 53.4)
        Week 11
    40.6 (33.2 to 48.2)
        Week 12
    41.5 (30.7 to 52.9)
        Week 25
    52.9 (45.1 to 60.6)
        Week 26
    50.3 (42.3 to 58.3)
        Week 51
    70.6 (62.9 to 77.6)
        Week 52
    70.2 (62.2 to 77.4)
        End of treatment
    61.6 (54.5 to 68.3)
    No statistical analyses for this end point

    Secondary: Change from baseline in SF-36 physical component by time point

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    End point title
    		 Change from baseline in SF-36 physical component by time point
    End point description
    The SF-36 is a 36-item survey that includes 1 multi-item scale measuring each of the following 8 health concepts: 1) physical functioning; 2) role limitations because of physical health problems; 3) bodily pain; 4) social functioning; 5) general mental health; 6) role limitations because of emotional problems; 7) vitality; and 8) general health perceptions.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 26, Week 38, Week 52, End of treatment
    End point values
    		 100 mg Z-338 group
    Number of subjects analysed
    207
    Units: Score
    arithmetic mean (standard deviation)
        Week 12
    3.4 ( 7.09 )
        Week 26
    4.5 ( 7.19 )
        Week 38
    4.4 ( 7.25 )
        Week 52
    5.2 ( 7.54 )
        End of treatment
    4.2 ( 7.43 )
    No statistical analyses for this end point

    Secondary: Change from baseline in SF-36 mental component by time point

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    End point title
    		 Change from baseline in SF-36 mental component by time point
    End point description
    The SF-36 is a 36-item survey that includes 1 multi-item scale measuring each of the following 8 health concepts: 1) physical functioning; 2) role limitations because of physical health problems; 3) bodily pain; 4) social functioning; 5) general mental health; 6) role limitations because of emotional problems; 7) vitality; and 8) general health perceptions.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 26, Week 38, Week 52, End of treatment
    End point values
    		 100 mg Z-338 group
    Number of subjects analysed
    207
    Units: Score
    arithmetic mean (standard deviation)
        Week 12
    4.2 ( 11.03 )
        Week 26
    6.5 ( 11.07 )
        Week 38
    6.1 ( 10.36 )
        Week 52
    7.6 ( 11.31 )
        End of treatment
    5.7 ( 10.68 )
    No statistical analyses for this end point

    Secondary: Change from baseline in SF-NDI scale (total) by time point

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    End point title
    		 Change from baseline in SF-NDI scale (total) by time point
    End point description
    The SF-NDI comprises a 15-symptom checklist and a 10-item survey specifically for FD measuring symptoms and health-related QoL. For the symptom checklist, subjects will be asked to score the frequency, intensity and bothersomeness of 15 upper gastrointestinal symptoms. For the 10-item QoL survey, subjects will be asked to answer 2 questions in each of 5 clinically relevant factors (subscales): tension; interference with daily activities; eating/drinking; knowledge/control; and work/study.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 26, Week 38, Week 52, End of treatment
    End point values
    		 100 mg Z-338 group
    Number of subjects analysed
    207
    Units: Score
    arithmetic mean (standard deviation)
        Week 12
    -0.9 ( 0.9 )
        Week 26
    -1 ( 0.89 )
        Week 38
    -1 ( 0.86 )
        Week 52
    -1.1 ( 0.86 )
        End of treatment
    -1 ( 0.84 )
    No statistical analyses for this end point

    Secondary: Change from baseline in WPAI absenteeism by time point

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    End point title
    		 Change from baseline in WPAI absenteeism by time point
    End point description
    The WPAI is an assessment of the amount of absenteeism (work time missed), presenteeism (impairment at work/reduced on-the-job effectiveness) and activity impairment. Subjects will be asked to answer a maximum of 6 questions on whether they are currently employed; hours missed due to health problems; hours missed due to other reasons; hours actually worked; degree that health affected productivity while working; and the degree that health affected regular activities.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 26, Week 38, Week 52, End of treatment
    End point values
    		 100 mg Z-338 group
    Number of subjects analysed
    207
    Units: Score
    arithmetic mean (standard deviation)
        Week 12
    0.7 ( 17.37 )
        Week 26
    -1 ( 13.29 )
        Week 38
    1.3 ( 15.54 )
        Week 52
    0.2 ( 15.27 )
        End of treatment
    0.9 ( 14.66 )
    No statistical analyses for this end point

    Secondary: Change from baseline in WPAI presenteeism by time point

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    End point title
    		 Change from baseline in WPAI presenteeism by time point
    End point description
    The WPAI is an assessment of the amount of absenteeism (work time missed), presenteeism (impairment at work/reduced on-the-job effectiveness) and activity impairment. Subjects will be asked to answer a maximum of 6 questions on whether they are currently employed; hours missed due to health problems; hours missed due to other reasons; hours actually worked; degree that health affected productivity while working; and the degree that health affected regular activities.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 26, Week 38, Week 52, End of treatment
    End point values
    		 100 mg Z-338 group
    Number of subjects analysed
    207
    Units: Score
    arithmetic mean (standard deviation)
        Week 12
    -11.9 ( 21.81 )
        Week 26
    -14.2 ( 23.27 )
        Week 38
    -13.9 ( 25.48 )
        Week 52
    -15.5 ( 19.94 )
        End of treatment
    -13.4 ( 24.54 )
    No statistical analyses for this end point

    Secondary: Change from baseline in WPAI work productivity loss by time point

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    End point title
    		 Change from baseline in WPAI work productivity loss by time point
    End point description
    The WPAI is an assessment of the amount of absenteeism (work time missed), presenteeism (impairment at work/reduced on-the-job effectiveness) and activity impairment. Subjects will be asked to answer a maximum of 6 questions on whether they are currently employed; hours missed due to health problems; hours missed due to other reasons; hours actually worked; degree that health affected productivity while working; and the degree that health affected regular activities.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 26, Week 38, Week 52, End of treatment
    End point values
    		 100 mg Z-338 group
    Number of subjects analysed
    207
    Units: Score
    arithmetic mean (standard deviation)
        Week 12
    -10.9 ( 23.85 )
        Week 26
    -13.4 ( 24.76 )
        Week 38
    -12.6 ( 27.23 )
        Week 52
    -14 ( 23.36 )
        End of treatment
    -12.4 ( 26.11 )
    No statistical analyses for this end point

    Secondary: Change from baseline in WPAI activity impairment by time point

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    End point title
    		 Change from baseline in WPAI activity impairment by time point
    End point description
    The WPAI is an assessment of the amount of absenteeism (work time missed), presenteeism (impairment at work/reduced on-the-job effectiveness) and activity impairment. Subjects will be asked to answer a maximum of 6 questions on whether they are currently employed; hours missed due to health problems; hours missed due to other reasons; hours actually worked; degree that health affected productivity while working; and the degree that health affected regular activities.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 26, Week 38, Week 52, End of treatment
    End point values
    		 100 mg Z-338 group
    Number of subjects analysed
    207
    Units: Score
    arithmetic mean (standard deviation)
        Week 12
    -12.4 ( 24.44 )
        Week 26
    -16.7 ( 25.16 )
        Week 38
    -15.1 ( 25.7 )
        Week 52
    -17.2 ( 24.56 )
        End of treatment
    -15.1 ( 25.14 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events will be monitored throughout the study for all subjects from the time of signing informed consent and will continue until 2 weeks after the End of Treatment (Visit 11 [Week 52]) or Early Termination visit, as applicable.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    100 mg Z-338 group
    Reporting group description
    		 -

    Serious adverse events
    		 100 mg Z-338 group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 207 (2.90%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Ovarian cancer
         subjects affected / exposed
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Prostate cancer stage I
         subjects affected / exposed
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Ligament rupture
         subjects affected / exposed
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Ileus
         subjects affected / exposed
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Uterine haemorrhage
         subjects affected / exposed
    1 / 207 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 100 mg Z-338 group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 207 (17.87%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    14 / 207 (6.76%)
         occurrences all number
    17
    Infections and infestations
    Influenza
         subjects affected / exposed
    15 / 207 (7.25%)
         occurrences all number
    15
    Nasopharyngitis
         subjects affected / exposed
    12 / 207 (5.80%)
         occurrences all number
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Aug 2015
    Modification 1: The CRO Project Physician was changed from Dr Tandy Amure to Dr Katerina Cooper. Modification 2: The language on sample size was modified to reduce the total number of subjects to be screened due to challenges in recruitment. Modification 3: The reference to the ICH E1 Guideline was updated for clarity.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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