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    Clinical Trial Results:
    A Long-Term Study of SM-13496 in Patients with Bipolar I Disorder.

    Summary
    EudraCT number
    		 2013-003039-31
    Trial protocol
    		 LT   SK  
    Global end of trial date
    17 Feb 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 May 2019
    First version publication date
    03 May 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D1002002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01986114
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 JapicCTI: 132319
    Sponsors
    Sponsor organisation name
    Sumitomo Dainippon Pharma Co. Ltd.
    Sponsor organisation address
    1-13-1 Kyobashi, Chuo-ku, Tokyo, Japan, 104-8356
    Public contact
    Drug Development Division, Sumitomo Dainippon Pharmaceutical, cc@ds-pharma.co.jp
    Scientific contact
    Drug Development Division, Sumitomo Dainippon Pharmaceutical, cc@ds-pharma.co.jp
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Apr 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Feb 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The study evaluates the long-term efficacy and safety of SM-13496 in patients with bipolar I disorder.
    Protection of trial subjects
    This study was conducted in accordance with the protocol, ICH GCP, local regulations, and the ethical principles that had their origin in the Declaration of Helsinki. The study was conducted in accordance with applicable local law(s) and regulation(s).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Jan 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Japan: 199
    Country: Number of subjects enrolled
    Malaysia: 11
    Country: Number of subjects enrolled
    Philippines: 8
    Country: Number of subjects enrolled
    Russian Federation: 129
    Country: Number of subjects enrolled
    Taiwan: 7
    Country: Number of subjects enrolled
    Ukraine: 117
    Country: Number of subjects enrolled
    Lithuania: 9
    Country: Number of subjects enrolled
    Slovakia: 15
    Worldwide total number of subjects
    495
    EEA total number of subjects
    24
    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)
    474
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The completers of the prior study (the placebo-controlled study; D1002001) whose most recent or current episode was depression, and newly recruited Japanese subjects whose most recent or current episode was mania, hypomania, or mixed could be enrolled in the present study.

    Pre-assignment
    Screening details
    		 For newly recruited Japanese subjects, the study consisted of the screening phase (1-14 days) and the treatment phase. SM-13496 was administered at a flexible dose (20-120 mg/day) for 28 weeks (outside Japan) or 52 weeks (in Japan).

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

    Arms
    Arm title
    		 SM-13496 20-120mg
    Arm description
    		 once daily orally SM-13496 (lurasidone HCl): SM-13496 20-120mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    SM-13496
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    SM-13496 20, 40, 60, 80, 100, or 120 mg/day, as 20 mg tablets, were administered orally once daily within 30 minutes after evening meal. For subjects who had completed the prior study, SM-13496 was administered at a dose of 60 mg/day (starting on Day 1) for the first week, and at a flexible dose within a range of 20 to 120 mg/day (starting on Day 8) thereafter. For subjects who had not participated in the prior study, SM-13496 was administered at a dose of 20 mg/day (starting on Day 1) for the first week, and at a flexible dose within a range of 20 to 120 mg/day (starting on Day 8) thereafter.

    Number of subjects in period 1
    		SM-13496 20-120mg
    Started
    495
    Completed
    339
    Not completed
    156
         Consent withdrawn by subject
    58
         Adverse event, non-fatal
    59
         Other reason
    7
         Lost to follow-up
    5
         Lack of efficacy
    23
         Noncompliance
    3
         Protocol deviation
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SM-13496 20-120mg
    Reporting group description
    		 once daily orally SM-13496 (lurasidone HCl): SM-13496 20-120mg

    Reporting group values
    		 SM-13496 20-120mg Total
    Number of subjects
    		 495 495
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 474 474
        From 65-84 years
    		 21 21
        85 years and over
    		 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42.6 ± 12.78 -
    Gender categorical
    Units: Subjects
        Female
    		 259 259
        Male
    		 236 236
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 225 225
        Native Hawaiian or Other Pacific Islander
    		 0 0
        Black or African American
    		 0 0
        White
    		 270 270
        More than one race
    		 0 0
        Unknown or Not Reported
    		 0 0
    Region of Enrollment
    Units: Subjects
        Japan
    		 199 199
        Philippines
    		 8 8
        Taiwan
    		 7 7
        Ukraine
    		 117 117
        Malaysia
    		 11 11
        Slovakia
    		 15 15
        Lithuania
    		 9 9
        Russia
    		 129 129
    Subject analysis sets

    Subject analysis set title
    SM-13496 20-120mg (Overall, 28 weeks)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    once daily orally SM-13496 (lurasidone HCl): SM-13496 20-120mg flexibly dosed up to 28 weeks

    Subject analysis set title
    SM-13496 20-120mg (Japan, 52 weeks)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    once daily orally SM-13496 (lurasidone HCl): SM-13496 20-120mg flexibly dosed up to 52 weeks

    Subject analysis sets values
    		 SM-13496 20-120mg (Overall, 28 weeks) SM-13496 20-120mg (Japan, 52 weeks)
    Number of subjects
    495
    199
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    42.6 ± 12.78
    41.6 ± 11.97
    Gender categorical
    Units: Subjects
        Female
    259
    97
        Male
    236
    102
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0
    0
        Asian
    225
    199
        Native Hawaiian or Other Pacific Islander
    0
    0
        Black or African American
    0
    0
        White
    270
    0
        More than one race
    0
    0
        Unknown or Not Reported
    0
    0
    Region of Enrollment
    Units: Subjects
        Japan
    199
    199
        Philippines
    8
    0
        Taiwan
    7
    0
        Ukraine
    117
    0
        Malaysia
    11
    0
        Slovakia
    15
    0
        Lithuania
    9
    0
        Russia
    129
    0

    End points

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    End points reporting groups
    Reporting group title
    SM-13496 20-120mg
    Reporting group description
    		 once daily orally SM-13496 (lurasidone HCl): SM-13496 20-120mg

    Subject analysis set title
    SM-13496 20-120mg (Overall, 28 weeks)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    once daily orally SM-13496 (lurasidone HCl): SM-13496 20-120mg flexibly dosed up to 28 weeks

    Subject analysis set title
    SM-13496 20-120mg (Japan, 52 weeks)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    once daily orally SM-13496 (lurasidone HCl): SM-13496 20-120mg flexibly dosed up to 52 weeks

    Primary: Incidence of adverse events (AEs) and adverse drug reactions (ADRs)

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    End point title
    		 Incidence of adverse events (AEs) and adverse drug reactions (ADRs) [1]
    End point description
    The number of subjects with at least one adverse events and adverse drug reactions
    End point type
    Primary
    End point timeframe
    28, 52 weeks
    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: The number of subjects with at least one AE or ADR for each preferred term (PT) and system organ class (SOC) were summarized for all subjects. Detailed results are reported in the Adverse events section.
    End point values
    		 SM-13496 20-120mg (Overall, 28 weeks) SM-13496 20-120mg (Japan, 52 weeks)
    Number of subjects analysed
    495
    199
    Units: subjects
    352
    169
    No statistical analyses for this end point

    Secondary: Change from long term study baseline to LOCF Endpoint in the Montgomery-Asberg Depression Rating Scale (MADRS) score

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    End point title
    		 Change from long term study baseline to LOCF Endpoint in the Montgomery-Asberg Depression Rating Scale (MADRS) score
    End point description
    Montgomery-Asberg Depression Rating Scale (MADRS)is a clinician-rated assessment of a subject's level of depression. The MADRS total score ranges from a minimum of 0 to a maximum of 60. For the MADRS total score, low scores indicate a better outcome and high scores indicate a worse outcome. When change from baseline is considered, a negative (decrease in score) value is considered a better outcome, and a positive (increase in score) value is considered a worse outcome. The MADRS contains ten (10) items. The total score is computed as the sum of the scores for the 10 items.
    End point type
    Secondary
    End point timeframe
    Baseline, 52 weeks and each month
    End point values
    		 SM-13496 20-120mg (Overall, 28 weeks) SM-13496 20-120mg (Japan, 52 weeks)
    Number of subjects analysed
    494
    198
    Units: units on a scale
        arithmetic mean (standard deviation)
    -4.4 ± 12.09
    1.1 ± 12.58
    No statistical analyses for this end point

    Secondary: Change from long term study baseline to LOCF Endpoint in the Young Mania Rating Scale (YMRS) total score.

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    End point title
    		 Change from long term study baseline to LOCF Endpoint in the Young Mania Rating Scale (YMRS) total score.
    End point description
    YMRS (Young Mania Rating Scale) is a clinician-rated assessment of the severity of mania in subjects with a diagnosis of bipolar disorder. The YMRS total score ranges from a minimum of 0 to a maximum of 60. For the YMRS total score, low scores indicate a better outcome and high scores indicate a worse outcome. When change from baseline is considered, a negative (decrease in score) value is considered a better outcome, and a positive (increase in score) value is considered a worse outcome. The YMRS contains eleven (11) items. The total score is computed as the sum of the scores for the 11 items.
    End point type
    Secondary
    End point timeframe
    Baseline, 52 weeks and each month
    End point values
    		 SM-13496 20-120mg (Overall, 28 weeks) SM-13496 20-120mg (Japan, 52 weeks)
    Number of subjects analysed
    494
    198
    Units: units on a scale
        arithmetic mean (standard deviation)
    -1.0 ± 4.54
    -2.0 ± 6.73
    No statistical analyses for this end point

    Secondary: Rate of recurrence/relapse of any mood event from clinical stability of bipolar disorder.

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    End point title
    		 Rate of recurrence/relapse of any mood event from clinical stability of bipolar disorder.
    End point description
    The number of subjects who experienced recurrence/relapse of any mood event from clinical stability of bipolar disorder.
    End point type
    Secondary
    End point timeframe
    Baseline to 52 weeks
    End point values
    		 SM-13496 20-120mg (Overall, 28 weeks) SM-13496 20-120mg (Japan, 52 weeks)
    Number of subjects analysed
    495
    199
    Units: subjects
        With relapse or recurrence
    14
    18
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event data was collected for 28 weeks (outside Japan) and 52 weeks (Japan).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    SM-13496 20-120mg (Overall, 28 weeks)
    Reporting group description
    		 once daily orally SM-13496 (lurasidone HCl): SM-13496 20-120mg flexibly dosed up to 28 weeks

    Reporting group title
    SM-13496 20-120mg (Japan, 52 weeks)
    Reporting group description
    		 once daily orally SM-13496 (lurasidone HCl): SM-13496 20-120mg flexibly dosed up to 52 weeks

    Serious adverse events
    		 SM-13496 20-120mg (Overall, 28 weeks) SM-13496 20-120mg (Japan, 52 weeks)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 495 (3.84%)
    12 / 199 (6.03%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Blood potassium decreased
         subjects affected / exposed
    1 / 495 (0.20%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glucose urine present
         subjects affected / exposed
    1 / 495 (0.20%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 495 (0.20%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine cancer
         subjects affected / exposed
    0 / 495 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Pelvic fracture
         subjects affected / exposed
    1 / 495 (0.20%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    1 / 495 (0.20%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychomotor hyperactivity
         subjects affected / exposed
    1 / 495 (0.20%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    8 / 495 (1.62%)
    3 / 199 (1.51%)
         occurrences causally related to treatment / all
    2 / 8
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcoholism
         subjects affected / exposed
    1 / 495 (0.20%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination, auditory
         subjects affected / exposed
    1 / 495 (0.20%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination, visual
         subjects affected / exposed
    1 / 495 (0.20%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    1 / 495 (0.20%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 495 (0.20%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    3 / 495 (0.61%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 495 (0.20%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    1 / 495 (0.20%)
    0 / 199 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 495 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lactic acidosis
         subjects affected / exposed
    0 / 495 (0.00%)
    1 / 199 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 SM-13496 20-120mg (Overall, 28 weeks) SM-13496 20-120mg (Japan, 52 weeks)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    250 / 495 (50.51%)
    137 / 199 (68.84%)
    Investigations
    Weight increased
         subjects affected / exposed
    31 / 495 (6.26%)
    17 / 199 (8.54%)
         occurrences all number
    31
    17
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    91 / 495 (18.38%)
    60 / 199 (30.15%)
         occurrences all number
    104
    64
    Headache
         subjects affected / exposed
    37 / 495 (7.47%)
    16 / 199 (8.04%)
         occurrences all number
    46
    19
    Parkinsonism
         subjects affected / exposed
    34 / 495 (6.87%)
    15 / 199 (7.54%)
         occurrences all number
    43
    25
    Somnolence
         subjects affected / exposed
    41 / 495 (8.28%)
    24 / 199 (12.06%)
         occurrences all number
    44
    24
    Dystonia
         subjects affected / exposed
    13 / 495 (2.63%)
    10 / 199 (5.03%)
         occurrences all number
    15
    11
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    16 / 495 (3.23%)
    10 / 199 (5.03%)
         occurrences all number
    17
    11
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    35 / 495 (7.07%)
    24 / 199 (12.06%)
         occurrences all number
    38
    25
    Diarrhoea
         subjects affected / exposed
    14 / 495 (2.83%)
    10 / 199 (5.03%)
         occurrences all number
    15
    11
    Vomiting
         subjects affected / exposed
    17 / 495 (3.43%)
    13 / 199 (6.53%)
         occurrences all number
    21
    13
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    51 / 495 (10.30%)
    53 / 199 (26.63%)
         occurrences all number
    63
    72

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

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