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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo Controlled Safety Study of DS-5565 for Treatment of Pain Due to Fibromyalgia in Subjects with Chronic Kidney Disease

    Summary
    EudraCT number
    		 2014-003972-21
    Trial protocol
    		 HU   CZ   ES   BG  
    Global end of trial date
    06 Jul 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Jun 2018
    First version publication date
    23 Jun 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DS5565-A-U307
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02496884
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Daiichi Sankyo, Inc.
    Sponsor organisation address
    211 Mt. Airy Road, Basking Ridge, United States, 07920
    Public contact
    Clinical Trial Information Contact, Daiichi Sankyo, Inc., 1 9089926400, eu_cta@dsi.com
    Scientific contact
    Clinical Trial Information Contact, Daiichi Sankyo, Inc., 1 9089926400, 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
    08 Sep 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Jul 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the safety and tolerability of subjects with FM and moderate to severe renal dysfunction during 13 weeks of renally-adjusted dosing of DS-5565 compared to placebo, followed by a short-term (4-week) safety follow-up.
    Protection of trial subjects
    This trial was conducted in accordance with the ethical principles of Good Clinical Practice, according to the International Council for Harmonisation (ICH) Harmonised Tripartite Guidelines. An independent DSMB was created to further protect the rights, safety, and well-being of subjects who were participating in this study by monitoring their progress and results. The independent DSMB was composed of qualified scientists, who were not investigators in the study and not otherwise directly associated with the sponsor. Additional protection was provided by special monitoring of liver enzyme elevations and liver dysfunction performed by a Hepatic Adjudication Committee (HAC), which was comprised of three qualified hepatologists who also were not investigators in the study and not otherwise directly associated with the sponsor. The HAC completed assessments on an ongoing basis. Adjudication of hepatic events was based on evaluation of electronic case report forms (eCRFs) and source documents, as available, including but not limited to hospital discharge summaries, diagnostic imaging, histopathology, consultation, and laboratory reports.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Jun 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
    Romania: 3
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Bulgaria: 5
    Country: Number of subjects enrolled
    United States: 47
    Worldwide total number of subjects
    56
    EEA total number of subjects
    9
    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)
    22
    From 65 to 84 years
    29
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    		 Randomized patients were recruited in four countries: Bulgaria (5), Romania (3), Spain (1), and the United States (47).

    Pre-assignment
    Screening details
    		 Of 231 patients enrolled, 175 discontinued before being randomized. Reasons for discontinuing before randomization included: screen failure (164), adverse events (1), withdrawal by patient (7), other, counted twice as enrolled (2), and other, no reason provided (1). The remaining 56 patients were randomized.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Carer, Subject, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 M-CKD Placebo
    Arm description
    		 Patients with M-CKD randomized to receive placebo twice daily (BID) during the treatment period.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo tablet
    Investigational medicinal product code
    Other name
    Placebo comparator
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo film-coated tablet for oral use

    Arm title
    		 M-CKD DS-5565 7.5 mg BID
    Arm description
    		 Patients with M-CKD randomized to receive DS-5565 BID during the treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    DS-5565 Tablet
    Investigational medicinal product code
    SUB60040
    Other name
    Mirogabalin
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    DS-5565 7.5 mg film-coated tablet for oral use

    Arm title
    		 S-CKD Placebo
    Arm description
    		 Patients with severe chronic kidney disease (S-CKD) randomized to receive placebo once daily (QD) during the treatment period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo tablet
    Investigational medicinal product code
    Other name
    Placebo comparator
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo film-coated tablet for oral use

    Arm title
    		 S-CKD DS-5565 7.5 mg QD
    Arm description
    		 Patients with S-CKD randomized to receive DS-5565 QD during the treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    DS-5565 Tablet
    Investigational medicinal product code
    SUB60040
    Other name
    Mirogabalin
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    DS-5565 7.5 mg film-coated tablet for oral use

    Number of subjects in period 1
    		M-CKD Placebo M-CKD DS-5565 7.5 mg BID S-CKD Placebo S-CKD DS-5565 7.5 mg QD
    Started
    17
    34
    1
    4
    Safety Analysis Set
    17
    34
    1
    4
    Modified Intent-to-Treat Set (mITT)
    17
    34
    1
    4
    Pharmacokinetic Analysis Set (PK)
    0 [1]
    33
    0 [2]
    4
    Completed Treatment per Protocol
    16
    27 [3]
    1
    3 [4]
    Completed
    15
    31
    1
    4
    Not completed
    2
    3
    0
    0
         Consent withdrawn by subject
    -
    3
    -
    -
         Counted twice as enrolled
    2
    -
    -
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Some patients who did not complete treatment per protocol were included in the safety follow-up.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Some patients who did not complete treatment per protocol were included in the safety follow-up.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Some patients who did not complete treatment per protocol were included in the safety follow-up.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Some patients who did not complete treatment per protocol were included in the safety follow-up.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    M-CKD Placebo
    Reporting group description
    		 Patients with M-CKD randomized to receive placebo twice daily (BID) during the treatment period.

    Reporting group title
    M-CKD DS-5565 7.5 mg BID
    Reporting group description
    		 Patients with M-CKD randomized to receive DS-5565 BID during the treatment period.

    Reporting group title
    S-CKD Placebo
    Reporting group description
    		 Patients with severe chronic kidney disease (S-CKD) randomized to receive placebo once daily (QD) during the treatment period.

    Reporting group title
    S-CKD DS-5565 7.5 mg QD
    Reporting group description
    		 Patients with S-CKD randomized to receive DS-5565 QD during the treatment period.

    Reporting group values
    		 M-CKD Placebo M-CKD DS-5565 7.5 mg BID S-CKD Placebo S-CKD DS-5565 7.5 mg QD Total
    Number of subjects
    		 17 34 1 4 56
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 8 12 1 1 22
        From 65-84 years
    		 9 18 0 2 29
        85 years and over
    		 0 4 0 1 5
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.4 ( 11.39 ) 68.4 ( 13.92 ) 53.0 ( 0 ) 74.0 ( 12.25 ) -
    Gender categorical
    Units: Subjects
        Female
    		 16 28 1 0 45
        Male
    		 1 6 0 4 11
    Chinese ethnicity
    Units: Subjects
        Yes
    		 0 0 0 0 0
        No
    		 17 34 1 4 56
    Race (alternative categorization)
    Units: Subjects
        White
    		 14 29 0 2 45
        Non-White
    		 3 5 1 2 11
    Baseline Average Daily Pain Score (ADPS)
    Patients were asked to rate their pain on a scale of 0-10, where 0=no pain and 10=worse pain experienced. The number of patients with an ADPS in each of two categories was recorded: less than 7 and more than 7.
    Units: Subjects
        ADPS less than 7
    		 8 9 1 2 20
        ADPS 7 or more
    		 9 25 0 2 36
    Baseline Average Daily Pain Score (ADPS)
    Patients were asked to rate their pain on a scale of 0-10, where 0=no pain and 10=the most pain experienced. The average ADPS at baseline was recorded.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 6.99 ( 1.353 ) 7.21 ( 0.962 ) 5.70 ( 0 ) 6.53 ( 0.822 ) -

    End points

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    End points reporting groups
    Reporting group title
    M-CKD Placebo
    Reporting group description
    		 Patients with M-CKD randomized to receive placebo twice daily (BID) during the treatment period.

    Reporting group title
    M-CKD DS-5565 7.5 mg BID
    Reporting group description
    		 Patients with M-CKD randomized to receive DS-5565 BID during the treatment period.

    Reporting group title
    S-CKD Placebo
    Reporting group description
    		 Patients with severe chronic kidney disease (S-CKD) randomized to receive placebo once daily (QD) during the treatment period.

    Reporting group title
    S-CKD DS-5565 7.5 mg QD
    Reporting group description
    		 Patients with S-CKD randomized to receive DS-5565 QD during the treatment period.

    Primary: Number of patients experiencing a Treatment Emergent Adverse Event (TEAE)

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    End point title
    		 Number of patients experiencing a Treatment Emergent Adverse Event (TEAE) [1]
    End point description
    A TEAE is any adverse event that emerges on or after the first dosing of double blind study medication and during study treatment up to 4 weeks after the last dose of double blind study medication (having been absent prior to treatment) or worsens relative to the pre-double blind treatment state. Relationship of TEAEs to study drug was assessed by the investigator. Clinically significant changes from baseline in clinical laboratory evaluations, neurological examinations, and electrocardiograms are reported as TEAEs.
    End point type
    Primary
    End point timeframe
    baseline through follow-up period 4 weeks after the last dose of study medication, within 25 months
    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 on these summary statistics.
    End point values
    		 M-CKD Placebo M-CKD DS-5565 7.5 mg BID S-CKD Placebo S-CKD DS-5565 7.5 mg QD
    Number of subjects analysed
    17
    34
    1
    4
    Units: Patients
        Patients with at least one TEAE
    8
    16
    0
    3
        Patients with a drug-related TEAE
    1
    9
    0
    0
        Patients with a serious TEAE
    0
    1
    0
    0
        Patients with a drug-related serious TEAE
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Patients Answering Yes to any question on the Columbia-Suicide Severity Rating Scale (C-SSRS)

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    End point title
    		 Patients Answering Yes to any question on the Columbia-Suicide Severity Rating Scale (C-SSRS) [2]
    End point description
    The C-SSRS is described as a scale developed at Columbia University that has 2-6 questions each in categories of Suicidal Ideation, Intensity of Ideation, Suicidal Behavior, and Actual Attempts. The higher the score, the higher the suicide risk.
    End point type
    Primary
    End point timeframe
    Screening, Baseline, Post-baseline (through Week 13)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No patients answered Yes, so it was not possible to perform analysis on these summary statistics.
    End point values
    		 M-CKD Placebo M-CKD DS-5565 7.5 mg BID S-CKD Placebo S-CKD DS-5565 7.5 mg QD
    Number of subjects analysed
    17
    34
    1
    4
    Units: Patients
        Yes at Screening
    0
    0
    0
    0
        Yes at Baseline
    0
    0
    0
    0
        Yes at Post-baseline
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Mean Weekly Average of Individual Daily Pain Scores (ADPS)

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    End point title
    		 Mean Weekly Average of Individual Daily Pain Scores (ADPS)
    End point description
    Each day participants will rate their worst pain over the last 24 hours on a scale from 0-10, where 0=no pain and 10=worst pain imaginable. Each week individual pain scores will be averaged, and the mean weekly score for the treatment group will be calculated.
    End point type
    Secondary
    End point timeframe
    through Week 13
    End point values
    		 M-CKD Placebo M-CKD DS-5565 7.5 mg BID S-CKD Placebo S-CKD DS-5565 7.5 mg QD
    Number of subjects analysed
    17
    34
    1
    4
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Baseline Period
    6.99 ( 1.353 )
    7.21 ( 0.962 )
    5.70 ( 0 )
    6.53 ( 0.822 )
        Week 1
    6.26 ( 1.526 )
    6.10 ( 1.628 )
    2.0 ( 0 )
    6.88 ( 0.150 )
        Week 2
    6.03 ( 1.681 )
    5.73 ( 2.055 )
    1.70 ( 0 )
    6.60 ( 0.800 )
        Week 3
    5.77 ( 1.720 )
    5.55 ( 1.949 )
    1.70 ( 0 )
    6.80 ( 0.400 )
        Week 4
    5.41 ( 1.914 )
    5.43 ( 1.986 )
    1.30 ( 0 )
    6.75 ( 0.500 )
        Week 5
    5.45 ( 1.648 )
    5.46 ( 2.078 )
    0.70 ( 0 )
    6.90 ( 0.987 )
        Week 6
    5.16 ( 1.751 )
    5.16 ( 2.180 )
    1.4 ( 0 )
    6.43 ( 1.914 )
        Week 7
    5.03 ( 2.096 )
    5.09 ( 2.143 )
    1.20 ( 0 )
    6.67 ( 1.528 )
        Week 8
    5.15 ( 2.034 )
    5.04 ( 2.225 )
    1.00 ( 0 )
    6.73 ( 1.518 )
        Week 9
    5.09 ( 1.816 )
    4.81 ( 2.243 )
    1.00 ( 0 )
    6.47 ( 1.909 )
        Week 10
    4.86 ( 2.060 )
    4.97 ( 2.195 )
    0.90 ( 0 )
    6.53 ( 1.747 )
        Week 11
    4.28 ( 1.987 )
    4.80 ( 2.308 )
    0.70 ( 0 )
    6.73 ( 1.124 )
        Week 12
    4.17 ( 2.158 )
    4.69 ( 2.199 )
    0.80 ( 0 )
    6.63 ( 2.274 )
        Week 13
    4.28 ( 2.454 )
    4.15 ( 1.844 )
    1.00 ( 0 )
    6.80 ( 2.227 )
    No statistical analyses for this end point

    Secondary: Patient Global Impression of Change (PGIC)

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    End point title
    		 Patient Global Impression of Change (PGIC)
    End point description
    At the end of treatment, patients rate their overall status on a scale of 1-7, where 1=very much improved and 7=very much worse using the standard PGIC questionnaire. The PGIC is a validated outcome measure for treatment of pain in the acute pain setting.
    End point type
    Secondary
    End point timeframe
    at Week 13 / end of treatment
    End point values
    		 M-CKD Placebo M-CKD DS-5565 7.5 mg BID S-CKD Placebo S-CKD DS-5565 7.5 mg QD
    Number of subjects analysed
    17
    34
    1
    4
    Units: Patients
        1-3 Improved
    12
    20
    1
    1
        4 No change
    3
    8
    0
    3
        5-7 Worsened
    1
    0
    0
    0
        Missing
    1
    6
    0
    0
    Statistical analysis title
    		 PGIC<=2 (Much improved or better)
    Statistical analysis description
    Frequency Difference vs Placebo
    Comparison groups
    M-CKD DS-5565 7.5 mg BID v M-CKD Placebo
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Newcombe-Wilson
    Point estimate
    2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27.4
         upper limit
    		 30
    Statistical analysis title
    		 CKD PGIC <=2 (much Improved or better)
    Statistical analysis description
    Frequency difference vs Placebo
    Comparison groups
    S-CKD Placebo v S-CKD DS-5565 7.5 mg QD
    Number of subjects included in analysis
    5
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Newcombe-Wilson
    Point estimate
    -100
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -100
         upper limit
    		 12.2

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    13 weeks
    Adverse event reporting additional description
    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 mirrors the number of participants, as they experienced the preferred term one or more times.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    M-CKD Placebo
    Reporting group description
    		 Patients with M-CKD randomized to receive placebo twice daily (BID) during the treatment period.

    Reporting group title
    M-CKD DS-5565 7.5 mg BID
    Reporting group description
    		 Patients with M-CKD randomized to receive DS-5565 BID during the treatment period.

    Reporting group title
    S-CKD Placebo
    Reporting group description
    		 Patients with severe chronic kidney disease (S-CKD) randomized to receive placebo once daily (QD) during the treatment period.

    Reporting group title
    S-CKD DS-5565 7.5 mg QD
    Reporting group description
    		 Patients with S-CKD randomized to receive DS-5565 QD during the treatment period.

    Serious adverse events
    		 M-CKD Placebo M-CKD DS-5565 7.5 mg BID S-CKD Placebo S-CKD DS-5565 7.5 mg QD
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 M-CKD Placebo M-CKD DS-5565 7.5 mg BID S-CKD Placebo S-CKD DS-5565 7.5 mg QD
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 17 (47.06%)
    16 / 34 (47.06%)
    0 / 1 (0.00%)
    3 / 4 (75.00%)
    General disorders and administration site conditions
    Drug withdrawal syndrome
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 34 (5.88%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 34 (5.88%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Chest pain
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary mass
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Asthma
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 34 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Psychiatric disorders
    Nervousness
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Investigations
    Weight increased
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 34 (5.88%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Creatinine renal clearance decreased
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 34 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Post-traumatic pain
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ligament sprain
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 34 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cardiac disorders
    Bundle branch block left
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 17 (0.00%)
    3 / 34 (8.82%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    3
    0
    1
    Headache
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 34 (5.88%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    0
    1
    Hypoaesthesia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 34 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Neutrophilia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 34 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dry eye
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 34 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Constipation
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dry mouth
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Nausea
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 34 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Ecchymosis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rash
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin lesion
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 34 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Back pain
         subjects affected / exposed
    2 / 17 (11.76%)
    0 / 34 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 17 (5.88%)
    3 / 34 (8.82%)
    0 / 1 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    1
    3
    0
    1
    Lobar pneumonia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Viral infection
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    0 / 17 (0.00%)
    2 / 34 (5.88%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Dehydration
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 17 (0.00%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hyperuricaemia
         subjects affected / exposed
    3 / 17 (17.65%)
    0 / 34 (0.00%)
    0 / 1 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Apr 2016
    • Excluded patients identified at screening as being at risk for suicide • Modified discontinuation criteria to provide extra safety measures for patients identified as being at risk for suicide
    31 May 2016
    • Changed sponsor's name from Daiichi Sankyo Development Limited to Daiichi Sankyo, Inc. • Updated birth control to highly effective methods, as follows: Female patients (or female partners of male patients) who are of child bearing potential should use a highly effective method of contraception throughout their participation in the study, such as hormonal methods associated with inhibition of ovulation, intra-uterine device, surgical sterilization (including partner’s vasectomy) and sexual abstinence. • Amended prohibited medications, by: o Requiring patient instructions to take no prohibited medication during the baseline period, prior to randomization, or during the subsequent treatment period, and that using prohibited medications could cause them to be discontinued from the study o Requiring psychiatric consultation before change or wash-out of psychiatric medication
    14 Mar 2017
    Modified the protocol to require the following: • Notification to the patients that Mini-international Neuropsychiatric Interview (MINI, version 6) and C-SSRS will be administered at any time during the study (including unscheduled visits) along with psychiatric evaluation at the investigator’s discretion • Any time the investigator or staff suspects potential mood disturbance, suicide risk, and/or substantial changes in psychosocial environment, the C-SSRS and MINI is to be administered, with a referral for psychiatric care • Patients assessed as having current severe or uncontrolled major depressive or anxiety disorders and/or suicidal risk are discontinued from the study and given immediate psychiatric care

    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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