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    Clinical Trial Results:
    An Open-Label Extension Study of DS-5565 for 52 Weeks in Pain Associated with Fibromyalgia

    Summary
    EudraCT number
    		 2013-005164-26
    Trial protocol
    		 GB   SE   DK   AT   SK   EE   CZ   ES   LT   HU   LV   PT   SI   FI   BG   PL  
    Global end of trial date
    19 Apr 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Apr 2018
    First version publication date
    18 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DS5565-A-E312
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02234583
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Daiichi Sankyo, Inc.
    Sponsor organisation address
    211 Mt. Airy Road, Basking Ridge, New Jersey, United States, 07920
    Public contact
    Clinical Trial Information Contact, Daiichi Sankyo, Inc, +1 7325905000, eu_cta@dsi.com
    Scientific contact
    Clinical Trial Information Contact, Daiichi Sankyo, Inc, +1 7325905000, eu_cta@dsi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Jul 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial is to assess the long-term safety of DS-5565 in subjects with fibromyalgia (FM). This is an open-label study of DS-5565 in subjects who either completed participation in a preceding Phase 3 study of DS-5565 in fibromyalgia (FM); ie, DS5565-A-E309, DS5565-A-E310, or DS5565-A-E311 or are de novo subjects. Eligible subjects will be assigned to receive open-label DS-5565 for 52 weeks, with a 4-week follow-up period. All subjects will receive DS-5565 15 mg once daily (QD) for the first three weeks of the treatment period. After three weeks, subjects may be titrated to 15 mg twice daily (BID) based on protocol-specified criteria.
    Protection of trial subjects
    The study was conducted in compliance with ethical principles that have their origin in the Declaration of Helsinki and in accordance with the following as appropriate: - European Union Commission Directive (2001/20/EC Apr 2001) - European Union Commission Directive (2005/28/EC Apr 2005) - ICH E6 Good Clinical Practice (GCP) Guideline - US Food and Drug Administration (FDA) Regulations
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Feb 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 42
    Country: Number of subjects enrolled
    Poland: 40
    Country: Number of subjects enrolled
    Portugal: 4
    Country: Number of subjects enrolled
    Romania: 4
    Country: Number of subjects enrolled
    Slovakia: 18
    Country: Number of subjects enrolled
    Slovenia: 7
    Country: Number of subjects enrolled
    Spain: 27
    Country: Number of subjects enrolled
    United Kingdom: 41
    Country: Number of subjects enrolled
    Austria: 15
    Country: Number of subjects enrolled
    Bulgaria: 20
    Country: Number of subjects enrolled
    Czech Republic: 38
    Country: Number of subjects enrolled
    Denmark: 12
    Country: Number of subjects enrolled
    Estonia: 10
    Country: Number of subjects enrolled
    Finland: 1
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Germany: 38
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    Latvia: 19
    Country: Number of subjects enrolled
    Lithuania: 4
    Country: Number of subjects enrolled
    Australia: 13
    Country: Number of subjects enrolled
    Canada: 52
    Country: Number of subjects enrolled
    Chile: 5
    Country: Number of subjects enrolled
    New Zealand: 18
    Country: Number of subjects enrolled
    Russian Federation: 11
    Country: Number of subjects enrolled
    Serbia: 3
    Country: Number of subjects enrolled
    South Africa: 19
    Country: Number of subjects enrolled
    Ukraine: 132
    Country: Number of subjects enrolled
    United States: 1482
    Worldwide total number of subjects
    2088
    EEA total number of subjects
    353
    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)
    1878
    From 65 to 84 years
    208
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Of 2485 patients enrolled, 2088 were treated in 28 countries and comprise the safety analysis set.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DS-5565 15 mg QD Modal
    Arm description
    		 Patients are reported under their modal treatment, ie, the treatment they received most frequently, which was DS-5565 15 mg once daily (QD).
    Arm type
    		 Experimental

    Investigational medicinal product name
    DS-5565 Tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral administration of 15 mg tablets once daily (QD)

    Arm title
    		 DS-5565 15 mg BID Modal
    Arm description
    		 Patients are reported under their modal treatment, ie, the treatment they received most frequently, which was DS-5565 15 mg twice daily (BID).
    Arm type
    		 Experimental

    Investigational medicinal product name
    DS-5565 Tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    DS-5565 15 mg twice daily (BID)

    Number of subjects in period 1
    		DS-5565 15 mg QD Modal DS-5565 15 mg BID Modal
    Started
    847
    1241
    Completed
    434
    685
    Not completed
    413
    556
         Consent withdrawn by subject
    109
    157
         Adverse event, non-fatal
    172
    156
         Lost to follow-up
    -
    1
         Lack of efficacy
    58
    103
         Protocol deviation
    35
    42
         No reason provided
    39
    97

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    DS-5565 15 mg QD Modal
    Reporting group description
    		 Patients are reported under their modal treatment, ie, the treatment they received most frequently, which was DS-5565 15 mg once daily (QD).

    Reporting group title
    DS-5565 15 mg BID Modal
    Reporting group description
    		 Patients are reported under their modal treatment, ie, the treatment they received most frequently, which was DS-5565 15 mg twice daily (BID).

    Reporting group values
    		 DS-5565 15 mg QD Modal DS-5565 15 mg BID Modal Total
    Number of subjects
    		 847 1241 2088
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.4 ± 11.18 49.3 ± 11.94 -
    Gender categorical
    Units: Subjects
        Female
    		 770 1130 1900
        Male
    		 77 111 188
    Baseline HADS Anxiety Subscale Score
    Units: Subjects
        Non-case (0-7)
    		 526 666 1192
        Borderline case (8-10)
    		 160 260 420
        Case (11 or more)
    		 100 239 339
        Missing
    		 61 76 137
    Baseline HADS Depression Subscale Score
    Units: Subjects
        Non-case (0-7)
    		 555 757 1312
        Borderline case (8-10)
    		 130 211 341
        Case (11 or more)
    		 101 197 298
        Missing
    		 61 76 137
    History of Psychological Disorder or Depression
    Units: Subjects
        Yes
    		 271 492 763
        No
    		 576 749 1325

    End points

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    End points reporting groups
    Reporting group title
    DS-5565 15 mg QD Modal
    Reporting group description
    		 Patients are reported under their modal treatment, ie, the treatment they received most frequently, which was DS-5565 15 mg once daily (QD).

    Reporting group title
    DS-5565 15 mg BID Modal
    Reporting group description
    		 Patients are reported under their modal treatment, ie, the treatment they received most frequently, which was DS-5565 15 mg twice daily (BID).

    Primary: Number of Patients with Treatment-emergent Adverse Events (TEAEs) as a Measure of Safety

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    End point title
    		 Number of Patients with Treatment-emergent Adverse Events (TEAEs) as a Measure of Safety [1]
    End point description
    Note: Further measures of safety and relatedness to drug are found in the AE module.
    End point type
    Primary
    End point timeframe
    Baseline to Week 52
    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: No further analysis was performed for this summary data.
    End point values
    		 DS-5565 15 mg QD Modal DS-5565 15 mg BID Modal
    Number of subjects analysed
    847
    1241
    Units: Patients
    669
    1056
    No statistical analyses for this end point

    Secondary: Change from Baseline in Average Daily Pain Score (ADPS) at Week 13 (Rollover)

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    End point title
    		 Change from Baseline in Average Daily Pain Score (ADPS) at Week 13 (Rollover)
    End point description
    The primary efficacy assessment was subject-reported pain intensity, recorded in an electronic daily diary using an 11-point numerical rating scale (NRS) ranging from 0 (no pain) to 10 (worst possible pain).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 13
    End point values
    		 DS-5565 15 mg QD Modal DS-5565 15 mg BID Modal
    Number of subjects analysed
    396
    794
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -1.03 ± 1.747
    -1.08 ± 1.800
    No statistical analyses for this end point

    Secondary: Change from Baseline in ADPS at Week 52 (Rollover)

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    End point title
    		 Change from Baseline in ADPS at Week 52 (Rollover)
    End point description
    The primary efficacy assessment was subject-reported pain intensity, recorded in an electronic daily diary using an 11-point numerical rating scale (NRS) ranging from 0 (no pain) to 10 (worst possible pain).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 DS-5565 15 mg QD Modal DS-5565 15 mg BID Modal
    Number of subjects analysed
    244
    428
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -1.14 ± 2.089
    -1.06 ± 1.995
    No statistical analyses for this end point

    Secondary: Change from Baseline in ADPS at Week 13 (De Novo)

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    End point title
    		 Change from Baseline in ADPS at Week 13 (De Novo)
    End point description
    The primary efficacy assessment was subject-reported pain intensity, recorded in an electronic daily diary using an 11-point numerical rating scale (NRS) ranging from 0 (no pain) to 10 (worst possible pain).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 13
    End point values
    		 DS-5565 15 mg QD Modal DS-5565 15 mg BID Modal
    Number of subjects analysed
    165
    237
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -3.66 ± 2.109
    -3.26 ± 2.326
    No statistical analyses for this end point

    Secondary: Change from Baseline in ADPS at Week 52 (De Novo)

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    End point title
    		 Change from Baseline in ADPS at Week 52 (De Novo)
    End point description
    The primary efficacy assessment was subject-reported pain intensity, recorded in an electronic daily diary using an 11-point numerical rating scale (NRS) ranging from 0 (no pain) to 10 (worst possible pain).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 DS-5565 15 mg QD Modal DS-5565 15 mg BID Modal
    Number of subjects analysed
    109
    121
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -4.41 ± 1.975
    -3.39 ± 2.597
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 13 in Average Daily Sleep Interference Score (ADSIS) - (Rollover)

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    End point title
    		 Change from Baseline to Week 13 in Average Daily Sleep Interference Score (ADSIS) - (Rollover)
    End point description
    ADSIS is assessed on an 11-point numeric rating scale ranging from 0=pain does not interfere with sleep to 10=pain completely interferes with sleep, unable to sleep. Note: The ADSIS was the mean value of all available reporting of the respective week. As Baseline was used: For Rollover subjects, scores from the End-of-Tapering visit in the preceding study, and for De Novo subjects, scores recorded during the 7 days prior to start of treatment. Note: Subjects were reported under their Modal treatment, ie, the treatment they received most frequently.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 13
    End point values
    		 DS-5565 15 mg QD Modal DS-5565 15 mg BID Modal
    Number of subjects analysed
    396
    794
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -1.06 ± 1.710
    -1.41 ± 1.942
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 52 in ADSIS (Rollover)

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    End point title
    		 Change from Baseline to Week 52 in ADSIS (Rollover)
    End point description
    ADSIS is assessed on an 11-point numeric rating scale ranging from 0=pain does not interfere with sleep to 10=pain completely interferes with sleep, unable to sleep. Note: The ADSIS was the mean value of all available reporting of the respective week. As Baseline was used: For Rollover subjects, scores from the End-of-Tapering visit in the preceding study, and for De Novo subjects, scores recorded during the 7 days prior to start of treatment. Note: Subjects were reported under their Modal treatment, ie, the treatment they received most frequently.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 DS-5565 15 mg QD Modal DS-5565 15 mg BID Modal
    Number of subjects analysed
    244
    428
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -1.25 ± 1.968
    -1.31 ± 2.102
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 13 in ADSIS (De Novo)

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    End point title
    		 Change from Baseline to Week 13 in ADSIS (De Novo)
    End point description
    ADSIS is assessed on an 11-point numeric rating scale ranging from 0=pain does not interfere with sleep to 10=pain completely interferes with sleep, unable to sleep. Note: The ADSIS was the mean value of all available reporting of the respective week. As Baseline was used: For Rollover subjects, scores from the End-of-Tapering visit in the preceding study, and for De Novo subjects, scores recorded during the 7 days prior to start of treatment. Note: Subjects were reported under their Modal treatment, ie, the treatment they received most frequently.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 13
    End point values
    		 DS-5565 15 mg QD Modal DS-5565 15 mg BID Modal
    Number of subjects analysed
    165
    237
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -3.98 ± 2.126
    -3.64 ± 2.297
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 52 in ADSIS (De Novo)

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    End point title
    		 Change from Baseline to Week 52 in ADSIS (De Novo)
    End point description
    ADSIS is assessed on an 11-point numeric rating scale ranging from 0=pain does not interfere with sleep to 10=pain completely interferes with sleep, unable to sleep. Note: The ADSIS was the mean value of all available reporting of the respective week. As Baseline was used: For Rollover subjects, scores from the End-of-Tapering visit in the preceding study, and for De Novo subjects, scores recorded during the 7 days prior to start of treatment. Note: Subjects were reported under their Modal treatment, ie, the treatment they received most frequently.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 DS-5565 15 mg QD Modal DS-5565 15 mg BID Modal
    Number of subjects analysed
    109
    121
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -4.61 ± 1.996
    -3.54 ± 2.537
    No statistical analyses for this end point

    Secondary: Number of Patients with Improvement in Overall Status at Week 52 as Assessed by Patient Global Impression of Change (PGIC) - (Rollover)

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    End point title
    		 Number of Patients with Improvement in Overall Status at Week 52 as Assessed by Patient Global Impression of Change (PGIC) - (Rollover)
    End point description
    This instrument shows pain intensity in the setting of chronic pain. The 7-point PGIC measures change in the subject's overall status using the following categorical scale: 1) very much improved, 2) much improved, 3) minimally improved, 4) no change, 5) minimally worse, 6) much worse, and 7) very much worse.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 DS-5565 15 mg QD Modal DS-5565 15 mg BID Modal
    Number of subjects analysed
    578
    962
    Units: Patients
    418
    696
    No statistical analyses for this end point

    Secondary: Number of Patients with Improvement in Overall Status at Week 52 as Assessed by PGIC (De Novo)

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    End point title
    		 Number of Patients with Improvement in Overall Status at Week 52 as Assessed by PGIC (De Novo)
    End point description
    This instrument shows pain intensity in the setting of chronic pain. The 7-point PGIC measures change in the subject's overall status using the following categorical scale: 1) very much improved, 2) much improved, 3) minimally improved, 4) no change, 5) minimally worse, 6) much worse, and 7) very much worse.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 DS-5565 15 mg QD Modal DS-5565 15 mg BID Modal
    Number of subjects analysed
    269
    279
    Units: Patients
    191
    217
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 52 in Hospital Anxiety Depression Scale (HADS) Depression and Anxiety Scores (Rollover)

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    End point title
    		 Change from Baseline to Week 52 in Hospital Anxiety Depression Scale (HADS) Depression and Anxiety Scores (Rollover)
    End point description
    The HADS questionnaire is a self-assessment scale to assess symptoms of anxiety and depression. The instrument consists of 7 questions related to anxiety and 7 related to depression, each rated on a 4-point scale (score of 0 to 3). Scores for anxiety and depression are independently summed to compute HADS-Anxiety and HADS-Depression subscale scores, with ranges from 0 to 21, where higher scores indicate greater severity.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 DS-5565 15 mg QD Modal DS-5565 15 mg BID Modal
    Number of subjects analysed
    278
    497
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Anxiety Subscale Score
    -0.5 ± 3.25
    0.1 ± 3.27
        Depression Subscale Score
    -1.0 ± 3.80
    -1.3 ± 3.61
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 52 in HADS Depression and Anxiety Scores (De Novo)

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    End point title
    		 Change from Baseline to Week 52 in HADS Depression and Anxiety Scores (De Novo)
    End point description
    The HADS questionnaire is a self-assessment scale to assess symptoms of anxiety and depression. The instrument consists of 7 questions related to anxiety and 7 related to depression, each rated on a 4-point scale (score of 0 to 3). Scores for anxiety and depression are independently summed to compute HADS-Anxiety and HADS-Depression subscale scores, with ranges from 0 to 21, where higher scores indicate greater severity.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 DS-5565 15 mg QD Modal DS-5565 15 mg BID Modal
    Number of subjects analysed
    124
    137
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Anxiety Subscale Score
    -1.9 ± 3.78
    -1.3 ± 3.32
        Depression Subscale Score
    -2.6 ± 4.34
    -1.7 ± 3.30
    No statistical analyses for this end point

    Secondary: Change from Baseline in EuroQol-Instrument 5 Dimensions (EQ-5D) - (Rollover)

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    End point title
    		 Change from Baseline in EuroQol-Instrument 5 Dimensions (EQ-5D) - (Rollover)
    End point description
    The EQ-5D is an instrument that shows high construct validity and responsiveness in patients with chronic pain and has been used specifically in FM. The EQ-5D includes a descriptive section with 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) that are combined into an overall health utilities index, and an NRS (100 mm VAS) that measures perception of overall health, with 0 indicating worst health and 100 representing best imaginable health.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 DS-5565 15 mg QD Modal DS-5565 15 mg BID Modal
    Number of subjects analysed
    278
    497
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    0.0404 ± 0.15612
    0.0608 ± 0.16397
    No statistical analyses for this end point

    Secondary: Change from Baseline in EQ-5D (De Novo)

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    End point title
    		 Change from Baseline in EQ-5D (De Novo)
    End point description
    The EQ-5D is an instrument that shows high construct validity and responsiveness in patients with chronic pain and has been used specifically in FM. The EQ-5D includes a descriptive section with 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) that are combined into an overall health utilities index, and an NRS (100 mm VAS) that measures perception of overall health, with 0 indicating worst health and 100 representing best imaginable health.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 DS-5565 15 mg QD Modal DS-5565 15 mg BID Modal
    Number of subjects analysed
    124
    137
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    0.1703 ± 0.16944
    0.1739 ± 0.20900
    No statistical analyses for this end point

    Secondary: Change from Baseline in Short Form 36 (SF-36) Transformed Scores (Rollover)

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    End point title
    		 Change from Baseline in Short Form 36 (SF-36) Transformed Scores (Rollover)
    End point description
    The SF-36 is a health survey that asks 36 questions to measure functional health and well-being from the subject's point of view. It is a measure of physical and mental health used across various disease areas, including FM. The SF-36 provides scores for 8 health domains (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health) as well as psychometrically-based physical component summary (PCS) and mental component summary (MCS) scores. The scores from all parameters were then transformed into a single score, and change from baseline calculated. Note: Subjects were reported under their Modal treatment, ie, the treatment they received most frequently. Note: High scores are better than low scores; thus, positive changes indicate improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 DS-5565 15 mg QD Modal DS-5565 15 mg BID Modal
    Number of subjects analysed
    278
    497
    Units: Transformed scores on a scale
        arithmetic mean (standard deviation)
    1.526 ± 8.8842
    0.653 ± 8.9221
    No statistical analyses for this end point

    Secondary: Change from Baseline in SF-36 Transformed Scores (De Novo)

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    End point title
    		 Change from Baseline in SF-36 Transformed Scores (De Novo)
    End point description
    The SF-36 is a health survey that asks 36 questions to measure functional health and well-being from the subject's point of view. It is a measure of physical and mental health used across various disease areas, including FM. The SF-36 provides scores for 8 health domains (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health) as well as psychometrically-based physical component summary (PCS) and mental component summary (MCS) scores. The scores from all parameters were then transformed into a single score, and change from baseline calculated. Note: Subjects were reported under their Modal treatment, ie, the treatment they received most frequently. Note: High scores are better than low scores; thus, positive changes indicate improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 DS-5565 15 mg QD Modal DS-5565 15 mg BID Modal
    Number of subjects analysed
    124
    136
    Units: Transformed scores on a scale
        arithmetic mean (standard deviation)
    6.205 ± 11.5925
    3.636 ± 9.9236
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    A treatment emergent adverse event (TEAE) is any adverse event that emerges on or after the first dosing of open-label extension (OLE) medication and during the study.
    Adverse event reporting additional description
    Total number of TEAEs counts all occurrences in all patients. In the system organ class and preferred term summary, a patient was counted once when one or more events were reported, so the number of events simply mirrors the number of patients experiencing the preferred term.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    DS-5565 15 mg QD Modal
    Reporting group description
    		 Patients are reported under their modal treatment, ie, the treatment they received most frequently, which was DS-5565 15 mg once daily (QD).

    Reporting group title
    DS-5565 15 mg BID Modal
    Reporting group description
    		 Patients are reported under their modal treatment, ie, the treatment they received most frequently, which was DS-5565 15 mg twice daily (BID). One death was due to an unknown cause, and was not considered related to study drug. One death for unknown cause was listed as an adverse event.

    Serious adverse events
    		 DS-5565 15 mg QD Modal DS-5565 15 mg BID Modal
    Total subjects affected by serious adverse events
         subjects affected / exposed
    41 / 847 (4.84%)
    94 / 1241 (7.57%)
         number of deaths (all causes)
    3
    2
         number of deaths resulting from adverse events
    3
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Invasive ductal breast carcinoma
         subjects affected / exposed
    2 / 847 (0.24%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 847 (0.00%)
    2 / 1241 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 847 (0.00%)
    2 / 1241 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    1 / 847 (0.12%)
    0 / 1241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer stage III
         subjects affected / exposed
    1 / 847 (0.12%)
    0 / 1241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Castleman's disease
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibroadenoma of breast
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    1 / 847 (0.12%)
    0 / 1241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 847 (0.12%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood pressure fluctuation
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral venous disease
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Hyperemesis gravidarum
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 847 (0.12%)
    4 / 1241 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 847 (0.00%)
    2 / 1241 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Bereavement
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    0 / 847 (0.00%)
    2 / 1241 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial hyperplasia
         subjects affected / exposed
    1 / 847 (0.12%)
    0 / 1241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine polyp
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    2 / 847 (0.24%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphonia
         subjects affected / exposed
    1 / 847 (0.12%)
    0 / 1241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 847 (0.12%)
    0 / 1241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    3 / 847 (0.35%)
    3 / 1241 (0.24%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    3 / 847 (0.35%)
    0 / 1241 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 847 (0.12%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal behaviour
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    2 / 847 (0.24%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatine phosphokinase abnormal
         subjects affected / exposed
    1 / 847 (0.12%)
    0 / 1241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 847 (0.12%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 847 (0.00%)
    2 / 1241 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acetabulum fracture
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaesthetic complication
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Burns third degree
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Fall
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 847 (0.12%)
    0 / 1241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periprosthetic fracture
         subjects affected / exposed
    1 / 847 (0.12%)
    0 / 1241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seroma
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Spine malformation
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    1 / 847 (0.12%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 847 (0.00%)
    2 / 1241 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 847 (0.12%)
    0 / 1241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 847 (0.00%)
    3 / 1241 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    2 / 847 (0.24%)
    0 / 1241 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 847 (0.12%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 847 (0.12%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Altered state of consciousness
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic inflammatory demyelinating polyradiculoneuropathy
         subjects affected / exposed
    1 / 847 (0.12%)
    0 / 1241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 847 (0.12%)
    0 / 1241 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 847 (0.12%)
    0 / 1241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 847 (0.12%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    0 / 847 (0.00%)
    2 / 1241 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated umbilical hernia
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 847 (0.12%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    1 / 847 (0.12%)
    0 / 1241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 847 (0.00%)
    2 / 1241 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 847 (0.00%)
    2 / 1241 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 847 (0.00%)
    2 / 1241 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    2 / 847 (0.24%)
    0 / 1241 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibromyalgia
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    3 / 847 (0.35%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 847 (0.00%)
    2 / 1241 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 847 (0.12%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 847 (0.00%)
    2 / 1241 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic hepatitis C
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious colitis
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    1 / 847 (0.12%)
    0 / 1241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 847 (0.00%)
    2 / 1241 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 847 (0.12%)
    0 / 1241 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 847 (0.00%)
    1 / 1241 (0.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 DS-5565 15 mg QD Modal DS-5565 15 mg BID Modal
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    666 / 847 (78.63%)
    847 / 1241 (68.25%)
    Investigations
    Weight increased
         subjects affected / exposed
    83 / 847 (9.80%)
    207 / 1241 (16.68%)
         occurrences all number
    83
    207
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    132 / 847 (15.58%)
    148 / 1241 (11.93%)
         occurrences all number
    132
    148
    Headache
         subjects affected / exposed
    122 / 847 (14.40%)
    157 / 1241 (12.65%)
         occurrences all number
    122
    157
    Somnolence
         subjects affected / exposed
    130 / 847 (15.35%)
    102 / 1241 (8.22%)
         occurrences all number
    130
    102
    General disorders and administration site conditions
    Drug withdrawal syndrome
         subjects affected / exposed
    61 / 847 (7.20%)
    135 / 1241 (10.88%)
         occurrences all number
    61
    135
    Fatigue
         subjects affected / exposed
    76 / 847 (8.97%)
    83 / 1241 (6.69%)
         occurrences all number
    76
    83
    Oedema peripheral
         subjects affected / exposed
    52 / 847 (6.14%)
    80 / 1241 (6.45%)
         occurrences all number
    52
    80
    Eye disorders
    Vision blurred
         subjects affected / exposed
    26 / 847 (3.07%)
    56 / 1241 (4.51%)
         occurrences all number
    26
    56
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    61 / 847 (7.20%)
    113 / 1241 (9.11%)
         occurrences all number
    61
    113
    Diarrhoea
         subjects affected / exposed
    40 / 847 (4.72%)
    97 / 1241 (7.82%)
         occurrences all number
    40
    97
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    34 / 847 (4.01%)
    63 / 1241 (5.08%)
         occurrences all number
    34
    63
    Depression
         subjects affected / exposed
    21 / 847 (2.48%)
    44 / 1241 (3.55%)
         occurrences all number
    21
    44
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    35 / 847 (4.13%)
    87 / 1241 (7.01%)
         occurrences all number
    35
    87
    Arthralgia
         subjects affected / exposed
    32 / 847 (3.78%)
    87 / 1241 (7.01%)
         occurrences all number
    32
    87
    Pain in extremity
         subjects affected / exposed
    27 / 847 (3.19%)
    64 / 1241 (5.16%)
         occurrences all number
    27
    64
    Fibromyalgia
         subjects affected / exposed
    26 / 847 (3.07%)
    61 / 1241 (4.92%)
         occurrences all number
    26
    61
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    43 / 847 (5.08%)
    134 / 1241 (10.80%)
         occurrences all number
    43
    134
    Nasopharyngitis
         subjects affected / exposed
    47 / 847 (5.55%)
    110 / 1241 (8.86%)
         occurrences all number
    47
    110
    Urinary tract infection
         subjects affected / exposed
    51 / 847 (6.02%)
    105 / 1241 (8.46%)
         occurrences all number
    51
    105
    Sinusitis
         subjects affected / exposed
    36 / 847 (4.25%)
    88 / 1241 (7.09%)
         occurrences all number
    36
    88
    Viral infection
         subjects affected / exposed
    14 / 847 (1.65%)
    27 / 1241 (2.18%)
         occurrences all number
    14
    27

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Jul 2014
    Protocol V2.0, dated 31 Jul 2014, corrected minor editorial errors, as well as the following content revisions:  Clarified secondary objectives  Clarified the study site for open-label study  Clarified Sponsor decision to update sample size determination  Added Sponsor decision to edit Exclusion Criteria  Clarified secondary endpoints  Clarified study procedures for Visit 2  Corrected study procedures to be consistent with schedule of events  Updated that all subjects needed to complete SF-36 and EQ-5D questionnaires  Clarified dosing instruction  Included the procedure for evaluating titration possibility  Clarified study procedures for De Novo subjects  Reworded protocol for clarification regarding the ADPS  Updated text on ECGs to include the difference between De Novo and Rollover subjects  Added Sponsor decision to add interim analyses  Added a description of the electronic device used to capture daily pain score  Clarified the language used for recording medical history  Updated the changes in study schedule
    29 Jan 2015
    Protocol V3.0, dated 29 Jan 2015, corrected minor editorial errors, as well as the following content revisions:  Revised the list numbering of Inclusion and Exclusion criteria for De Novo subjects  Added scanning laser ophthalmoscopy to fundoscopic examination of the eyes as an alternative method  Changed the position of creatine kinase as a separate bullet point in the relevant section for clarity  Updated birth control methods based on feedback from Health Authority and provided further direction on how to deal with borderline pregnancy results  Clarified the usage of acetaminophen/paracetamol  Extended the Screening Period for De Novo subjects to 35 days  Updated the instruction for performing ECGs  Corrected Visit 5 (week 1) to include a visit window of ± 3  Deleted “modified” from Cockcroft-Gault Equation and lean body mass
    07 Apr 2016
    Protocol V4.0, dated 07 Apr 2016 corrected minor editorial errors, as well as the following content revisions:  Reflected the DSMB’s recommendation to implement a protocol amendment due to an increased incidence of suicidal ideation of subjects on study drugs versus placebo  Clarified that in the study, the C-SSRS was to be administered at all clinic visits and clarified the correct actions if, based on the C-SSRS and Investigator judgment, a subject was identified as being at risk for suicide

    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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