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    Clinical Trial Results:
    A 2-Year, Open-Label, Single-Arm Safety Study of Flexibly Dosed Paliperidone Extended Release (1.5-12 mg/day) in the Treatment of Adolescents (12 to 17 Years of Age) With Schizophrenia

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    2007-000577-38
    Trial protocol
    FI   BE   EE   PL   BG   Outside EU/EEA  
    Global end of trial date
    18 Jul 2012

    Results information
    Results version number
    v2(current)
    This version publication date
    02 Jun 2016
    First version publication date
    30 Jul 2015
    Other versions
    v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    Review of data

    Trial information

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    Trial identification
    Sponsor protocol code
    R076477-PSZ-3002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00488319
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen-Cilag International NV
    Sponsor organisation address
    Turnhoutseweg 30, 2340 Beerse, Belgium,
    Public contact
    Janssen-Cilag International NV, Janssen-Cilag International NV, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Janssen-Cilag International NV, Janssen-Cilag International NV, ClinicalTrialsEU@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000014-PIP01-07
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Jul 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Jul 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jul 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the long-term (2-year) safety and tolerability of paliperidone extended release (ER) in at least 100 adolescent subjects (12 to 17 years of age, inclusive) with schizophrenia.
    Protection of trial subjects
    This study had an independent Data Safety Monitoring Board (DSMB) to ensure subject safety throughout the study. Safety evaluations included monitoring of clinical laboratory tests (hematology, serum chemistry, lipid levels, fasting glucose, insulin and urinalysis), urine drug screen, vital sign measurements (temperature, pulse, and blood pressure), physical examinations and Tanner Staging, electrocardiograms (ECGs), pregnancy tests, investigation of weight gain, height, waist circumference and metabolic disturbances, monitoring of extrapyramidal symptoms (EPS), Columbia Suicide Severity Rating Scale, C-CASA assessment of potentially suicide-related events and other adverse events (included psychiatric adverse events).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    27 Jun 2007
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 6
    Country: Number of subjects enrolled
    Estonia: 3
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    India: 64
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 40
    Country: Number of subjects enrolled
    Poland: 47
    Country: Number of subjects enrolled
    Romania: 20
    Country: Number of subjects enrolled
    Russian Federation: 109
    Country: Number of subjects enrolled
    Ukraine: 48
    Country: Number of subjects enrolled
    United States: 60
    Worldwide total number of subjects
    400
    EEA total number of subjects
    79
    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)
    397
    Adults (18-64 years)
    3
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study evaluated the long-term (2 year) safety and tolerability of paliperidone ER in adolescent subjects with schizophrenia. This study was conducted from 27 June 2007 to 18 July 2012 at 55 centers in 10 countries. A total of 400 subjects received at least 1 dose of the study drug and were included in the safety analysis.

    Pre-assignment
    Screening details
    Subjects enrolled in this study came from three different sources: subjects who enrolled directly, subjects who were randomly assigned to placebo in the R076477PSZ3001 (NCT00518323) study and subjects who were randomly assigned to paliperidone ER in the R076477PSZ3001 (NCT00518323) study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo/Pali
    Arm description
    Subjects in this group were previously assigned to placebo in the R076477PSZ3001 (NCT00518323) study. They started with an oral dose of 6 milligram (mg) tablets daily, regardless of prior treatment assignment in R076477PSZ3001 (NCT00518323). The initial 6 mg daily dose was increased in increments of 3 mg, not more frequently than once every 5 days until the maximum dose of 12 mg daily was reached. If 12 mg was not well tolerated, then the dose could be reduced down to 9 mg daily. Alternatively the dose could be decreased to 3 mg or 1.5 mg daily, if the initial 6 mg dose was not well tolerated.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects in this group were previously assigned to placebo in the R076477PSZ3001 (NCT00518323) study. They started with an oral dose of 6 mg tablets daily. The initial 6 mg daily dose was increased in increments of 3 mg, not more frequently than once every 5 days until the maximum dose of 12 mg daily was reached.

    Arm title
    Pali (DB)/Pali
    Arm description
    Subjects in this group were previously assigned to paliperidone ER in the R076477PSZ3001 (NCT00518323) study. They started with an oral dose of 6 mg tablets daily, regardless of prior treatment assignment in R076477PSZ3001 (NCT00518323). The initial 6 mg daily dose was increased in increments of 3 mg, not more frequently than once every 5 days until the maximum dose of 12 mg daily was reached. If 12 mg was not well tolerated, then the dose could be reduced down to 9 mg daily. Alternatively the dose could be decreased to 3 mg or 1.5 mg daily, if the initial 6 mg dose was not well tolerated.
    Arm type
    Experimental

    Investigational medicinal product name
    Paliperidone ER
    Investigational medicinal product code
    F071
    Other name
    INVEGA
    Pharmaceutical forms
    Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All enrolled subjects received a starting dose of paliperidone ER 6 mg daily and increased in increments of 3 mg, not more frequently than once every 5 days until the maximum dose of 12 mg daily was reached.

    Arm title
    Pali (NO DB)/Pali
    Arm description
    Subjects in this group were directly enrolled into the study and started with an oral dose of 6 mg tablets daily. The initial 6 mg daily dose was increased in increments of 3 mg, not more frequently than once every 5 days until the maximum dose of 12 mg daily was reached. If 12 mg was not well tolerated, then the dose could be reduced down to 9 mg daily. Alternatively the dose could be decreased to 3 mg or 1.5 mg daily, if the initial 6 mg dose was not well tolerated.
    Arm type
    Experimental

    Investigational medicinal product name
    Paliperidone ER
    Investigational medicinal product code
    F071
    Other name
    INVEGA
    Pharmaceutical forms
    Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received an oral dose of 6 mg tablets daily. The initial 6 mg daily dose was increased in increments of 3 mg, not more frequently than once every 5 days until the maximum dose of 12 mg daily was reached.

    Number of subjects in period 1
    Placebo/Pali Pali (DB)/Pali Pali (NO DB)/Pali
    Started
    39
    118
    243
    Completed
    24
    75
    121
    Not completed
    15
    43
    122
         Other
    -
    4
    12
         Lack of efficacy
    6
    12
    27
         Adverse Event
    1
    2
    23
         Subject Choice (Subject Withdrew Consent)
    5
    20
    44
         Lost to follow-up
    3
    5
    16

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo/Pali
    Reporting group description
    Subjects in this group were previously assigned to placebo in the R076477PSZ3001 (NCT00518323) study. They started with an oral dose of 6 milligram (mg) tablets daily, regardless of prior treatment assignment in R076477PSZ3001 (NCT00518323). The initial 6 mg daily dose was increased in increments of 3 mg, not more frequently than once every 5 days until the maximum dose of 12 mg daily was reached. If 12 mg was not well tolerated, then the dose could be reduced down to 9 mg daily. Alternatively the dose could be decreased to 3 mg or 1.5 mg daily, if the initial 6 mg dose was not well tolerated.

    Reporting group title
    Pali (DB)/Pali
    Reporting group description
    Subjects in this group were previously assigned to paliperidone ER in the R076477PSZ3001 (NCT00518323) study. They started with an oral dose of 6 mg tablets daily, regardless of prior treatment assignment in R076477PSZ3001 (NCT00518323). The initial 6 mg daily dose was increased in increments of 3 mg, not more frequently than once every 5 days until the maximum dose of 12 mg daily was reached. If 12 mg was not well tolerated, then the dose could be reduced down to 9 mg daily. Alternatively the dose could be decreased to 3 mg or 1.5 mg daily, if the initial 6 mg dose was not well tolerated.

    Reporting group title
    Pali (NO DB)/Pali
    Reporting group description
    Subjects in this group were directly enrolled into the study and started with an oral dose of 6 mg tablets daily. The initial 6 mg daily dose was increased in increments of 3 mg, not more frequently than once every 5 days until the maximum dose of 12 mg daily was reached. If 12 mg was not well tolerated, then the dose could be reduced down to 9 mg daily. Alternatively the dose could be decreased to 3 mg or 1.5 mg daily, if the initial 6 mg dose was not well tolerated.

    Reporting group values
    Placebo/Pali Pali (DB)/Pali Pali (NO DB)/Pali Total
    Number of subjects
    39 118 243 400
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    39 116 242 397
        Adults (18-64 years)
    0 2 1 3
        From 65 to 84 years
    0 0 0 0
        85 years and over
    0 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    15.8 ± 1.48 15.3 ± 1.59 15.3 ± 1.53 -
    Title for Gender
    Units: subjects
        Female
    21 44 92 157
        Male
    18 74 151 243

    End points

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    End points reporting groups
    Reporting group title
    Placebo/Pali
    Reporting group description
    Subjects in this group were previously assigned to placebo in the R076477PSZ3001 (NCT00518323) study. They started with an oral dose of 6 milligram (mg) tablets daily, regardless of prior treatment assignment in R076477PSZ3001 (NCT00518323). The initial 6 mg daily dose was increased in increments of 3 mg, not more frequently than once every 5 days until the maximum dose of 12 mg daily was reached. If 12 mg was not well tolerated, then the dose could be reduced down to 9 mg daily. Alternatively the dose could be decreased to 3 mg or 1.5 mg daily, if the initial 6 mg dose was not well tolerated.

    Reporting group title
    Pali (DB)/Pali
    Reporting group description
    Subjects in this group were previously assigned to paliperidone ER in the R076477PSZ3001 (NCT00518323) study. They started with an oral dose of 6 mg tablets daily, regardless of prior treatment assignment in R076477PSZ3001 (NCT00518323). The initial 6 mg daily dose was increased in increments of 3 mg, not more frequently than once every 5 days until the maximum dose of 12 mg daily was reached. If 12 mg was not well tolerated, then the dose could be reduced down to 9 mg daily. Alternatively the dose could be decreased to 3 mg or 1.5 mg daily, if the initial 6 mg dose was not well tolerated.

    Reporting group title
    Pali (NO DB)/Pali
    Reporting group description
    Subjects in this group were directly enrolled into the study and started with an oral dose of 6 mg tablets daily. The initial 6 mg daily dose was increased in increments of 3 mg, not more frequently than once every 5 days until the maximum dose of 12 mg daily was reached. If 12 mg was not well tolerated, then the dose could be reduced down to 9 mg daily. Alternatively the dose could be decreased to 3 mg or 1.5 mg daily, if the initial 6 mg dose was not well tolerated.

    Primary: The Number of Subjects Who Experienced Adverse Events as a Measure of Safety and Tolerability

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    End point title
    The Number of Subjects Who Experienced Adverse Events as a Measure of Safety and Tolerability [1]
    End point description
    A serious adverse event (SAE) as defined by the International Conference on Harmonisation (ICH) is any untoward medical occurrence that at any dose results in death, is life-threatening (the subject was at risk of death at the time of the even; it does not refer to an event that hypothetically might have caused death if it were more severe), requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect. Safety analysis set included all subjects who received at least 1 dose of open label study drug.
    End point type
    Primary
    End point timeframe
    Up to 2 years
    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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    Placebo/Pali Pali (DB)/Pali Pali (NO DB)/Pali
    Number of subjects analysed
    39
    118
    243
    Units: Number of subjects
        Treatment Emergent Adverse Events (TEAEs)
    32
    88
    221
        Possibly-related TEAEs
    24
    61
    185
        One or More Serious TEAEs
    9
    4
    46
    No statistical analyses for this end point

    Secondary: Change From Open-label Baseline to Open-label Endpoint in Positive and Negative Syndrome Scale for Schizophrenia (PANSS) Scores - Last Observation Carried Forward (LOCF)

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    End point title
    Change From Open-label Baseline to Open-label Endpoint in Positive and Negative Syndrome Scale for Schizophrenia (PANSS) Scores - Last Observation Carried Forward (LOCF)
    End point description
    The PANSS is a medical scale that assesses various symptoms of schizophrenia. The symptoms are rated on a 7-point scale from 1 (absent) to 7 (extreme psychopathology). The total score is the sum of all 30 PANSS items, with a range of 30 (absent) to 210 (extreme ill). Efficacy analysis set included all ITT open-label subjects who received at least 1 dose of open label study drug and had at least 1 postbaseline assessment in open-label phase.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104 or the last post-baseline assessment
    End point values
    Placebo/Pali Pali (DB)/Pali Pali (NO DB)/Pali
    Number of subjects analysed
    39
    117 [2]
    237 [3]
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -18.9 ± 21.47
    -12.6 ± 19.92
    -22.4 ± 22.25
    Notes
    [2] - 'N' signifies number of subjects analysed for this end point.
    [3] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Secondary: Change From Open-label Baseline to Open-label Endpoint in the Positive and Negative Syndrome Scale for Schizophrenia (PANSS) Based on Marder Factors - LOCF

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    End point title
    Change From Open-label Baseline to Open-label Endpoint in the Positive and Negative Syndrome Scale for Schizophrenia (PANSS) Based on Marder Factors - LOCF
    End point description
    PANSS scale (30 item) for assessment of schizophrenia provides a total score and scores for 3 subscales, i.e., positive (7 items), negative (7 items), and general psychopathology (16 items) subscales. Each item is scored on a scale of 1 (absent) to 7 (extreme). Positive Factor Score (range: 8 to 56) and Disorganized Thoughts Factor Score (range: 7 to 49): sum of select scores from positive, negative and psychopathology subscales. Negative Factor Score (range: 7 to 49): sum of select scores from negative and general psychopathology subscales. Uncontrolled Hostility/Excitement Factor Score (range: 4 to 28): sum of select scores from positive and general psychopathology subscales. Anxiety or Depression Factor Score (range: 4 to 28): sum of select scores from general psychopathology subscale. Higher scores indicate worsening. Efficacy analysis set included all ITT open-label subjects who received at least 1 dose of study drug and had at least 1 postbaseline assessment in open-label phase.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104 or the last post-baseline assessment
    End point values
    Placebo/Pali Pali (DB)/Pali Pali (NO DB)/Pali
    Number of subjects analysed
    39
    117 [4]
    237 [5]
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Positive Symptoms
    -5.1 ± 6.45
    -3.4 ± 6.11
    -7 ± 7.12
        Negative Symptoms
    -4.3 ± 6.3
    -3.8 ± 4.8
    -5.7 ± 6.68
        Disorganized Thoughts
    -4.8 ± 5.57
    -3.3 ± 4.41
    -4.9 ± 5.52
        Uncontrolled Hostility/Excitement
    -2.6 ± 4.17
    -1.2 ± 4.41
    -2.1 ± 4.68
        Anxiety/Depression
    -2.1 ± 3.35
    -0.9 ± 3.41
    -2.8 ± 3.61
    Notes
    [4] - 'N' signifies number of subjects analysed for this end point.
    [5] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Secondary: Change From Open-label Baseline to Open-label Endpoint in the Clinical Global Impression Severity (CGI-S) Scale - LOCF

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    End point title
    Change From Open-label Baseline to Open-label Endpoint in the Clinical Global Impression Severity (CGI-S) Scale - LOCF
    End point description
    The CGI-S rating scale is a 7-point global assessment that measures the clinician's impression of the severity of illness exhibited by a subject. A rating of 1 is equivalent to "Normal, not at all ill" and a rating of 7 is equivalent to "Among the most extremely ill subjects". Higher scores indicate worsening. Efficacy analysis set included all ITT open-label subjects who received at least 1 dose of open label study drug and had at least 1 postbaseline assessment in open-label phase.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104 or the last post-baseline assessment
    End point values
    Placebo/Pali Pali (DB)/Pali Pali (NO DB)/Pali
    Number of subjects analysed
    39
    117 [6]
    237 [7]
    Units: scores on a scale
        median (full range (min-max))
    -1 (-3 to 2)
    -1 (-3 to 3)
    -1 (-5 to 3)
    Notes
    [6] - 'N' signifies number of subjects analysed for this end point.
    [7] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Secondary: Change From Open-label Baseline to Open-label Endpoint in the Children’s Global Assessment Scale (CGAS) - LOCF

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    End point title
    Change From Open-label Baseline to Open-label Endpoint in the Children’s Global Assessment Scale (CGAS) - LOCF
    End point description
    The CGAS is a 100 point rating scale which measures the psychological, social, and school functioning for children 6 to 17 years of age. The score ranges from 1 to 100, divided into 10 equal intervals to rate the impairment level of general functioning (poor to superior functioning). Higher scores denote better functioning. Efficacy analysis set included all ITT open-label subjects who received at least 1 dose of open label study drug and had at least 1 postbaseline assessment in open-label phase.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104 or the last post-baseline assessment
    End point values
    Placebo/Pali Pali (DB)/Pali Pali (NO DB)/Pali
    Number of subjects analysed
    39
    117 [8]
    237 [9]
    Units: scores on a scale
        arithmetic mean (standard deviation)
    11.3 ± 16.65
    8.7 ± 16.02
    15.6 ± 17.77
    Notes
    [8] - 'N' signifies number of subjects analysed for this end point.
    [9] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Secondary: Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Motor Speed Domain Test Variable, Finger Tapping Dominant- and Non-Dominant Hand, Scaled - LOCF

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    End point title
    Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Motor Speed Domain Test Variable, Finger Tapping Dominant- and Non-Dominant Hand, Scaled - LOCF
    End point description
    A comprehensive neuropsychological examination that measures different domains of cognitive functioning was provided. They were either assessed as T-scores [mean=50, standard deviation (SD)=10 range 1-100]; z-scores [mean=0, SD=1, and can be positive or negative] or scaled scores [mean=10, SD=3, and can be positive or negative]. The theory-of-mind total score is a raw score that ranges from 1 to 100. Higher scores for all scales denote better performance. Efficacy analysis set included all ITT open-label subjects who received at least 1 dose of open label study drug and had at least 1 postbaseline assessment in open-label phase.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo/Pali Pali (DB)/Pali Pali (NO DB)/Pali
    Number of subjects analysed
    29 [10]
    88 [11]
    154 [12]
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Finger Tapping Dominant Hand
    0.2 ± 1.15
    0.1 ± 1.65
    0.3 ± 1.36
        Finger Tapping Non Dominant Hand
    0.2 ± 1.2
    0.4 ± 2.05
    0.2 ± 1.55
    Notes
    [10] - 'N' signifies number of subjects analysed for this end point.
    [11] - 'N' signifies number of subjects analysed for this end point.
    [12] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Secondary: Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Attention/Working Memory Domain Test Variable Coding, Scaled - LOCF

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    End point title
    Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Attention/Working Memory Domain Test Variable Coding, Scaled - LOCF
    End point description
    A comprehensive neuropsychological examination that measures different domains of cognitive functioning was provided. They were either assessed as T-scores [mean=50, SD =10 range 1-100]; z-scores [mean=0, SD=1, and can be positive or negative] or scaled scores [mean=10, SD=3, and can be positive or negative]. The theory-of-mind total score is a raw score that ranges from 1 to 100. Higher scores for all scales denote better performance. Efficacy analysis set included all ITT open-label subjects who received at least 1 dose of open label study drug and had at least 1 postbaseline assessment in open-label phase.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo/Pali Pali (DB)/Pali Pali (NO DB)/Pali
    Number of subjects analysed
    27 [13]
    90 [14]
    143 [15]
    Units: scores on a scale
        arithmetic mean (standard deviation)
    1.9 ± 3.25
    1.5 ± 2.54
    0.1 ± 2.6
    Notes
    [13] - 'N' signifies number of subjects analysed for this end point.
    [14] - 'N' signifies number of subjects analysed for this end point.
    [15] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Secondary: Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Attention/Working Memory Domain Test Variable Digit Span, Scaled - LOCF

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    End point title
    Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Attention/Working Memory Domain Test Variable Digit Span, Scaled - LOCF
    End point description
    A comprehensive neuropsychological examination that measures different domains of cognitive functioning was provided. They were either assessed as T-scores [mean=50, SD=10 range 1-100]; z-scores [mean=0, SD=1, and can be positive or negative] or scaled scores [mean=10, SD=3, and can be positive or negative]. The theory-of-mind total score is a raw score that ranges from 1 to 100. Higher scores for all scales denote better performance. Efficacy analysis set included all ITT open-label subjects who received at least 1 dose of open label study drug and had at least 1 postbaseline assessment in open-label phase.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo/Pali Pali (DB)/Pali Pali (NO DB)/Pali
    Number of subjects analysed
    28 [16]
    95 [17]
    159 [18]
    Units: scores on a scale
        arithmetic mean (standard deviation)
    0.9 ± 2.42
    0.8 ± 2.81
    0.8 ± 2.71
    Notes
    [16] - 'N' signifies number of subjects analysed for this end point.
    [17] - 'N' signifies number of subjects analysed for this end point.
    [18] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Secondary: Change From Open-label Baseline to Open-label - Cognitive Domain: Verbal Learning and Memory Domain Test Variable Wide Range Assessment of Memory and Learning Story - Total, Scaled - LOCF

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    End point title
    Change From Open-label Baseline to Open-label - Cognitive Domain: Verbal Learning and Memory Domain Test Variable Wide Range Assessment of Memory and Learning Story - Total, Scaled - LOCF
    End point description
    A comprehensive neuropsychological examination that measures different domains of cognitive functioning was provided. They were either assessed as T-scores [mean=50, SD=10 range 1-100]; z-scores [mean=0, SD=1, and can be positive or negative] or scaled scores [mean=10, SD=3, and can be positive or negative]. The theory-of-mind total score is a raw score that ranges from 1 to 100. Higher scores for all scales denote better performance. Efficacy analysis set included all ITT open-label subjects who received at least 1 dose of open label study drug and had at least 1 postbaseline assessment in open-label phase. SD for Placebo/Paliperidone group in this end point was not estimable because only one subject was analysed for this end point. Therefore, value mentioned for SD is 99999= NA (Not Applicable).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo/Pali Pali (DB)/Pali Pali (NO DB)/Pali
    Number of subjects analysed
    1 [19]
    9 [20]
    17 [21]
    Units: scores on a scale
        arithmetic mean (standard deviation)
    0 ± 99999
    0.6 ± 3.57
    1.7 ± 1.36
    Notes
    [19] - 'N' signifies number of subjects analysed for this end point.
    [20] - 'N' signifies number of subjects analysed for this end point.
    [21] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Secondary: Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Verbal Learning and Memory Domain Test Variable California Verbal Learning Test-Total Trials, Scaled - LOCF

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    End point title
    Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Verbal Learning and Memory Domain Test Variable California Verbal Learning Test-Total Trials, Scaled - LOCF
    End point description
    A comprehensive neuropsychological examination that measures different domains of cognitive functioning was provided. They were either assessed as T-scores [mean=50, SD=10 range 1-100]; z-scores [mean=0, SD=1, and can be positive or negative] or scaled scores [mean=10, SD=3, and can be positive or negative]. The theory-of-mind total score is a raw score that ranges from 1 to 100. Higher scores for all scales denote better performance. Efficacy analysis set included all ITT open-label subjects who received at least 1 dose of open label study drug and had at least 1 postbaseline assessment in open-label phase. SD for group Placebo/Paliperidone was not estimable because only one subject was analysed for this end point. Therefore, value mentioned for SD i.e. 99999= NA (Not Applicable).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo/Pali Pali (DB)/Pali Pali (NO DB)/Pali
    Number of subjects analysed
    1 [22]
    11 [23]
    18 [24]
    Units: scores on a scale
        arithmetic mean (standard deviation)
    29 ± 99999
    3.5 ± 12.29
    8.2 ± 12.19
    Notes
    [22] - 'N' signifies number of subjects analysed for this end point.
    [23] - 'N' signifies number of subjects analysed for this end point.
    [24] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Secondary: Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Visual Learning and Memory Domain Test Variable, Rey Complex Figure Test - Total, Scaled - LOCF

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    End point title
    Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Visual Learning and Memory Domain Test Variable, Rey Complex Figure Test - Total, Scaled - LOCF
    End point description
    A comprehensive neuropsychological examination that measures different domains of cognitive functioning was provided. They were either assessed as T-scores [mean=50, SD=10 range 1-100]; z-scores [mean=0, SD=1, and can be positive or negative] or scaled scores [mean=10, SD=3, and can be positive or negative]. The theory-of-mind total score is a raw score that ranges from 1 to 100. Higher scores for all scales denote better performance. Efficacy analysis set included all ITT open-label subjects who received at least 1 dose of open label study drug and had at least 1 postbaseline assessment in open-label phase.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo/Pali Pali (DB)/Pali Pali (NO DB)/Pali
    Number of subjects analysed
    29 [25]
    92 [26]
    150 [27]
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -0.5 ± 1.56
    -0.3 ± 2.02
    0.3 ± 2.39
    Notes
    [25] - 'N' signifies number of subjects analysed for this end point.
    [26] - 'N' signifies number of subjects analysed for this end point.
    [27] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Secondary: Change From Open Label Baseline to Open Label Endpoint - Cognitive Domain: Social Cognition Domain Test Variable - Theory of Mind-Total - LOCF

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    End point title
    Change From Open Label Baseline to Open Label Endpoint - Cognitive Domain: Social Cognition Domain Test Variable - Theory of Mind-Total - LOCF
    End point description
    A comprehensive neuropsychological examination that measures different domains of cognitive functioning was provided. They were either assessed as T-scores [mean=50, SD=10 range 1-100]; z-scores [mean=0, SD=1, and can be positive or negative] or scaled scores [mean=10, SD=3, and can be positive or negative]. The theory-of-mind total score is a raw score that ranges from 1 to 100. Higher scores for all scales denote better performance. Efficacy analysis set included all ITT open-label subjects who received at least 1 dose of open label study drug and had at least 1 postbaseline assessment in open-label phase.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo/Pali Pali (DB)/Pali Pali (NO DB)/Pali
    Number of subjects analysed
    29 [28]
    91 [29]
    149 [30]
    Units: scores on a scale
        arithmetic mean (standard deviation)
    3.4 ± 7.04
    4.1 ± 6.68
    5.6 ± 9.2
    Notes
    [28] - 'N' signifies number of subjects analysed for this end point.
    [29] - 'N' signifies number of subjects analysed for this end point.
    [30] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Secondary: Change From Open Label Baseline to Open Label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Trials Part A Time: Scaled - LOCF

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    End point title
    Change From Open Label Baseline to Open Label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Trials Part A Time: Scaled - LOCF
    End point description
    A comprehensive neuropsychological examination that measures different domains of cognitive functioning was provided. They were either assessed as T-scores [mean=50, SD=10 range 1-100]; z-scores [mean=0, SD=1, and can be positive or negative] or scaled scores [mean=10, SD=3, and can be positive or negative]. The theory-of-mind total score is a raw score that ranges from 1 to 100. Higher scores for all scales denote better performance. Efficacy analysis set included all ITT open-label subjects who received at least 1 dose of open label study drug and had at least 1 postbaseline assessment in open-label phase.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo/Pali Pali (DB)/Pali Pali (NO DB)/Pali
    Number of subjects analysed
    2 [31]
    15 [32]
    21 [33]
    Units: scores on a scale
        arithmetic mean (standard deviation)
    1.8 ± 1.06
    -2.3 ± 4.97
    1.5 ± 7.66
    Notes
    [31] - 'N' signifies number of subjects analysed for this end point.
    [32] - 'N' signifies number of subjects analysed for this end point.
    [33] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Secondary: Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Child Color Trials Test 1 Time: Scaled - LOCF

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    End point title
    Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Child Color Trials Test 1 Time: Scaled - LOCF
    End point description
    A comprehensive neuropsychological examination that measures different domains of cognitive functioning was provided. They were either assessed as T-scores [mean=50, SD =10 range 1-100]; z-scores [mean=0, SD=1, and can be positive or negative] or scaled scores [mean=10, SD=3, and can be positive or negative]. The theory-of-mind total score is a raw score that ranges from 1 to 100. Higher scores for all scales denote better performance. Efficacy analysis set included all ITT open-label subjects who received at least 1 dose of open label study drug and had at least 1 postbaseline assessment in open-label phase.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo/Pali Pali (DB)/Pali Pali (NO DB)/Pali
    Number of subjects analysed
    21 [34]
    58 [35]
    101 [36]
    Units: scores on a scale
        arithmetic mean (standard deviation)
    0 ± 20.82
    3.6 ± 11.9
    6.2 ± 14.41
    Notes
    [34] - 'N' signifies number of subjects analysed for this end point.
    [35] - 'N' signifies number of subjects analysed for this end point.
    [36] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Secondary: Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Phonetic Verbal Fluency: Scaled - LOCF

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    End point title
    Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Phonetic Verbal Fluency: Scaled - LOCF
    End point description
    A comprehensive neuropsychological examination that measures different domains of cognitive functioning was provided. They were either assessed as T-scores [mean=50, SD =10 range 1-100]; z-scores [mean=0, SD=1, and can be positive or negative] or scaled scores [mean=10, SD=3, and can be positive or negative]. The theory-of-mind total score is a raw score that ranges from 1 to 100. Higher scores for all scales denote better performance. Efficacy analysis set included all ITT open-label subjects who received at least 1 dose of open label study drug and had at least 1 postbaseline assessment in open-label phase.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo/Pali Pali (DB)/Pali Pali (NO DB)/Pali
    Number of subjects analysed
    21 [37]
    78 [38]
    79 [39]
    Units: scores on a scale
        arithmetic mean (standard deviation)
    0.3 ± 1.48
    0.2 ± 1.07
    0.5 ± 1.09
    Notes
    [37] - 'N' signifies number of subjects analysed for this end point.
    [38] - 'N' signifies number of subjects analysed for this end point.
    [39] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Secondary: Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Semantic Verbal Fluency, Scaled - LOCF

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    End point title
    Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Speed of Processing Domain Test Variable Semantic Verbal Fluency, Scaled - LOCF
    End point description
    A comprehensive neuropsychological examination that measures different domains of cognitive functioning was provided. They were either assessed as T-scores [mean=50, SD=10 range 1-100]; z-scores [mean=0, SD=1, and can be positive or negative] or scaled scores [mean=10, SD=3, and can be positive or negative]. The theory-of-mind total score is a raw score that ranges from 1 to 100. Higher scores for all scales denote better performance. Efficacy analysis set included all ITT open-label subjects who received at least 1 dose of open label study drug and had at least 1 postbaseline assessment in open-label phase.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo/Pali Pali (DB)/Pali Pali (NO DB)/Pali
    Number of subjects analysed
    20 [40]
    76 [41]
    78 [42]
    Units: scores on a scale
        arithmetic mean (standard deviation)
    0.2 ± 1.23
    0.1 ± 0.82
    0.2 ± 0.9
    Notes
    [40] - 'N' signifies number of subjects analysed for this end point.
    [41] - 'N' signifies number of subjects analysed for this end point.
    [42] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Secondary: Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Executive Functioning (Reasoning and Problem Solving) Domain Test Variable, Trials Part B Time, Scaled - LOCF

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    End point title
    Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Executive Functioning (Reasoning and Problem Solving) Domain Test Variable, Trials Part B Time, Scaled - LOCF
    End point description
    A comprehensive neuropsychological examination that measures different domains of cognitive functioning was provided. They were either assessed as T-scores [mean=50, SD=10 range 1-100]; z-scores [mean=0, SD=1, and can be positive or negative] or scaled scores [mean=10, SD=3, and can be positive or negative]. The theory-of-mind total score is a raw score that ranges from 1 to 100. Higher scores for all scales denote better performance. Efficacy analysis set included all ITT open-label subjects who received at least 1 dose of open label study drug and had at least 1 postbaseline assessment in open-label phase.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo/Pali Pali (DB)/Pali Pali (NO DB)/Pali
    Number of subjects analysed
    0 [43]
    15 [44]
    18 [45]
    Units: scores on a scale
        arithmetic mean (standard deviation)
    ±
    0.2 ± 2.67
    0.7 ± 2.53
    Notes
    [43] - No subjects was analysed in Placebo/Paliperidone group for this end point.
    [44] - 'N' signifies number of subjects analysed for this end point.
    [45] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Secondary: Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Executive Functioning (Reasoning and Problem Solving) Domain Test Variable - Wisconsin Card Sort Test-Total Errors: Scaled - LOCF

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    End point title
    Change From Open-label Baseline to Open-label Endpoint - Cognitive Domain: Executive Functioning (Reasoning and Problem Solving) Domain Test Variable - Wisconsin Card Sort Test-Total Errors: Scaled - LOCF
    End point description
    A comprehensive neuropsychological examination that measures different domains of cognitive functioning was provided. They were either assessed as T-scores [mean=50, SD=10 range 1-100]; z-scores [mean=0, SD=1, and can be positive or negative] or scaled scores [mean=10, SD=3, and can be positive or negative]. The theory-of-mind total score is a raw score that ranges from 1 to 100. Higher scores for all scales denote better performance. Efficacy analysis set included all ITT open-label subjects who received at least 1 dose of open label study drug and had at least 1 postbaseline assessment in open-label phase.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    Placebo/Pali Pali (DB)/Pali Pali (NO DB)/Pali
    Number of subjects analysed
    15 [46]
    66 [47]
    109 [48]
    Units: scores on a scale
        arithmetic mean (standard deviation)
    4.3 ± 11.13
    4.6 ± 11.09
    7 ± 13.16
    Notes
    [46] - 'N' signifies number of subjects analysed for this end point.
    [47] - 'N' signifies number of subjects analysed for this end point.
    [48] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Secondary: Change From Open-label Baseline to Open-label Endpoint in the Sleep Visual Analog Scale (VAS): Quality of Sleep - LOCF

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    End point title
    Change From Open-label Baseline to Open-label Endpoint in the Sleep Visual Analog Scale (VAS): Quality of Sleep - LOCF
    End point description
    Sleep VAS is a self-administered scale that rates the quality of sleep and daytime drowsiness. Subjects make a mark on a line to represent how well they have slept in the previous 7 days (“very badly” to “very well”) and how often they have felt drowsy within the previous 7 days (“not at all” to “all the time”). The score for each item ranges from 0 to 100 millimeter (mm). For quality of sleep, a score of 0 indicates “Very badly” and a score of 100 indicates “Very well.” For daytime drowsiness, a score of 0 indicates “Not at all” and a score of 100 indicates “All the time.” Improvement of the condition is indicated by the positive change for the quality of sleep and the negative change for the daytime drowsiness. Efficacy analysis set included all ITT open-label subjects who received at least 1 dose of open label study drug and had at least 1 postbaseline assessment in open-label phase.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104 or the last post-baseline assessment
    End point values
    Placebo/Pali Pali (DB)/Pali Pali (NO DB)/Pali
    Number of subjects analysed
    36 [49]
    116 [50]
    223 [51]
    Units: scores on a scale
        arithmetic mean (standard deviation)
    8.2 ± 30.51
    2.7 ± 18.48
    9.8 ± 32.47
    Notes
    [49] - 'N' signifies number of subjects analysed for this end point.
    [50] - 'N' signifies number of subjects analysed for this end point.
    [51] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Secondary: Change From Open-label Baseline to Open-label Endpoint in the Sleep Visual Analog Scale (VAS): Daytime Drowsiness - LOCF

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    End point title
    Change From Open-label Baseline to Open-label Endpoint in the Sleep Visual Analog Scale (VAS): Daytime Drowsiness - LOCF
    End point description
    Sleep VAS is a self-administered scale that rates the quality of sleep and daytime drowsiness. Subjects make a mark on a line to represent how well they have slept in the previous 7 days (“very badly” to “very well”) and how often they have felt drowsy within the previous 7 days (“not at all” to “all the time”). The score for each item ranges from 0 to 100 mm. For quality of sleep, a score of 0 indicates “Very badly” and a score of 100 indicates “Very well.” For daytime drowsiness, a score of 0 indicates “Not at all” and a score of 100 indicates “All the time.” Improvement of the condition is indicated by the positive change for the quality of sleep and negative change for the daytime drowsiness. Efficacy analysis set included all ITT open-label subjects who received at least 1 dose of open label study drug and had at least 1 postbaseline assessment in open-label phase.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104 or the last post-baseline assessment
    End point values
    Placebo/Pali Pali (DB)/Pali Pali (NO DB)/Pali
    Number of subjects analysed
    36 [52]
    116 [53]
    223 [54]
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -7.4 ± 18.83
    -5.1 ± 22.39
    -3.9 ± 32.3
    Notes
    [52] - 'N' signifies number of subjects analysed for this end point.
    [53] - 'N' signifies number of subjects analysed for this end point.
    [54] - 'N' signifies number of subjects analysed for this end point.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 2 years
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Placebo/Pali
    Reporting group description
    Patients in this group were previously assigned to placebo in the R076477PSZ3001 (NCT00518323) study. They started with an oral dose of 6 mg tablets daily, regardless of prior treatment assignment in R076477PSZ3001 (NCT00518323). The initial 6 mg daily dose was increased in increments of 3 mg, not more frequently than once every 5 days until the maximum dose of 12 mg daily was reached. If 12 mg was not well tolerated, then the dose could be reduced down to 9 mg daily. Alternatively the dose could be decreased to 3 mg or 1.5 mg daily, if the initial 6 mg dose was not well tolerated.

    Reporting group title
    Pali (DB)/Pali
    Reporting group description
    Patients in this group were previously assigned to paliperidone extended-release in the R076477PSZ3001 (NCT00518323) study. They started with an oral dose of 6 mg tablets daily, regardless of prior treatment assignment in R076477PSZ3001 (NCT00518323). The initial 6 mg daily dose was increased in increments of 3 mg, not more frequently than once every 5 days until the maximum dose of 12 mg daily was reached. If 12 mg was not well tolerated, then the dose could be reduced down to 9 mg daily. Alternatively the dose could be decreased to 3 mg or 1.5 mg daily, if the initial 6 mg dose was not well tolerated.

    Reporting group title
    Pali (NO DB)/Pali
    Reporting group description
    Patients in this group were directly enrolled into the study and started with an oral dose of 6 mg tablets daily. The initial 6 mg daily dose was increased in increments of 3 mg, not more frequently than once every 5 days until the maximum dose of 12 mg daily was reached. If 12 mg was not well tolerated, then the dose could be reduced down to 9 mg daily. Alternatively the dose could be decreased to 3 mg or 1.5 mg daily, if the initial 6 mg dose was not well tolerated.

    Serious adverse events
    Placebo/Pali Pali (DB)/Pali Pali (NO DB)/Pali
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 39 (23.08%)
    4 / 118 (3.39%)
    46 / 243 (18.93%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Frostbite
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 118 (0.85%)
    0 / 243 (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
    Spinal Compression Fracture
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    1 / 243 (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
    Upper Limb Fracture
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    1 / 243 (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
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    1 / 243 (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
    Blood and lymphatic system disorders
    Lymphadenitis
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 118 (0.00%)
    0 / 243 (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
    Akathisia
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    1 / 243 (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
    Dystonia
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    2 / 243 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokinesia
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    1 / 243 (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
    Oromandibular Dystonia
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    1 / 243 (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
    Speech Disorder
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    1 / 243 (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
    General disorders and administration site conditions
    Irritability
         subjects affected / exposed
    1 / 39 (2.56%)
    1 / 118 (0.85%)
    0 / 243 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Adjustment Disorder
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    1 / 243 (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
    Aggression
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 118 (0.85%)
    3 / 243 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 118 (0.85%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 118 (0.00%)
    3 / 243 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delusion
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    2 / 243 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delusion of Grandeur
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    1 / 243 (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
    Depressed Mood
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    1 / 243 (0.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    1 / 243 (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 Symptom
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    1 / 243 (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
    Flight of Ideas
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    1 / 243 (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
    Hallucination
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    2 / 243 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hallucination, Auditory
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    2 / 243 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intentional Self-Injury
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 118 (0.00%)
    0 / 243 (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
    Mania
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    1 / 243 (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
    Oppositional Defiant Disorder
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    1 / 243 (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
    Paranoia
         subjects affected / exposed
    0 / 39 (0.00%)
    1 / 118 (0.85%)
    0 / 243 (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
    Psychotic Disorder
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    2 / 243 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    7 / 39 (17.95%)
    2 / 118 (1.69%)
    21 / 243 (8.64%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 2
    4 / 30
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia, Paranoid Type
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 118 (0.00%)
    2 / 243 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia, Undifferentiated Type
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    1 / 243 (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
    Self Injurious Behaviour
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    1 / 243 (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
    Suicidal Ideation
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    7 / 243 (2.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    3 / 243 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tension
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    1 / 243 (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
    Gastrointestinal disorders
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    1 / 243 (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
    Gastritis
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    1 / 243 (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
    Vomiting
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    1 / 243 (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
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    1 / 243 (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
    Nephrolithiasis
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    1 / 243 (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
    Skin and subcutaneous tissue disorders
    Ingrowing Nail
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    1 / 243 (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
    Musculoskeletal Stiffness
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    1 / 243 (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
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    2 / 243 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 118 (0.00%)
    0 / 243 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo/Pali Pali (DB)/Pali Pali (NO DB)/Pali
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 39 (66.67%)
    74 / 118 (62.71%)
    192 / 243 (79.01%)
    Investigations
    Weight Increased
         subjects affected / exposed
    2 / 39 (5.13%)
    12 / 118 (10.17%)
    59 / 243 (24.28%)
         occurrences all number
    2
    12
    72
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    2 / 39 (5.13%)
    1 / 118 (0.85%)
    3 / 243 (1.23%)
         occurrences all number
    2
    1
    3
    Tachycardia
         subjects affected / exposed
    2 / 39 (5.13%)
    1 / 118 (0.85%)
    8 / 243 (3.29%)
         occurrences all number
    2
    1
    9
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal Pain
         subjects affected / exposed
    2 / 39 (5.13%)
    2 / 118 (1.69%)
    7 / 243 (2.88%)
         occurrences all number
    2
    2
    8
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    0 / 39 (0.00%)
    10 / 118 (8.47%)
    42 / 243 (17.28%)
         occurrences all number
    0
    14
    49
    Dizziness
         subjects affected / exposed
    4 / 39 (10.26%)
    8 / 118 (6.78%)
    13 / 243 (5.35%)
         occurrences all number
    4
    8
    15
    Dystonia
         subjects affected / exposed
    1 / 39 (2.56%)
    6 / 118 (5.08%)
    13 / 243 (5.35%)
         occurrences all number
    3
    11
    17
    Headache
         subjects affected / exposed
    4 / 39 (10.26%)
    9 / 118 (7.63%)
    46 / 243 (18.93%)
         occurrences all number
    5
    12
    74
    Sedation
         subjects affected / exposed
    1 / 39 (2.56%)
    0 / 118 (0.00%)
    14 / 243 (5.76%)
         occurrences all number
    1
    0
    18
    Somnolence
         subjects affected / exposed
    10 / 39 (25.64%)
    18 / 118 (15.25%)
    45 / 243 (18.52%)
         occurrences all number
    10
    27
    57
    Tremor
         subjects affected / exposed
    1 / 39 (2.56%)
    12 / 118 (10.17%)
    31 / 243 (12.76%)
         occurrences all number
    2
    15
    40
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 39 (7.69%)
    3 / 118 (2.54%)
    3 / 243 (1.23%)
         occurrences all number
    3
    3
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    4 / 39 (10.26%)
    7 / 118 (5.93%)
    14 / 243 (5.76%)
         occurrences all number
    5
    8
    17
    Insomnia
         subjects affected / exposed
    7 / 39 (17.95%)
    11 / 118 (9.32%)
    40 / 243 (16.46%)
         occurrences all number
    10
    18
    53
    Schizophrenia
         subjects affected / exposed
    2 / 39 (5.13%)
    10 / 118 (8.47%)
    14 / 243 (5.76%)
         occurrences all number
    3
    12
    18
    Suicidal Ideation
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    30 / 243 (12.35%)
         occurrences all number
    0
    0
    48
    Gastrointestinal disorders
    Abdominal Pain Upper
         subjects affected / exposed
    0 / 39 (0.00%)
    2 / 118 (1.69%)
    14 / 243 (5.76%)
         occurrences all number
    0
    2
    22
    Nausea
         subjects affected / exposed
    1 / 39 (2.56%)
    3 / 118 (2.54%)
    27 / 243 (11.11%)
         occurrences all number
    1
    3
    32
    Salivary Hypersecretion
         subjects affected / exposed
    2 / 39 (5.13%)
    9 / 118 (7.63%)
    22 / 243 (9.05%)
         occurrences all number
    3
    11
    28
    Vomiting
         subjects affected / exposed
    0 / 39 (0.00%)
    3 / 118 (2.54%)
    22 / 243 (9.05%)
         occurrences all number
    0
    4
    33
    Reproductive system and breast disorders
    Galactorrhoea
         subjects affected / exposed
    3 / 39 (7.69%)
    4 / 118 (3.39%)
    9 / 243 (3.70%)
         occurrences all number
    3
    5
    11
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    14 / 243 (5.76%)
         occurrences all number
    0
    0
    15
    Musculoskeletal and connective tissue disorders
    Muscle Rigidity
         subjects affected / exposed
    1 / 39 (2.56%)
    6 / 118 (5.08%)
    19 / 243 (7.82%)
         occurrences all number
    2
    6
    22
    Musculoskeletal Stiffness
         subjects affected / exposed
    0 / 39 (0.00%)
    0 / 118 (0.00%)
    14 / 243 (5.76%)
         occurrences all number
    0
    0
    22
    Metabolism and nutrition disorders
    Increased Appetite
         subjects affected / exposed
    2 / 39 (5.13%)
    3 / 118 (2.54%)
    9 / 243 (3.70%)
         occurrences all number
    2
    3
    11
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 39 (5.13%)
    1 / 118 (0.85%)
    2 / 243 (0.82%)
         occurrences all number
    2
    2
    2
    Nasopharyngitis
         subjects affected / exposed
    3 / 39 (7.69%)
    18 / 118 (15.25%)
    32 / 243 (13.17%)
         occurrences all number
    4
    27
    47
    Rhinitis
         subjects affected / exposed
    2 / 39 (5.13%)
    2 / 118 (1.69%)
    9 / 243 (3.70%)
         occurrences all number
    2
    2
    9

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 May 2007
    Amendment INT-1: Added clarification that an effective dose had to be 6 mg or less; the period of dose increments was modified; and the minimum weight required for inclusion in the study was lowered.
    11 Jun 2008
    Amendment INT 2: Extended the study duration from 6 months to 2 years; increased the number of visits, blood draws, evaluations, and dosing for the extended study duration; increased the sample size from 300 to 400 subjects; testing for testosterone in men was added to assess long-term endocrine effects; analyses were planned to be performed when 100 subjects completed at least 6 months of treatment and at the end of the 2-year study.
    13 May 2009
    Amendment INT-3: Included the C-SSRS as a safety assessment for Visits 2 to 19.
    01 Apr 2010
    Amendment INT-4: A statement was added which specified that stadiometers were required to measure subjects’ height. At the time of the amendment, 369 subjects were enrolled in the study.
    14 May 2010
    Amendment INT-5: Negative symptoms were added as a secondary end point. At the time of the amendment, 382 subjects were enrolled in the study.
    04 Apr 2011
    Amendment INT-6: Additional antiparkinsonian drugs (i.e. trihexyphenidyl, diphenhydramine, etc.) were added as alternatives to benztropine and biperiden for managing treatment-emergent EPS; the timing of study drug intake was adjusted based on subject tolerability and logistic reasons; and the eCRF completion period was changed from within 2 days to 3 days following a subject’s visit. At the time of the amendment, all subjects were enrolled in the study.

    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.
    The study was an open label study. Limitations also included the lack of a concurrent placebo group and small number of subjects in the lower age group.
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