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    Clinical Trial Results:
    A Randomized, Multicenter, Double-Blind, Weight-Based, Fixed-Dose, Parallel-Group, Placebo-Controlled Study of the Efficacy and Safety of Extended Release Paliperidone for the Treatment of Schizophrenia in Adolescent Subjects, 12 to 17 Years of Age

    Summary
    EudraCT number
    		 2007-000576-16
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    30 Mar 2009

    Results information
    Results version number
    		 v2(current)
    This version publication date
    29 May 2016
    First version publication date
    04 Jul 2015
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Review of data

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    R076477PSZ3001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00518323
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen-Cilag International NV
    Sponsor organisation address
    Turnhoutseweg 30, Belgium, Belgium,
    Public contact
    Turnhoutseweg 30, Belgium, 44 1494658336, Michael B Emanuel, Janssen-Cilag International NV, 44 1494658, memanuel@gcogb.jnj.com
    Scientific contact
    Turnhoutseweg 30, Belgium, , Michael B Emanuel, Janssen-Cilag International NV, 44 1494658, memanuel@gcogb.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
    30 Mar 2009
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Mar 2009
    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 efficacy, safety, and tolerability of 3 weight-based, fixed-dose groups of paliperidone ER (to fully explore the tolerability range) as compared with placebo in adolescent subjects 12 to 17 years of age, inclusive, with schizophrenia.
    Protection of trial subjects
    The safety assessments included laboratory measurements (for example, serum chemistry (including glucose), hematology, urinalysis), Investigation of weight gain and metabolic disturbances, Prolactin, ECG, Vital sign measurements, Physical examinations, Tanner staging, Pregnancy testing, Urine drug screen. The Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Rating Scale (BARS), and Simpson Angus Rating Scale (SARS) were used to assess extrapyramidal symptoms (EPS) and dyskinesia. Adverse events and vital signs were monitored throughout the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Aug 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    India: 45
    Country: Number of subjects enrolled
    Romania: 10
    Country: Number of subjects enrolled
    Russian Federation: 82
    Country: Number of subjects enrolled
    Ukraine: 34
    Country: Number of subjects enrolled
    United States: 30
    Worldwide total number of subjects
    201
    EEA total number of subjects
    10
    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)
    201
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment started 8 August 2007 in medical clinics located around the world. The study ended on 30 March 2009.

    Pre-assignment
    Screening details
    		 Participants who were eligible for the study had their current disallowed psychotropic medications washed out prior to assignment to treatment groups. Participants who violated inclusion criteria before assignment (eg, because they continued to take a disallowed medication) were to be removed from the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    Double blinding was used during the 6-week treatment period (i.e., subjects, parent(s), legal guardian(s), investigators and the sponsor remained blinded to the study drug) to reduce potential bias during data collection and evaluation of clinical endpoints.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pali ER Low
    Arm description
    		 Paliperidone ER 1.5 mg for subjects weighing 29 kg and above
    Arm type
    		 Experimental

    Investigational medicinal product name
    INVEGA prolonged release tablets
    Investigational medicinal product code
    F067
    Other name
    Paliperidone ER
    Pharmaceutical forms
    Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were randomly assigned to 1 of the 4 following treatment groups: Oral placebo tablets, Oral paliperidone ER tablet - low dose group (1.5 milligram per day [mg/day] for all participants), Oral paliperidone ER tablet - medium dose group (3 mg/day for Participants weighing between 29 to <51 kg and 6 mg/day for Participants weighing >=51 kg), Oral paliperidone ER tablet - high dose group (6 mg/day for Participants weighing between 29 to <51 kg and 12 mg/day for Participants weighing >=51 kg).

    Arm title
    		 Pali ER Medium
    Arm description
    		 Paliperidone ER 3 mg (for subjects weighing between 29 kg and less than 51 kg) or 6 mg (for subjects weighing 51 kg and above)
    Arm type
    		 Experimental

    Investigational medicinal product name
    INVEGA prolonged release tablets
    Investigational medicinal product code
    F067
    Other name
    Paliperidone ER
    Pharmaceutical forms
    Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were randomly assigned to 1 of the 4 following treatment groups: Oral placebo tablets, Oral paliperidone ER tablet - low dose group (1.5 milligram per day [mg/day] for all participants), Oral paliperidone ER tablet - medium dose group (3 mg/day for Participants weighing between 29 to <51 kg and 6 mg/day for Participants weighing >=51 kg), Oral paliperidone ER tablet - high dose group (6 mg/day for Participants weighing between 29 to <51 kg and 12 mg/day for Participants weighing >=51 kg).

    Arm title
    		 Pali ER High
    Arm description
    		 Paliperidone ER 6 mg (for subjects weighing between 29 kg and less than 51 kg) or 12 mg (for subjects weighing 51 kg and above)
    Arm type
    		 Experimental

    Investigational medicinal product name
    INVEGA prolonged release tablets
    Investigational medicinal product code
    F067
    Other name
    Paliperidone ER
    Pharmaceutical forms
    Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were randomly assigned to 1 of the 4 following treatment groups: Oral placebo tablets, Oral paliperidone ER tablet - low dose group (1.5 milligram per day [mg/day] for all participants), Oral paliperidone ER tablet - medium dose group (3 mg/day for Participants weighing between 29 to <51 kg and 6 mg/day for Participants weighing >=51 kg), Oral paliperidone ER tablet - high dose group (6 mg/day for Participants weighing between 29 to <51 kg and 12 mg/day for Participants weighing >=51 kg).

    Arm title
    		 Placebo
    Arm description
    		 Matching Placebo to Paliperidone extended release tablet.
    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
    Participants were randomly assigned to oral placebo overencapsulated tablets.

    Number of subjects in period 1
    		Pali ER Low Pali ER Medium Pali ER High Placebo
    Started
    54
    48
    48
    51
    Completed
    35
    40
    37
    26
    Not completed
    19
    8
    11
    25
         Adverse Event
    1
    1
    1
    -
         Other
    3
    1
    1
    -
         Subject Choice (Subject Withdrew Consent)
    1
    2
    4
    2
         Lost to follow-up
    -
    2
    1
    3
         Lack of efficacy
    14
    2
    4
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pali ER Low
    Reporting group description
    		 Paliperidone ER 1.5 mg for subjects weighing 29 kg and above

    Reporting group title
    Pali ER Medium
    Reporting group description
    		 Paliperidone ER 3 mg (for subjects weighing between 29 kg and less than 51 kg) or 6 mg (for subjects weighing 51 kg and above)

    Reporting group title
    Pali ER High
    Reporting group description
    		 Paliperidone ER 6 mg (for subjects weighing between 29 kg and less than 51 kg) or 12 mg (for subjects weighing 51 kg and above)

    Reporting group title
    Placebo
    Reporting group description
    		 Matching Placebo to Paliperidone extended release tablet.

    Reporting group values
    		 Pali ER Low Pali ER Medium Pali ER High Placebo Total
    Number of subjects
    		 54 48 48 51 201
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 54 48 48 51 201
        Adults (18-64 years)
    		 0 0 0 0 0
        From 65 to 84 years
    		 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 15.1 ± 1.5 15.3 ± 1.6 15.5 ± 1.6 15.7 ± 1.4 -
    Title for Gender
    Units: subjects
        Female
    		 24 17 14 28 83
        Male
    		 30 31 34 23 118

    End points

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    End points reporting groups
    Reporting group title
    Pali ER Low
    Reporting group description
    		 Paliperidone ER 1.5 mg for subjects weighing 29 kg and above

    Reporting group title
    Pali ER Medium
    Reporting group description
    		 Paliperidone ER 3 mg (for subjects weighing between 29 kg and less than 51 kg) or 6 mg (for subjects weighing 51 kg and above)

    Reporting group title
    Pali ER High
    Reporting group description
    		 Paliperidone ER 6 mg (for subjects weighing between 29 kg and less than 51 kg) or 12 mg (for subjects weighing 51 kg and above)

    Reporting group title
    Placebo
    Reporting group description
    		 Matching Placebo to Paliperidone extended release tablet.

    Primary: Change in the PANSS Total Score From Baseline to the Last Postrandomization Assessment in the Double-blind Period of the Study

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    End point title
    		 Change in the PANSS Total Score From Baseline to the Last Postrandomization Assessment in the Double-blind Period of the Study
    End point description
    The Positive and Negative Syndrome Scale (PANSS) measures the severity of psychotic symptoms of schizophrenia. Scores range from 30 to 210, where 30=best and 210=worst. The change in PANSS total score for all eligible subjects was measured from the beginning of the study to the end. The number of participants in the intent-to-treat (ITT) analysis set was used. This set includes patients who received study drug and have at least 1 efficacy measurement. The Last Observation Carried Forward method was used for imputation; ie, the last measure for subjects who ended study early was carried forward as if they completed the study.
    End point type
    Primary
    End point timeframe
    6 weeks
    End point values
    		 Pali ER Low Pali ER Medium Pali ER High Placebo
    Number of subjects analysed
    54
    48
    47
    51
    Units: units on a scale
        arithmetic mean (standard deviation)
    -9.8 ± 16.31
    -17.3 ± 14.33
    -13.8 ± 15.74
    -7.9 ± 20.15
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    If there were approximately 49 subjects per treatment group who had Week 6 (LOCF or end point) PANSS total measurements, the study was expected to have approximately 80% power to detect a clinically relevant difference of 13.2 points between any paliperidone ER group compared with placebo for the primary outcome measure.
    Comparison groups
    Pali ER Low v Placebo v Pali ER Medium v Pali ER High
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.508 [2]
    Method
    		 ANOVA
    Parameter type
    		 Median difference (final values)
    Point estimate
    -2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.36
         upper limit
    		 4.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.17
    Notes
    [1] - Used ANCOVA model with treatment(placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors and baseline value as a covariate.
    [2] - The p value was associated with the closed testing procedure using Dunnett’s test.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    If there were approximately 49 subjects per treatment group who had Week 6 (LOCF or end point) PANSS total measurements, the study was expected to have approximately 80% power to detect a clinically relevant difference of 13.2 points between any paliperidone ER group compared with placebo for the primary outcome measure.
    Comparison groups
    Pali ER Medium v Placebo v Pali ER Low v Pali ER High
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.006 [4]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -10.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.58
         upper limit
    		 -3.67
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.27
    Notes
    [3] - Used ANCOVA model with treatment(placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors and baseline value as a covariate.
    [4] - The p value was associated with the closed testing procedure using Dunnett’s test.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    If there were approximately 49 subjects per treatment group who had Week 6 (LOCF or end point) PANSS total measurements, the study was expected to have approximately 80% power to detect a clinically relevant difference of 13.2 points between any paliperidone ER group compared with placebo for the primary outcome measure.
    Comparison groups
    Pali ER High v Placebo v Pali ER Low v Pali ER Medium
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.086 [6]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -6.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.07
         upper limit
    		 -0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.29
    Notes
    [5] - Used ANCOVA model with treatment(placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors and baseline value as a covariate.
    [6] - The p value was associated with the closed testing procedure using Dunnett’s test.

    Secondary: Change From Baseline to End Point in Clinical Global Impression-Severity (CGI-S) Scale

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    End point title
    		 Change From Baseline to End Point in Clinical Global Impression-Severity (CGI-S) Scale
    End point description
    The CGI-S rating scale was used to assess the severity of a subject’s overall clinical condition. Scores range from 1 to 7, where 1=best and 7=worst. The number of participants in the intent-to-treat (ITT) analysis set was used. This set includes patients who received study drug and have at least 1 efficacy measurement. The Last Observation Carried Forward method was used for imputation; ie, the last measure for subjects who ended study early was carried forward as if they completed the study.
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Pali ER Low Pali ER Medium Pali ER High Placebo
    Number of subjects analysed
    54
    48
    47
    51
    Units: units on a scale
        median (full range (min-max))
    0 (-3 to 1)
    -1 (-3 to 0)
    -1 (-3 to 1)
    0 (-3 to 1)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis of the change in the CGI-S score at end point was performed using an analysis of covariance model on the ranks of the change in score at end point with treatment (placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors, and (non-ranked) baseline CGI-S score as a covariate.
    Comparison groups
    Pali ER Low v Placebo v Pali ER High v Pali ER Medium
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.968 [7]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [7] - Comparison with placebo was without multiplicity adjustment.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Analysis of the change in the CGI-S score at end point was performed using an analysis of covariance model on the ranks of the change in score at end point with treatment (placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors, and (non-ranked) baseline CGI-S score as a covariate.
    Comparison groups
    Pali ER Medium v Placebo v Pali ER High v Pali ER Low
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [8]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [8] - Comparison with placebo was without multiplicity adjustment.
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    Analysis of the change in the CGI-S score at end point was performed using an analysis of covariance model on the ranks of the change in score at end point with treatment (placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors, and (non-ranked) baseline CGI-S score as a covariate.
    Comparison groups
    Pali ER High v Placebo v Pali ER Low v Pali ER Medium
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.021 [9]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [9] - Comparison with placebo was without multiplicity adjustment.

    Secondary: Change From Baseline to End Point in Children's Global Assessment (CGAS) Score

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    End point title
    		 Change From Baseline to End Point in Children's Global Assessment (CGAS) Score
    End point description
    The CGAS score assesses psychological, social, and school functioning for children 6 to 17 years of age. Scores range from 1 to 100, where 100=best and 1=worst. The number of participants in the intent-to-treat (ITT) analysis set was used. This set includes patients who received study drug and have at least 1 efficacy measurement. The Last Observation Carried Forward method was used for imputation; ie, the last measure for subjects who ended study early was carried forward as if they completed the study.
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Pali ER Low Pali ER Medium Pali ER High Placebo
    Number of subjects analysed
    54
    48
    47
    51
    Units: units on a scale
        arithmetic mean (standard deviation)
    4.4 ± 10.72
    13.1 ± 12.07
    8.6 ± 11.18
    5 ± 13.82
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Pali ER Low v Placebo v Pali ER Medium v Pali ER High
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.846 [11]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.54
         upper limit
    		 3.73
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.1
    Notes
    [10] - Used ANCOVA model with treatment (placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors and baseline value as a covariate.
    [11] - Comparison with placebo was without multiplicity adjustment.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Pali ER Medium v Placebo v Pali ER Low v Pali ER High
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 < 0.001 [13]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    8.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.28
         upper limit
    		 12.82
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.17
    Notes
    [12] - Used ANCOVA model with treatment(placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors and baseline value as a covariate.
    [13] - Comparison with placebo was without multiplicity adjustment.
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Pali ER High v Placebo v Pali ER Low v Pali ER Medium
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.067 [15]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.28
         upper limit
    		 8.33
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.18
    Notes
    [14] - Used ANCOVA model with treatment(placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors and baseline value as a covariate.
    [15] - Comparison with placebo was without multiplicity adjustment.

    Secondary: Change From Baseline to End Point in Sleep Visual Analog Scale (VAS) for Quality of Sleep.

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    End point title
    		 Change From Baseline to End Point in Sleep Visual Analog Scale (VAS) for Quality of Sleep.
    End point description
    The sleep VAS for sleep quality is a scale for measuring the quality of sleep experienced by a patient. Scores range from 0 to 100, where 100=best and 0=worst. The number of participants in the intent-to-treat (ITT) analysis set was used. This set includes patients who received study drug and have at least 1 efficacy measurement. The Last Observation Carried Forward method was used for imputation; ie, the last measure for subjects who ended study early was carried forward as if they completed the study.
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Pali ER Low Pali ER Medium Pali ER High Placebo
    Number of subjects analysed
    54
    48
    47
    50
    Units: units on a scale
        arithmetic mean (standard deviation)
    6.6 ± 24.57
    16 ± 27.06
    14.4 ± 22.72
    -0.3 ± 34.21
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Pali ER Low v Placebo v Pali ER Medium v Pali ER High
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 = 0.058 [17]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    8.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.29
         upper limit
    		 16.56
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.27
    Notes
    [16] - Used ANCOVA model with treatment(placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors and baseline value as a covariate.
    [17] - Comparison with placebo was without multiplicity adjustment.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Pali ER Medium v Placebo v Pali ER Low v Pali ER High
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 < 0.001 [19]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    16.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.08
         upper limit
    		 25.43
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.4
    Notes
    [18] - Used ANCOVA model with treatment(placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors and baseline value as a covariate.
    [19] - Comparison with placebo was without multiplicity adjustment.
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Pali ER High v Placebo v Pali ER Low v Pali ER Medium
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 = 0.003 [21]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    13.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.76
         upper limit
    		 22.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.43
    Notes
    [20] - Used ANCOVA model with treatment(placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors and baseline value as a covariate.
    [21] - Comparison with placebo was without multiplicity adjustment.

    Secondary: Change From Baseline to End Point in Sleep VAS for Daytime Drowsiness

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    End point title
    		 Change From Baseline to End Point in Sleep VAS for Daytime Drowsiness
    End point description
    The sleep VAS for daytime drowsiness is a scale for measuring the drowsiness experienced by a patient. Scores range from 0 to 100, where 100=best and 0=worst. The number of participants in the intent-to-treat (ITT) analysis set was used. This set includes patients who received study drug and have at least 1 efficacy measurement. The Last Observation Carried Forward method was used for imputation; ie, the last measure for subjects who ended study early was carried forward as if they completed the study.
    End point type
    Secondary
    End point timeframe
    6 weeks
    End point values
    		 Pali ER Low Pali ER Medium Pali ER High Placebo
    Number of subjects analysed
    54
    48
    47
    50
    Units: units on a scale
        arithmetic mean (standard deviation)
    -6.2 ± 24.69
    -7.2 ± 25.22
    1 ± 29.55
    -2.8 ± 30.27
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Pali ER Medium v Pali ER Low v Pali ER High
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [22]
    P-value
    		 = 0.237 [23]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.11
         upper limit
    		 3.26
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.15
    Notes
    [22] - Used ANCOVA model with treatment(placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors and baseline value as a covariate.
    [23] - Comparison with placebo was without multiplicity adjustment.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Pali ER Medium v Placebo v Pali ER Low v Pali ER High
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [24]
    P-value
    		 = 0.119 [25]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -6.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.15
         upper limit
    		 1.74
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.28
    Notes
    [24] - Used ANCOVA model with treatment(placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors and baseline value as a covariate.
    [25] - Comparison with placebo was without multiplicity adjustment.
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    Pali ER High v Placebo v Pali ER Low v Pali ER Medium
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.574 [26]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11
         upper limit
    		 6.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.34
    Notes
    [26] - Used ANCOVA model with treatment(placebo, pali ER Low, pali ER Medium, and pali ER High) and country as factors and baseline value as a covariate.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Pali ER Low
    Reporting group description
    		 Paliperidone ER 1.5 mg for subjects weighing 29 kg and above

    Reporting group title
    Pali ER Medium
    Reporting group description
    		 Paliperidone ER 3 mg (for subjects weighing between 29 kg and less than 51 kg) or 6 mg (for subjects weighing 51 kg and above)

    Reporting group title
    Pali ER High
    Reporting group description
    		 Paliperidone ER 6 mg (for subjects weighing between 29 kg and less than 51 kg) or 12 mg (for subjects weighing 51 kg and above)

    Reporting group title
    Placebo
    Reporting group description
    		 No text entered.

    Serious adverse events
    		 Pali ER Low Pali ER Medium Pali ER High Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 54 (3.70%)
    1 / 48 (2.08%)
    1 / 48 (2.08%)
    1 / 51 (1.96%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Gastrointestinal disorders
    Mallory-Weiss Syndrome
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 48 (2.08%)
    0 / 48 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic Disorder
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 48 (0.00%)
    0 / 48 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 48 (0.00%)
    1 / 48 (2.08%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pali ER Low Pali ER Medium Pali ER High Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 54 (35.19%)
    20 / 48 (41.67%)
    33 / 48 (68.75%)
    24 / 51 (47.06%)
    Investigations
    Weight Increased
         subjects affected / exposed
    4 / 54 (7.41%)
    2 / 48 (4.17%)
    1 / 48 (2.08%)
    0 / 51 (0.00%)
         occurrences all number
    4
    2
    1
    0
    Cardiac disorders
    Tachycardia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 48 (4.17%)
    4 / 48 (8.33%)
    0 / 51 (0.00%)
         occurrences all number
    0
    2
    5
    0
    Nervous system disorders
    Cogwheel Rigidity
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 48 (0.00%)
    4 / 48 (8.33%)
    0 / 51 (0.00%)
         occurrences all number
    0
    0
    7
    0
    Akathisia
         subjects affected / exposed
    2 / 54 (3.70%)
    4 / 48 (8.33%)
    8 / 48 (16.67%)
    0 / 51 (0.00%)
         occurrences all number
    2
    4
    8
    0
    Dystonia
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 48 (2.08%)
    4 / 48 (8.33%)
    0 / 51 (0.00%)
         occurrences all number
    2
    1
    9
    0
    Headache
         subjects affected / exposed
    5 / 54 (9.26%)
    3 / 48 (6.25%)
    5 / 48 (10.42%)
    2 / 51 (3.92%)
         occurrences all number
    5
    3
    6
    2
    Somnolence
         subjects affected / exposed
    3 / 54 (5.56%)
    7 / 48 (14.58%)
    10 / 48 (20.83%)
    1 / 51 (1.96%)
         occurrences all number
    3
    8
    12
    1
    Tremor
         subjects affected / exposed
    1 / 54 (1.85%)
    4 / 48 (8.33%)
    4 / 48 (8.33%)
    0 / 51 (0.00%)
         occurrences all number
    1
    7
    4
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 48 (0.00%)
    4 / 48 (8.33%)
    6 / 51 (11.76%)
         occurrences all number
    0
    0
    6
    7
    Vomiting
         subjects affected / exposed
    0 / 54 (0.00%)
    3 / 48 (6.25%)
    4 / 48 (8.33%)
    5 / 51 (9.80%)
         occurrences all number
    0
    3
    6
    6
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    3 / 54 (5.56%)
    1 / 48 (2.08%)
    0 / 48 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    4
    1
    0
    2
    Anxiety
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 48 (0.00%)
    4 / 48 (8.33%)
    2 / 51 (3.92%)
         occurrences all number
    0
    0
    4
    2
    Insomnia
         subjects affected / exposed
    5 / 54 (9.26%)
    3 / 48 (6.25%)
    6 / 48 (12.50%)
    11 / 51 (21.57%)
         occurrences all number
    10
    3
    8
    16
    Schizophrenia
         subjects affected / exposed
    5 / 54 (9.26%)
    0 / 48 (0.00%)
    2 / 48 (4.17%)
    4 / 51 (7.84%)
         occurrences all number
    5
    0
    2
    4
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 48 (0.00%)
    1 / 48 (2.08%)
    3 / 51 (5.88%)
         occurrences all number
    1
    0
    1
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 May 2007
    This amendment was done to balance a number of important study design concerns as follows: 1) Lower weight subjects may have nearly double the drug exposure compared with higher weight subjects. Therefore, a regimen for lower weight subjects was milligram per kilogram (mg/kg) with half of the dose strength; 2) a regulatory agency objective requires that the entire dose range be explored. The current design used doses of ranging from 1.5 mg to 12 mg of paliperidone ER and the design allowed testing of the lowest possible dose of 1.5 mg; 3) Each paliperidone ER dose group covered nonoverlapping mg/kg values and thus allowed for a clear interpretation of each paliperidone ER group. The combinations of 3mg and 6 mg for the paliperidone ER medium dose group and that of 6mg and 12mg for the paliperidone ER high dose group wer interpreted as mg/kg over a range of mg/kg values as captured by the mg/kg of those subjects randomly assigned to those categories.

    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.
    No information about longer-term (ie, >6 weeks) efficacy and safety in adolescents or in young (<12 years) children with schizophrenia. Results with doses less than 1.5 mg or more than 12 mg cannot be extrapolated from the data.
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