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    Clinical Trial Results:
    A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, FLEXIBLE-DOSE, PARALLEL-GROUP STUDY OF LURASIDONE ADJUNCTIVE TO LITHIUM OR DIVALPROEX FOR THE PREVENTION OF RECURRENCE IN SUBJECTS WITH BIPOLAR I DISORDER

    Summary
    EudraCT number
    		 2011-000986-10
    Trial protocol
    		 HU   SK   CZ   PL  
    Global end of trial date
    04 Apr 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Jun 2016
    First version publication date
    22 Jun 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    D1050296
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01358357
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Sunovion Pharmaceuticals Inc.
    Sponsor organisation address
    One Bridge Plaza Suite 510, Fort Lee, New Jersey, United States, NJ 07024
    Public contact
    Rob Goldman, Sunovion Pharmaceuticals Inc., +1 201-228-8319, Robert.Goldman@sunovion.com
    Scientific contact
    Rob Goldman, Sunovion Pharmaceuticals Inc., +1 201-228-8319, Robert.Goldman@sunovion.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
    04 Jan 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Apr 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy and safety of lurasidone (in combination with lithium or divalproex) for the maintenance treatment of bipolar I disorder in subjects with or without rapid cycling and/or psychotic features.
    Protection of trial subjects
    The study was conducted according to the protocol, International Conference on Harmonisation (ICH) Good Clinical Practice (GCP), ICH guidelines, and the ethical principles that have their origin in the Declaration of Helsinki. The study was conducted in accordance with applicable local law(s) and regulation(s). Use of nonprescription pain medications (eg, aspirin) was allowed during all phases of the study provided these medications did not have a propensity for psychotropic effects and did not interfere with the evaluation of study medication
    Background therapy
    		 Prior therapies/ drugs: - Ongoing psychotherapy treatment for at least 12 weeks prior to screening was permitted during the study - Lorazepam, temazepam, eszopiclone, zaleplon, zolpidem, and zolpidem CR permitted Concomitant Non-psychotropic drugs: To treat mild, chronic medical conditions if the dose and regimen were stable (± 25%) for at least 30 days prior to screening: - β-adrenergic antagonists to treat stable hypertension could be continued during the study - Nonprescription pain medications (eg, aspirin) weres allowed during the study provided these medications did not have a propensity for psychotropic effects and did not interfere with the evaluation of study drug - Short-term treatment of a medical condition (no more than 14 days) was allowed provided that the drug were not cytochrome P450 3A4 (CYP3A4) inhibitors/inducers and did not consistently prolong the QTc interval Concomitant Psychotropic drugs: - Benztropine (up to 6 mg/day) permitted as needed for movement disorders. When it was not available or an inadequate response or intolerability to benztropine treatment occurred, biperiden (up to 16 mg/day) or trihexyphenidyl (up to 15 mg/day) or diphenhydramine (up to 100 mg/day) were used to treat acute EPS. Treatment with propranolol (up to 120 mg/day) was permitted as needed for akathisia. Medications used to treat movement disorders were not given prophylactically - When anticholinergic agents or sedative/hypnotic agents (or any agents that may cause sedation) were administered, these were taken at the same time each day and were not taken within 8 hours of scheduled assessments. Similar drugs at equivalent dosages were substituted - Lorazepam, temazepam, eszopiclone, zaleplon, zolpidem, and zolpidem CR permitted with some restricctions - Anxiolytics, sedatives, or hypnotics were not administered within 8 hours prior to any psychiatric assessments. Opiates rarely used If above not available, similars used as per Op. Manual/Med.Monitor
    Evidence for comparator
    		 Bipolar disorder is a chronic and often disabling condition with a lifetime prevalence of approximately 4.4%. The episodic nature of bipolar disorder means that the majority of subjects can expect a lifelong course of recurrent acute episodes, in addition to residual symptoms in the intervening years.Despite therapeutic intervention, relapse rates for subjects who are receiving treatment range from 40% to 60%, even after a first life-time episode with as many as one-half of subjects experiencing a 2nd mood episode within a year of recovery: the goal of effective maintenance treatment is to prevent relapse, reduce subsyndromal symptoms, decrease hospitalizations, decrease morbidity and mortality, and improve functioning and quality of life At present, the following atypical antipsychotics have demonstrated the ability to maintain efficacy in bipolar I disorder in previously stabilized subjects either as monotherapy or in combination with lithium or divalproex: olanzapine, aripiprazole, quetiapine, and ziprasidone. Lurasidone is an atypical antipsychotic agent with a unique chemical structure. Lurasidone has high affinity for dopamine D2, serotonin 5-HT2A and serotonin 5-HT7 receptors where it has antagonist effects. In addition, lurasidone is a partial agonist at the serotonin 5-HT1A receptor. More than 2,500 lurasidone-treated subjects have participated in over 40 clinical studies, including five 6-week, double-blind, placebo-controlled studies involving hospitalized subjects with schizophrenia. Clinical trials demonstrated that lurasidone was efficacious in the treatment of schizophrenia and generally well tolerated The current randomized, placebo-controlled, flexible-dose, parallel-group study was designed to evaluate the efficacy of lurasidone compared with placebo in preventing recurrence of affective symptoms in subjects with bipolar I disorder who demonstrated a stable response to acute treatment with lurasidone in combination with lithium or divalproex.
    Actual start date of recruitment
    06 Jun 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 3 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Poland: 52
    Country: Number of subjects enrolled
    Slovakia: 9
    Country: Number of subjects enrolled
    Bulgaria: 53
    Country: Number of subjects enrolled
    Czech Republic: 62
    Country: Number of subjects enrolled
    France: 23
    Country: Number of subjects enrolled
    Hungary: 51
    Country: Number of subjects enrolled
    United States: 471
    Country: Number of subjects enrolled
    Argentina: 51
    Country: Number of subjects enrolled
    Chile: 25
    Country: Number of subjects enrolled
    Croatia: 6
    Country: Number of subjects enrolled
    Japan: 25
    Country: Number of subjects enrolled
    Russian Federation: 81
    Country: Number of subjects enrolled
    Serbia: 54
    Worldwide total number of subjects
    965
    EEA total number of subjects
    256
    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)
    935
    From 65 to 84 years
    30
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 1412 patients were evaluated for eligibility during a screening/wash-out period of 3-14 days (28 days for subjects on fluoxetine): other than lithium or divalproex, subjects were tapered off selected psychotropic drugs according to labeling recommendations and usual medical practice. Screen Failures: 447. 965 patients entered Open-Label Phase

    Period 1
    Period 1 title
    Open-label Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Lurasidone + lithium / divalproex
    Arm description
    		 Upon meeting entry criteria, subjects began open-label treatment with lurasidone (20-80 mg/day) and either lithium or divalproex (if not currently taking one of these mood stabilizers) on the evening of Visit 2 (open-label phase baseline). For subjects previously not on either lithium or divalproex, Investigators determined which mood stabilizer was most appropriate to initiate: lithium and divalproex were dosed to achieve serum trough concentrations of 0.4-1.2 mEq/L and 50-125 μg/mL, respectively. All country-approved formulations of lithium or divalproex (including extended-release and controlled-release formulations) were permitted (with the exception of lithium orotate and magnesium valproate). Subjects remained in the open-label phase for a maximum of 20 weeks until they achieved and maintained consistent clinical stability.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lurasidone Hydrochloride
    Investigational medicinal product code
    SM-13496
    Other name
    CAS Number: 367514-88-3, EV Substance code: SUB34204
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lurasidone was dosed as follows: 20 mg/day on Days 1-3; 40 mg/day on Days 4-7; and flexibly (20-80 mg/day) thereafter. Beginning on Day 8, if dose adjustments were necessary, they were to occur at weekly intervals and in increments/decrements of 1 dose level (ie, 20 mg/day), based on Investigator judgment in order to optimize efficacy and tolerability. However, dose reductions for tolerability purposes were permitted to occur more frequently than at weekly intervals and more than 1 dose level at a time (maximum of 2 dose levels at a time).

    Number of subjects in period 1
    		Lurasidone + lithium / divalproex
    Started
    965
    Completed
    503
    Not completed
    462
         Consent withdrawn by subject
    112
         Did not meet criteria for double-blind phase
    16
         Study terminated by Sponsor
    5
         Adverse event, non-fatal
    59
         Mood episode
    42
         Lost to follow-up
    76
         Protocol deviation
    45
         Lack of efficacy
    107
    Period 2
    Period 2 title
    Double-blind Phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Data analyst, Carer, Assessor, Subject
    Blinding implementation details
    Stratified randomization was performed at double-blind phase baseline using an Interactive Voice Response System (IVRS) to ensure balance across the 2 groups relative to mood stabilizer treatment (lithium or divalproex).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lurasidone + lithium / divalproex
    Arm description
    		 Lurasidone in combination with either lithium or divalproex for up to 28 weeks: the last open-label dose level was maintained entering the double-blind phase (Visit 13). Subsequent dose adjustments, if necessary, were to occur at weekly intervals and in increments/decrements of 1 dose level, based on Investigator judgment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lurasidone Hydrochloride
    Investigational medicinal product code
    SM-13496
    Other name
    CAS Number: 367514-88-3, EV Substance code: SUB34204
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The last open-label dose level was maintained entering the double-blind phase (Visit 13)

    Arm title
    		 Placebo + lithium / divalproex
    Arm description
    		 Placebo in combination with either lithium or divalproex) for up to 28 weeks. Subjects randomized to matching placebo, the lurasidone dose taken during the open-label phase was discontinued. Subsequent dose adjustments, if necessary, were to occur at weekly intervals and in increments/decrements of 1 dose level, based on Investigator judgment. Subjects who completed the double-blind phase of the study or experienced a protocol-specified recurrence of any mood event during the double-blind phase were eligible to participate in a separate 3-month, open-label lurasidone extension study (D1050308).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For subjects randomized to matching placebo, the lurasidone dose was discontinued. Subsequent dose adjustments, if necessary, were to occur at weekly intervals and in increments/decrements of 1 dose level, based on Investigator judgment.

    Number of subjects in period 2 [1]
    		Lurasidone + lithium / divalproex Placebo + lithium / divalproex
    Started
    246
    250
    Completed
    166
    150
    Not completed
    80
    100
         Consent withdrawn by subject
    16
    12
         Adverse event, non-fatal: no mood event recurrence
    8
    5
         Administrative
    -
    1
         Lost to follow-up
    5
    7
         Recurrence of mood event
    48
    64
         Study terminated by the Sponsor
    2
    -
         Protocol deviation
    1
    11
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Of the 503 subjects who completed the open-label phase, 7 subjects were not randomized to the double-blind phase (3 subjects due to a mood episode, 3 subjects due to not meeting the criteria for the double blind phase, and 1 subject due to an insufficient clinical response), thus only 496 subjects were randomized to the double blind phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Open-label Phase
    Reporting group description
    		 ’OL/DB baseline’ values in the following table represent Open-Label (OL) Baseline

    Reporting group values
    		 Open-label Phase Total
    Number of subjects
    		 965 965
    Age categorical
    Units: Subjects
        85 years and over
    		 0 0
        <55
    		 771 771
        >=55
    		 194 194
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42.5 ( 12.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 568 568
        Male
    		 397 397
    Region
    Units: Subjects
        North America
    		 471 471
        Asia
    		 25 25
        Europe
    		 393 393
        South America
    		 76 76
    Race
    Units: Subjects
        White
    		 782 782
        Black or African American
    		 123 123
        Asian
    		 33 33
        American Indian or Alaska native
    		 7 7
        Native Hawaiian or Other Pacific Islander
    		 2 2
        Other
    		 18 18
    OL/DB baseline YMRS total score
    Units: rating scales
        arithmetic mean (standard deviation)
    		 12.9 ( 9.23 ) -
    OL/DB baseline MADRS total score
    Units: rating scales
        arithmetic mean (standard deviation)
    		 21.3 ( 10.35 ) -
    OL/DB baseline CGI-BP-S overall score
    Units: rating scales
        arithmetic mean (standard deviation)
    		 4.15 ( 0.72 ) -
    Subject analysis sets

    Subject analysis set title
    Intent-to treat population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT population included all subjects who were randomized and received at least 1 dose of study medication in the double-blind phase. Each subject was assigned to the randomized treatment. ’OL/DB baseline’ values in the following table represent Double-blind (DB) Baseline

    Subject analysis set title
    Double-blind safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Double-blind Safety Population included all subjects who received at least one dose of study medication in the Double-blind phase. Each subject was assigned to the treatment they actually received. ’OL/DB baseline’ values in the following table represent Double-blind (DB) Baseline

    Subject analysis set title
    Per-Protocol Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PP population included all ITT subjects who received the randomized study medication, were 75% - 125% compliant over the double-blind phase, and had no major protocol deviations. ’OL/DB baseline’ values in the following table represent Double-blind (DB) Baseline

    Subject analysis sets values
    		 Intent-to treat population Double-blind safety population Per-Protocol Population
    Number of subjects
    496
    496
    458
    Age categorical
    Units: Subjects
        85 years and over
    0
    0
    0
        <55
    378
    378
    347
        >=55
    118
    118
    111
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    44.4 ( 12.36 )
    44.4 ( 12.36 )
    44.6 ( 12.41 )
    Gender categorical
    Units: Subjects
        Female
    279
    279
    259
        Male
    217
    217
    199
    Region
    Units: Subjects
        North America
    149
    149
    135
        Asia
    10
    10
    9
        Europe
    279
    279
    260
        South America
    58
    58
    54
    Race
    Units: Subjects
        White
    429
    429
    401
        Black or African American
    44
    44
    39
        Asian
    13
    13
    11
        American Indian or Alaska native
    2
    2
    2
        Native Hawaiian or Other Pacific Islander
    0
    0
    0
        Other
    8
    8
    5
    OL/DB baseline YMRS total score
    Units: rating scales
        arithmetic mean (standard deviation)
    2.2 ( 2.66 )
    2.2 ( 2.66 )
    2.1 ( 2.61 )
    OL/DB baseline MADRS total score
    Units: rating scales
        arithmetic mean (standard deviation)
    4 ( 3.56 )
    4 ( 3.56 )
    4.1 ( 3.6 )
    OL/DB baseline CGI-BP-S overall score
    Units: rating scales
        arithmetic mean (standard deviation)
    1.67 ( 0.694 )
    1.67 ( 0.694 )
    1.66 ( 0.7 )

    End points

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    End points reporting groups
    Reporting group title
    Lurasidone + lithium / divalproex
    Reporting group description
    		 Upon meeting entry criteria, subjects began open-label treatment with lurasidone (20-80 mg/day) and either lithium or divalproex (if not currently taking one of these mood stabilizers) on the evening of Visit 2 (open-label phase baseline). For subjects previously not on either lithium or divalproex, Investigators determined which mood stabilizer was most appropriate to initiate: lithium and divalproex were dosed to achieve serum trough concentrations of 0.4-1.2 mEq/L and 50-125 μg/mL, respectively. All country-approved formulations of lithium or divalproex (including extended-release and controlled-release formulations) were permitted (with the exception of lithium orotate and magnesium valproate). Subjects remained in the open-label phase for a maximum of 20 weeks until they achieved and maintained consistent clinical stability.
    Reporting group title
    Lurasidone + lithium / divalproex
    Reporting group description
    		 Lurasidone in combination with either lithium or divalproex for up to 28 weeks: the last open-label dose level was maintained entering the double-blind phase (Visit 13). Subsequent dose adjustments, if necessary, were to occur at weekly intervals and in increments/decrements of 1 dose level, based on Investigator judgment.

    Reporting group title
    Placebo + lithium / divalproex
    Reporting group description
    		 Placebo in combination with either lithium or divalproex) for up to 28 weeks. Subjects randomized to matching placebo, the lurasidone dose taken during the open-label phase was discontinued. Subsequent dose adjustments, if necessary, were to occur at weekly intervals and in increments/decrements of 1 dose level, based on Investigator judgment. Subjects who completed the double-blind phase of the study or experienced a protocol-specified recurrence of any mood event during the double-blind phase were eligible to participate in a separate 3-month, open-label lurasidone extension study (D1050308).

    Subject analysis set title
    Intent-to treat population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT population included all subjects who were randomized and received at least 1 dose of study medication in the double-blind phase. Each subject was assigned to the randomized treatment. ’OL/DB baseline’ values in the following table represent Double-blind (DB) Baseline

    Subject analysis set title
    Double-blind safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Double-blind Safety Population included all subjects who received at least one dose of study medication in the Double-blind phase. Each subject was assigned to the treatment they actually received. ’OL/DB baseline’ values in the following table represent Double-blind (DB) Baseline

    Subject analysis set title
    Per-Protocol Population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PP population included all ITT subjects who received the randomized study medication, were 75% - 125% compliant over the double-blind phase, and had no major protocol deviations. ’OL/DB baseline’ values in the following table represent Double-blind (DB) Baseline

    Primary: Time to recurrence of any mood event (during double-blind [DB] phase)

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    End point title
    		 Time to recurrence of any mood event (during double-blind [DB] phase)
    End point description
    Mood event was defined as any of the following: • Fulfilled Diagnostic and Statistical Manual of Mental Disorders, 4th Ed., Text Revision (DSM-IV-TR) criteria for manic, mixed manic, hypomanic, or depressive episode. • Required treatment intervention for manic, mixed manic, hypomanic, or depressive symptoms with any antipsychotic (other than study drug), antidepressant, mood stabilizer (other than lithium or divalproex), anxiolytic agents, benzodiazepine (beyond dosage allowed for anxiety, agitation, or insomnia). • Psychiatric hospitalization for any bipolar mood episode. • Young Mania Rating Scale (YMRS) or Montgomery-Asberg Depression Rating Scale (MADRS) total score ≥ 18 or Clinical Global Impression-Bipolar Version, Severity of Illness (CGI-BP-S) score ≥ 4 at 2 consecutive assessments no more than 10 days apart. • Discontinuation from the study because of a mood event (as determined by the Investigator).
    End point type
    Primary
    End point timeframe
    28 weeks
    End point values
    		 Lurasidone + lithium / divalproex Placebo + lithium / divalproex Intent-to treat population
    Number of subjects analysed
    246
    250
    496
    Units: Number of Recurrence events
    48
    64
    112
    Statistical analysis title
    		 Analysis of time to recurrence of any mood event
    Statistical analysis description
    The primary efficacy analysis for the time to recurrence of any mood event will be performed using a stratified Cox model to assess the hazard ratio of recurrence between the two treatment groups on the ITT population.
    Comparison groups
    Lurasidone + lithium / divalproex v Placebo + lithium / divalproex
    Number of subjects included in analysis
    496
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.078 [2]
    Method
    		 stratified Cox model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 1.04
    Notes
    [1] - It was assumed that the recurrence event rates during the double-blind phase were to be 24% and 39% for subjects treated with lurasidone and placebo, respectively. A total of 120 recurrence events were required to achieve 90% power to detect the 15% difference in subjects who had a recurrence event during the double-blind phase between the treatment groups using a log-rank test with two sided alpha level of 0.05.
    [2] - A hazard ratio of time to recurrence and its corresponding 95% Wald CI were estimated for lurasidone arm vs the placebo arm, using a Cox proportional hazards model. Cox model included treatment effect as fixed effect, and stratified by pooled country

    Secondary: Time to All-cause Discontinuation

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    End point title
    		 Time to All-cause Discontinuation
    End point description
    Time to all-cause discontinuation is defined as: ((date of discontinuation - date of randomization) + 1). For subjects who completed the study or discontinued early due to sponsor's decision to stop the study, time to discontinuation is censored at time of completion or discontinuation.
    End point type
    Secondary
    End point timeframe
    28 weeks double-blind phase
    End point values
    		 Lurasidone + lithium / divalproex Placebo + lithium / divalproex Intent-to treat population
    Number of subjects analysed
    246
    250
    496
    Units: number of recurrence events
    78
    100
    178
    Statistical analysis title
    		 Time to all-cause discontinuation
    Statistical analysis description
    Time to all-cause discontinuation is defined as: ((date of discontinuation - date of randomization) + 1). For subjects who completed the study or discontinued early due to sponsor's decision to stop the study, time to discontinuation is censored at time of completion or discontinuation
    Comparison groups
    Placebo + lithium / divalproex v Lurasidone + lithium / divalproex
    Number of subjects included in analysis
    496
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.034 [3]
    Method
    		 stratified Cox model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 0.98
    Notes
    [3] - A hazard ratio of time to discontinuation and its corresponding 95% Wald CI were estimated for lurasidone vs placebo arms, using a Cox proportional hazards model. Cox model included treatment effect as fixed effect, and stratified by pooled country

    Secondary: Time to recurrence of a manic, mixed manic, hypomanic or depressed episode

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    End point title
    		 Time to recurrence of a manic, mixed manic, hypomanic or depressed episode
    End point description
    Recurrence is defined as any event of manic, mixed manic, hypomanic, or depressed episode. For subjects who discontinued early or completed the study without experiencing a recurrence event, time to recurrence is censored at the time of discontinuation or completion.
    End point type
    Secondary
    End point timeframe
    28 weeks double-blind phase
    End point values
    		 Lurasidone + lithium / divalproex Placebo + lithium / divalproex Intent-to treat population
    Number of subjects analysed
    246
    250
    496
    Units: Number of recurrence events
    41
    54
    95
    Statistical analysis title
    		 Time to Recurrence of a Manic, Mxd Manic, HM or DE
    Comparison groups
    Lurasidone + lithium / divalproex v Placebo + lithium / divalproex
    Number of subjects included in analysis
    496
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.113 [4]
    Method
    		 stratified Cox model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.08
    Notes
    [4] - A hazard ratio of time to recurrence and its corresponding 95% Wald CI were estimated for lurasidone versus placebo arms, using a Cox proportional hazards model. The Cox model included treatment as a fixed effect, stratified by pooled countries.

    Secondary: Proportion of subjects with recurrence of manic, mixed manic, hypomanic or depressing episode

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    End point title
    		 Proportion of subjects with recurrence of manic, mixed manic, hypomanic or depressing episode
    End point description
    End point type
    Secondary
    End point timeframe
    28 weeks double-blind phase
    End point values
    		 Lurasidone + lithium / divalproex Placebo + lithium / divalproex Intent-to treat population
    Number of subjects analysed
    246
    250
    496
    Units: subjects
    41
    54
    95
    No statistical analyses for this end point

    Secondary: Global Severity: CGI-BP-S, YMRS, MADRS, QIDS-SR16, and PANSS-P

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    End point title
    		 Global Severity: CGI-BP-S, YMRS, MADRS, QIDS-SR16, and PANSS-P
    End point description
    CGI-BP-S is a clinical-rated assessment of th subject's current illness state (mania, depression, and overall bipolar illness), on a 7-point scale, where a higher score is associated with greater illness severity. YMRS is an 11-item instrument used to assess the severity of mania in subjects wiht a bipolar disorder. Ratings are based on patient self-reporting, combined with clinician observation (accorded greater score). YMRS total score ranges from 0-60, with higher scores indicating greater severity of mania. MADRS is a clinician-rated assessment of the subject's level of depression containing 10 items scored in a range of 0 to 6 points, with higher scores indicating increased depressive symptoms. QIDS-SR16 is a 16-item self-report measure of depressive symptomatology which uses a computerized assessment interface for administration. The total score ranges form 0 to 27, with higher scores indicating greater severity of depression. PANSS-P rates 7 positive symptoms of schizophrenia.
    End point type
    Secondary
    End point timeframe
    Outcome Measure Timeframe: 28 weeks double-blind phase
    End point values
    		 Lurasidone + lithium / divalproex Placebo + lithium / divalproex
    Number of subjects analysed
    246 [5]
    250 [6]
    Units: score
    least squares mean (standard error)
        CGI-BP-S overall
    0.4 ( 0.085 )
    0.49 ( 0.085 )
        CGI-BP-S mania
    0.1 ( 0.062 )
    0.21 ( 0.062 )
        CGI-BP-S depression
    0.35 ( 0.082 )
    0.42 ( 0.081 )
        YMRS
    1 ( 0.43 )
    1.8 ( 0.43 )
        MADRS
    3 ( 0.57 )
    3.5 ( 0.57 )
        QIDS-SR16
    0.9 ( 0.27 )
    1.1 ( 0.27 )
        PANSS-P
    0.2 ( 0.13 )
    0.3 ( 0.13 )
    Notes
    [5] - No. subjects analysed for the below questionnaires: CGI, YMRS, MADRS: 244 QIDS: 239 PANSS-P: 240
    [6] - No. subjects analysed for the below questionnaires: CGI, YMRS, MADRS: 250 QIDS: 243 PANSS-P: 247
    Statistical analysis title
    		 CGI-BP-S overall score: change from DB Phase BL
    Statistical analysis description
    The CGI-BP-S overall score is a single value, clinician-rated assessment of overall bipolar illness severity and ranges from 1= ‘Normal, not at all ill’ to 7= ‘Among the most extremely ill patients’. A higher score is associated with greater illness severity. Subjects were analyzed based on the treatment they were randomized. 2 lurasidone + Li/VPA subjects did not have post-DB baseline CGI-BP-S overall score. Results at DB Week 28 (LOCF).
    Comparison groups
    Placebo + lithium / divalproex v Lurasidone + lithium / divalproex
    Number of subjects included in analysis
    496
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.406 [8]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference of luras. vs placebo
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.29
         upper limit
    		 0.12
    Notes
    [7] - 2 lurasidone + Li/VPA subjects did not have post-DB baseline CGI-BP-S overall score therefore number of subjects included in analysis for the CGI-BP-S overall score were finally 494.
    [8] - Analysis of Covariance (ANCOVA) model contains treatment, and pooled country, and mood stabilizer (lithium or divalproex) as fixed factors and baseline as a covariate.
    Statistical analysis title
    		 CGI-BP-S mania score: change from DB Phase BL
    Statistical analysis description
    The CGI-BP-S mania score is a single value, clinician-rated assessment of mania illness severity and ranges from 1= ‘Normal, not at all ill’ to 7= ‘Among the most extremely ill patients’. A higher score is associated with greater illness severity. Results at DB Week 28 (LOCF)
    Comparison groups
    Lurasidone + lithium / divalproex v Placebo + lithium / divalproex
    Number of subjects included in analysis
    496
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.162 [10]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference of luras. vs placebo
    Point estimate
    -0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 0.04
    Notes
    [9] - 2 lurasidone + Li/VPA subjects did not have post-DB baseline CGI-BP-S mania score therefore number of subjects included in analysis for the CGI-BP-S mania score were finally 494.
    [10] - Analysis of Covariance (ANCOVA) model contains treatment, and pooled country, and mood stabilizer (lithium or divalproex) as fixed factors and baseline as a covariate.
    Statistical analysis title
    		 CGI-BP-S depression score: change from DB Phase BL
    Statistical analysis description
    The CGI-BP-S depression score is a single value, clinician-rated assessment of depression illness severity and ranges from 1= ‘Normal, not at all ill’ to 7= ‘Among the most extremely ill patients’. A higher score is associated with greater illness severity. Results at DB Week 28 (LOCF)
    Comparison groups
    Lurasidone + lithium / divalproex v Placebo + lithium / divalproex
    Number of subjects included in analysis
    496
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.496 [12]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference of luras. vs placebo
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.27
         upper limit
    		 0.13
    Notes
    [11] - 2 lurasidone + Li/VPA subjects did not have post-DB baseline CGI-BP-S depression score therefore the number of subjects included in analysis for the CGI-BP-S depression score were finally 494.
    [12] - Analysis of Covariance (ANCOVA) model contains treatment, and pooled country, and mood stabilizer (lithium or divalproex) as fixed factors and baseline as a covariate.
    Statistical analysis title
    		 YMRS total score: change from DB Phase BL
    Statistical analysis description
    The YMRS is an 11 item instrument used to assess the severity of mania in subjects with a diagnosis of bipolar disorder. Ratings are based on patient self reporting, combined with clinician observation (accorded greater score). The YMRS total score is calculated as the sum of the 11 items. The YMRS total score ranges from 0 to 60. Higher scores are associated with greater severity of mania. Results at DB Week 28 (LOCF)
    Comparison groups
    Lurasidone + lithium / divalproex v Placebo + lithium / divalproex
    Number of subjects included in analysis
    496
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.128 [14]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference of luras. vs placebo
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 0.2
    Notes
    [13] - 2 lurasidone + Li/VPA subjects did not have post-DB baseline YMRS total score therefore the number of subjects included in analysis for the YMRS total score were finally 494.
    [14] - Analysis of Covariance (ANCOVA) model contains treatment, and pooled country, and mood stabilizer (lithium or divalproex) as fixed factors and baseline as a covariate.
    Statistical analysis title
    		 MADRS total score: change from DB Phase BL
    Statistical analysis description
    The MADRS consists of 10 items, each rated on a Likert scale, from 0=”Normal” to 6=”Most Severe”. The MADRS total score is calculated as the sum of the 10 items. The MADRS total score ranges from 0 to 60. Higher scores are associated with greater severity of depressive symptoms. Results at DB Week 28 (LOCF)
    Comparison groups
    Lurasidone + lithium / divalproex v Placebo + lithium / divalproex
    Number of subjects included in analysis
    496
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.485 [16]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference of luras. vs placebo
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.9
         upper limit
    		 0.9
    Notes
    [15] - 2 lurasidone + Li/VPA subjects did not have post-DB baseline MADRS total score therefore the number of subjects included in analysis for the MADRS total score were finally 494.
    [16] - Analysis of Covariance (ANCOVA) model contains treatment, and pooled country, and mood stabilizer (lithium or divalproex) as fixed factors and baseline as a covariate.
    Statistical analysis title
    		 QIDS-SR16 total score: change from DB Phase BL
    Statistical analysis description
    The QIDS-SR16 is a 16-item self-report measure of depressive symptomatology which uses a computerized assessment interface for administration. The scoring system for the QIDS-SR16 converts responses to 16 separate items into nine DSM-IV symptom criterion domains. Nine domains comprise: depressed mood; concentration/decision making; self outlook; suicidal ideation; decreased interest; decreased energy; sleep disturbance; appetite/weight disturbance; and psychomotor disturbance. LOCF results
    Comparison groups
    Lurasidone + lithium / divalproex v Placebo + lithium / divalproex
    Number of subjects included in analysis
    496
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.582 [18]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference of luras. vs placebo
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 0.5
    Notes
    [17] - QIDS-SR16 total score is calculated as the sum of the 9 domain scores. QIDS-SR16 total score ranges from 0 to 27 with a high score indicating more severe symptoms. 7 lurasidone + Li/VPA subjects and 7 placebo +Li/VPA subjects did not have post-DB baseline QIDS-SR16 total score therefore the number of subjects included in analysis for the QIDS-SR16 total score were finally 482.
    [18] - Analysis of Covariance (ANCOVA) model contains treatment, and pooled country, and mood stabilizer (lithium or divalproex) as fixed factors and baseline as a covariate.
    Statistical analysis title
    		 PANSS-P subscale score: change from DB Phase BL
    Statistical analysis description
    The PANSS-P is a subset of items in the PANSS, an interview-based measure of the severity of psychopathology in adults with psychotic disorders. The measure contains seven questions to assess delusions, conceptual disorganization, hallucinations behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. An anchored Likert scale from 1-7, where values of 2 and above indicate the presence of progressively more severe symptoms, is used to score each item. LOCF Results
    Comparison groups
    Lurasidone + lithium / divalproex v Placebo + lithium / divalproex
    Number of subjects included in analysis
    496
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.42 [20]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference of luras. vs placebo
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 0.2
    Notes
    [19] - The PANSS-P subscale score is the sum of the 7 items and ranges from 7 through 49. A higher score is associated with greater illness severity. 6 lurasidone + Li/VPA subjects and 3 placebo +Li/VPA subjects did not have post-DB baseline PANSS-P score therefore the number of subjects included in analysis for the PANSS-P score were finally 487.
    [20] - Analysis of Covariance (ANCOVA) model contains treatment, and pooled country, and mood stabilizer (lithium or divalproex) as fixed factors and baseline as a covariate.

    Secondary: SDS Total Score: change from DB phase BL

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    End point title
    		 SDS Total Score: change from DB phase BL
    End point description
    The SDS is a composite of 3 self-rated items designed to measure the extent to which 3 major sectors in the patient’s life are impaired by depressive symptoms. This anchored visual analog scale uses spatiovisual, numeric, and verbal descriptive anchors simultaneously to assess disability across 3 domains (work, social life, and family life) on a 10-point visual analog scale. The total score of global functional impairment ranges from 0 to 30, with higher scores indicating a greater degree of disability.
    End point type
    Secondary
    End point timeframe
    28 weeks
    End point values
    		 Lurasidone + lithium / divalproex Placebo + lithium / divalproex
    Number of subjects analysed
    183
    193
    Units: scores
        least squares mean (standard error)
    0.4 ( 0.59 )
    0.6 ( 0.61 )
    Statistical analysis title
    		 SDS total score: change from DB Phase BL
    Statistical analysis description
    The SDS total score is a composite of three self-rated items designed to measure the extent to which three major sectors in the patient’s life are impaired by depressive symptoms. The SDS total score is calculated as the sum of the 3 items. The SDS total score ranges from 0 to 30. Higher scores are associated with greater severity of global functional impairments. Results at DB Week 28 (LOCF)
    Comparison groups
    Lurasidone + lithium / divalproex v Placebo + lithium / divalproex
    Number of subjects included in analysis
    376
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 = 0.788
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference of luras. vs placebo
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 1.2
    Notes
    [21] - If a subject has not worked/studied at all during the past week for reasons unrelated to the disorder, the SDS total score will be set to missing. 63 lurasidone + Li/VPA subjects and 57 placebo +Li/VPA subjects did not have post-DB baseline SDS total score therefore the number of subjects included in analysis for the SDS total score were finally 376 .

    Secondary: Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form

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    End point title
    		 Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form
    End point description
    The Q-LES-Q-SF is a 16-item self-report measure of the degree of enjoyment and satisfaction in various areas of daily living. Q-LES-Q-SF percent maximum possible scores range from 0-100, where higher scores indicate better quality of life.
    End point type
    Secondary
    End point timeframe
    28 weeks
    End point values
    		 Lurasidone + lithium / divalproex Placebo + lithium / divalproex
    Number of subjects analysed
    234
    239
    Units: score
        least squares mean (standard error)
    -1.7 ( 1.022 )
    -2.07 ( 1.035 )
    Statistical analysis title
    		 Q-LES-Q-SF: change from DB Phase BL
    Statistical analysis description
    Q-LES-Q-SF is a 16-item self-report measure of the degree of enjoyment and satisfaction in various areas of daily living. The questionnaire was developed and validated for use in depressed outpatient subjects and has eight summary scales that reflect major areas of functioning: physical health, mood, leisure time activities, social relationships, general activities, work, household duties and school/coursework. Each item is rated on a 5-point scale, ranging from 1 (very poor) to 5 (very good).
    Comparison groups
    Lurasidone + lithium / divalproex v Placebo + lithium / divalproex
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [22]
    P-value
    		 = 0.772 [23]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference of luras. vs placebo
    Point estimate
    0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.14
         upper limit
    		 2.88
    Notes
    [22] - The Q-LES-Q-SF percentage maximum possible score is calculated as 100 × (Raw Score – 14 [Minimum Score]) / (70 [Maximum Score] – 14 [Minimum Score]). Higher percent maximum scores indicate better quality of life. 12 lurasidone + Li/VPA subjects and 11 placebo +Li/VPA subjects did not have post-DB baseline Q-LES-Q-SF percent maximum possible score therefore the number of subjects included in this analysis were finally 473. Results at DB Week 28 (LOCF)
    [23] - Analysis of Covariance (ANCOVA) model contains treatment, and pooled country, and mood stabilizer (lithium or divalproex) as fixed factors and baseline as a covariate.

    Secondary: Sleep quality assessed by the Pittsburgh Insomnia Rating Scale (PIRS-2).

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    End point title
    		 Sleep quality assessed by the Pittsburgh Insomnia Rating Scale (PIRS-2).
    End point description
    The PIRS-2 is a 2-item self-report of insomnia. The PIRS-2 total score ranges from 0-6, where higher scores indicating greater impairment.
    End point type
    Secondary
    End point timeframe
    28 weeks
    End point values
    		 Lurasidone + lithium / divalproex Placebo + lithium / divalproex
    Number of subjects analysed
    239
    243
    Units: score
        least squares mean (standard error)
    0.4 ( 0.1 )
    0.5 ( 0.1 )
    Statistical analysis title
    		 PIRS-2 total score: change from DB Phase BL
    Statistical analysis description
    The PIRS-2 is a 2-item self-report of insomnia assessed via a computer interface. Each item is scored from 0-3. The PIRS-2 total score is calculated as the sum of the 2 items. The PIRS total score ranges from 0 to 6. Higher scores are associated with greater severity of insomnia. Results at DB Week 28 (LOCF)
    Comparison groups
    Lurasidone + lithium / divalproex v Placebo + lithium / divalproex
    Number of subjects included in analysis
    482
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [24]
    P-value
    		 = 0.38 [25]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean difference of luras. vs placebo
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.1
    Notes
    [24] - 7 lurasidone + Li/VPA subjects and 7 placebo +Li/VPA subjects did not have post-DB baseline PIRS-2 total score therefore the number of subjects included in this analysis were finally 482 .
    [25] - Analysis of Covariance (ANCOVA) model contains treatment, and pooled country, and mood stabilizer (lithium or divalproex) as fixed factors and baseline as a covariate.

    Secondary: SF-12 Health Survey

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    End point title
    		 SF-12 Health Survey
    End point description
    The SF-12 is a multipurpose short-form generic measure of health status. It was developed to be a much shorter, yet valid, alternative to the SF-36 for use in large surveys of general and specific populations as well as large longitudinal studies of health outcomes. The standard (4-week) recall version was utilized. Higher scores indicate better quality of life.
    End point type
    Secondary
    End point timeframe
    28 weeks
    End point values
    		 Lurasidone + lithium / divalproex Placebo + lithium / divalproex
    Number of subjects analysed
    236
    244
    Units: score
    arithmetic mean (standard deviation)
        SF-12 Health Survey Component Scores: Mental
    47.3 ( 10.97 )
    46.1 ( 11.19 )
        SF-12 Health Survey Component Scores: Physical
    51.5 ( 7.44 )
    51.7 ( 7.89 )
    No statistical analyses for this end point

    Secondary: Medication Satisfaction Questionnaire

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    End point title
    		 Medication Satisfaction Questionnaire
    End point description
    The MSQ is a single-item assessment that requires the subject to use a 7-point, Likert-type scale to rate how satisfied they are with their current medication used to treat bipolar disorder, with a higher score indicating higher satisfaction.
    End point type
    Secondary
    End point timeframe
    28 weeks
    End point values
    		 Lurasidone + lithium / divalproex Placebo + lithium / divalproex
    Number of subjects analysed
    222
    222
    Units: score
        arithmetic mean (standard deviation)
    5.2 ( 1.45 )
    5.1 ( 1.44 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    - During open label phase (up to 20 weeks) - During double blind phase (up to 28 weeks)
    Adverse event reporting additional description
    Adverse Events were collected and recorded from the date the informed consent form was signed until the end of participation in the study. SAEs were collected for each subject through 14 days after the subject’s last dose of study drug: after the 14-day timeframe, investigator did report SAEs “spontaneously if considered at least PS related
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Open-label safety
    Reporting group description
    		 Open-label safety population included all subjects who received at least 1 dose of study medication ( lurasidone (20-80 mg/day, and either lithium or divalproex), in the open-label phase.

    Reporting group title
    Placebo + Li/VPA
    Reporting group description
    		 subjects who were randomized and received at least 1 dose of study medication (placebo + Li/VPA) in the double-blind phase

    Reporting group title
    Lurasidone + Li/VPA
    Reporting group description
    		 subjects who were randomized and received at least 1 dose of study medication (Lurasidone + Li/VPA) in the double-blind phase

    Serious adverse events
    		 Open-label safety Placebo + Li/VPA Lurasidone + Li/VPA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    41 / 962 (4.26%)
    11 / 250 (4.40%)
    13 / 246 (5.28%)
         number of deaths (all causes)
    0
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign ovarian tumour
         subjects affected / exposed
    1 / 962 (0.10%)
    0 / 250 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    0 / 962 (0.00%)
    1 / 250 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Brain neoplasm
         subjects affected / exposed
    1 / 962 (0.10%)
    0 / 250 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 962 (0.00%)
    1 / 250 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 962 (0.10%)
    0 / 250 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine prolapse
         subjects affected / exposed
    1 / 962 (0.10%)
    0 / 250 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 962 (0.00%)
    1 / 250 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 962 (0.10%)
    0 / 250 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mania
         subjects affected / exposed
    5 / 962 (0.52%)
    3 / 250 (1.20%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 5
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    10 / 962 (1.04%)
    1 / 250 (0.40%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    5 / 10
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    2 / 962 (0.21%)
    0 / 250 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bipolar I disorder
         subjects affected / exposed
    2 / 962 (0.21%)
    2 / 250 (0.80%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bipolar disorder
         subjects affected / exposed
    0 / 962 (0.00%)
    0 / 250 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depressive symptoms
         subjects affected / exposed
    2 / 962 (0.21%)
    0 / 250 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    2 / 962 (0.21%)
    0 / 250 (0.00%)
    2 / 246 (0.81%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicidal attempt
         subjects affected / exposed
    2 / 962 (0.21%)
    0 / 250 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intentional self-injury
         subjects affected / exposed
    0 / 962 (0.00%)
    0 / 250 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute psychosis
         subjects affected / exposed
    1 / 962 (0.10%)
    0 / 250 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 962 (0.10%)
    0 / 250 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Insomnia
         subjects affected / exposed
    1 / 962 (0.10%)
    0 / 250 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    1 / 962 (0.10%)
    0 / 250 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Somatoform disorder
         subjects affected / exposed
    1 / 962 (0.10%)
    0 / 250 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 962 (0.00%)
    1 / 250 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 962 (0.00%)
    1 / 250 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    2 / 962 (0.21%)
    0 / 250 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    1 / 962 (0.10%)
    0 / 250 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 962 (0.10%)
    0 / 250 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 962 (0.10%)
    0 / 250 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 962 (0.10%)
    0 / 250 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 962 (0.10%)
    0 / 250 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 962 (0.10%)
    0 / 250 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 962 (0.00%)
    1 / 250 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 962 (0.10%)
    0 / 250 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 962 (0.10%)
    0 / 250 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    1 / 962 (0.10%)
    1 / 250 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelitiasis
         subjects affected / exposed
    0 / 962 (0.00%)
    0 / 250 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 962 (0.00%)
    0 / 250 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Chondromalacia
         subjects affected / exposed
    1 / 962 (0.10%)
    0 / 250 (0.00%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 962 (0.00%)
    0 / 250 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint swelling
         subjects affected / exposed
    0 / 962 (0.00%)
    0 / 250 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Patellofemoral pain syndrome
         subjects affected / exposed
    0 / 962 (0.00%)
    1 / 250 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 962 (0.00%)
    0 / 250 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 962 (0.00%)
    1 / 250 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 962 (0.00%)
    1 / 250 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypokalemia
         subjects affected / exposed
    0 / 962 (0.00%)
    0 / 250 (0.00%)
    1 / 246 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 962 (0.00%)
    1 / 250 (0.40%)
    0 / 246 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Open-label safety Placebo + Li/VPA Lurasidone + Li/VPA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    474 / 962 (49.27%)
    151 / 250 (60.40%)
    153 / 246 (62.20%)
    Investigations
    Weight increased
         subjects affected / exposed
    22 / 962 (2.29%)
    13 / 250 (5.20%)
    24 / 246 (9.76%)
         occurrences all number
    22
    13
    24
    Nervous system disorders
    Headache
         subjects affected / exposed
    88 / 962 (9.15%)
    17 / 250 (6.80%)
    21 / 246 (8.54%)
         occurrences all number
    88
    17
    21
    Akathisia
         subjects affected / exposed
    80 / 962 (8.32%)
    8 / 250 (3.20%)
    9 / 246 (3.66%)
         occurrences all number
    80
    8
    9
    Somnolence
         subjects affected / exposed
    69 / 962 (7.17%)
    2 / 250 (0.80%)
    4 / 246 (1.63%)
         occurrences all number
    69
    2
    4
    Tremor
         subjects affected / exposed
    43 / 962 (4.47%)
    11 / 250 (4.40%)
    15 / 246 (6.10%)
         occurrences all number
    43
    11
    15
    Sedation
         subjects affected / exposed
    34 / 962 (3.53%)
    1 / 250 (0.40%)
    0 / 246 (0.00%)
         occurrences all number
    34
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    29 / 962 (3.01%)
    3 / 250 (1.20%)
    3 / 246 (1.22%)
         occurrences all number
    29
    3
    3
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    111 / 962 (11.54%)
    4 / 250 (1.60%)
    7 / 246 (2.85%)
         occurrences all number
    111
    4
    7
    Vomiting
         subjects affected / exposed
    59 / 962 (6.13%)
    4 / 250 (1.60%)
    5 / 246 (2.03%)
         occurrences all number
    59
    4
    5
    Diarrhoea
         subjects affected / exposed
    53 / 962 (5.51%)
    7 / 250 (2.80%)
    5 / 246 (2.03%)
         occurrences all number
    53
    7
    5
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    77 / 962 (8.00%)
    16 / 250 (6.40%)
    9 / 246 (3.66%)
         occurrences all number
    77
    16
    9
    Anxiety
         subjects affected / exposed
    41 / 962 (4.26%)
    11 / 250 (4.40%)
    4 / 246 (1.63%)
         occurrences all number
    41
    11
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    39 / 962 (4.05%)
    12 / 250 (4.80%)
    15 / 246 (6.10%)
         occurrences all number
    39
    12
    15
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 962 (1.04%)
    9 / 250 (3.60%)
    2 / 246 (0.81%)
         occurrences all number
    10
    9
    2
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    30 / 962 (3.12%)
    2 / 250 (0.80%)
    0 / 246 (0.00%)
         occurrences all number
    30
    2
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 May 2011
    Amendment 1, 06 May 2011, implemented the following non-administrative changes: - The BMI was changed to a system-derived value in the eCRF; therefore, the BMI criterion was removed from the inclusion/exclusion criteria and visit assessments and the BMI determination appendix was deleted. - Additional visits were added to the DB phase in order to monitor the subject’s postrandomization status more frequently (weekly for the first 2 weeks immediately after randomization visit, and every 2 weeks thereafter). In addition, an interim telephone call was added during the DB phase to assess the subject’s status (AEs and concomitant medications) at weekly intervals. In addition to scheduled visits, subject ’s would be contacted via an interim telephone call by site staff to monitor AEs and concomitant medications at Week 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, and 27. - The allowed hospitalization period during the screening/wash-out phase was extended from 24 hours to up-to a maximum of 7 days. - Safety reporting requirements were updated to include a 14-day follow-up period requirement post last dose of study drug. - Removed the exclusion criteria requiring subject scores ≥ 4 on MADRS item number 10 (suicidal thoughts) at screening. - The key secondary analysis was revised to use heterogenous compound symmetry, which is more appropriate than the spatial exponential covariance pattern model that was originally planned.
    17 Jan 2013
    Amendment 2, 17 Jan 2013, implemented the following non-administrative changes: - Safety reporting and monitoring contact information was updated. - Various contact information was updated. - The key secondary endpoint, CG-BP-S, was changed to a secondary endpoint. - The C-SSRS was changed from an efficacy to a safety assessment. - The YMRS/MADRS inclusion criterion was modified to allow the open-label baseline time point in addition to screening. - Subjects who experience a protocol-specified recurrence of any mood event during the double-blind phase were also allowed the option to enroll in a separate 3-month, open-label lurasidone extension study. - Adjustments for multiplicity were deleted. - Pharmacogenomic blood sample collection, processing, storage, and shipment information was updated.
    06 Jan 2014
    Amendment 3, 06 Jan 2014, implemented the following non-administrative changes: - Updated the number of recurrence events and the resulting number of subjects needed to be randomized. - Updated the safety reporting information. - Updated various contact information. Various typographical and grammatical edits to improve consistency and overall readability have been incorporated.

    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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    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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