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    Clinical Trial Results:
    The significance of deviation in time from the 12-hour standard serum-clozapine monitoring

    Summary
    EudraCT number
    		 2015-002520-82
    Trial protocol
    		 DK  
    Global end of trial date
    09 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Mar 2017
    First version publication date
    29 Mar 2017
    Other versions
    Summary report(s)
    		 Article manuscript
    Figure 1
    Table 1
    Table 2
    Table 3
    Table 4
    Supporting Information

    Trial information

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    Trial identification
    Sponsor protocol code
    CLO-MEAS
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02625103
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Psychiatric Centre Copenhagen
    Sponsor organisation address
    Edel Sauntes Alle 10, Copenhagen O, Denmark, 2100
    Public contact
    Psykiatrisk Afdeling O, Psykiatrisk Center København, 0045 38647072, a.fink-jensen@dadlnet.dk
    Scientific contact
    Psykiatrisk Afdeling O, Psykiatrisk Center København, 0045 38647072, a.fink-jensen@dadlnet.dk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Aug 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Dec 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the significance of deviation in time from the 12-hour standard blood sampling timepoint when Therapeutic Drug monitoring (TDM) clozapine
    Protection of trial subjects
    none
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Sep 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 48
    Worldwide total number of subjects
    48
    EEA total number of subjects
    48
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    48
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited from outpatient services in the Capital Region of Denmark. Patients were included from September 2015 to December 2015.

    Pre-assignment
    Screening details
    		 54 subjects were screened and 48 subjects (88.9 %) were included in the study. 2 subjects were subsequently excluded: 1 patient suffered a serious adverse reaction (SAR) i.e. agranulocytosis and sepsis, during sampling time, and 1 patient had had a clozapine dose-adjustment 10 days prior to the trial and was excluded as a screening failure.

    Period 1
    Period 1 title
    Primary inclusion
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Included subjects
    Arm description
    		 Subjects are patients in stable treatment with clozapine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clozapine
    Investigational medicinal product code
    Other name
    Leponex
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    As for habitual individual use

    Number of subjects in period 1
    		Included subjects
    Started
    48
    Subject exclusion
    46
    Completed
    46
    Not completed
    2
         Adverse event, non-fatal
    1
         Protocol deviation
    1
    Period 2
    Period 2 title
    Final inclusion
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Final inclusion
    Arm description
    		 Included subjects are patients in stable treatment with clozapine
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clozapine
    Investigational medicinal product code
    Other name
    Leponex
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    As for habitual individual use

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: 2 of the enrolled subjects were excluded after trial participation. Period 2 is the baseline period after the extraction of excluded data. See article-manuscript for clarification.
    Number of subjects in period 2 [2]
    		Final inclusion
    Started
    46
    Completed
    46
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 2 of the enrolled subjects were subsequently excluded. Only data from the remaining 46 subjects of final inclusion were used for data analysis. See article-manuscript for clarification.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Final inclusion
    Reporting group description
    		 -

    Reporting group values
    		 Final inclusion Total
    Number of subjects
    		 46 46
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 46 46
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 42 (20 to 59) -
    Gender categorical
    Units: Subjects
        Female
    		 20 20
        Male
    		 26 26
    Smoking status
    Units: Subjects
        Smokers
    		 17 17
        Non-smoker
    		 29 29
    CRP status
    Units: Subjects
        CRP > 5 mg/L
    		 16 16
        CRP < 5 mg/L
    		 30 30
    Chronic blood dyscrasia
    Habitual WBC differential status within a six months retrospective data collection period was assessed. Chronic blood dyscrasia was defined as a minimum of 50% of the retrospective observations, for a given cell line, located either under or above the normal reference range. Only subjects with three or more WBC differential observations, within the retrospective period, were included for chronic blood dyscrasia evaluation. See up-loaded Table 1 and manuscript for clarification.
    Units: Subjects
        Chronic blood dyscrasia
    		 31 31
        No chronic blood dyscrasia
    		 15 15
    Number of daily clozapine administrations
    Units: Subjects
        1 daily administration
    		 29 29
        2 daily administratio2
    		 12 12
        3 daily administrations
    		 4 4
        4 daily administrations
    		 1 1
    Co-medications of relevance
    Relevant co-administrations was defined as drug-groups with known affecters of clozapine concentration. See up-loaded Table 1 and manuscript for clarification.
    Units: Subjects
        Relevantly co-medicated
    		 34 34
        Not relevantly co-medicted
    		 12 12
    Study specific age
    Units: Subjects
        Age > 45 years
    		 21 21
        Age < 45 years
    		 25 25
    BMI
    Units: kg/cm2
        median (full range (min-max))
    		 30.9 (20.1 to 48.8) -
    Daily caffeine consumption
    Units: mg
        median (full range (min-max))
    		 744.9 (0 to 2224.2) -
    Clozapine evening dose
    Units: mg
        median (full range (min-max))
    		 237.5 (50 to 500) -
    Clozapine day doses
    Units: mg
        median (full range (min-max))
    		 300 (50 to 800) -
    Subject analysis sets

    Subject analysis set title
    Chronic blood dyscrasia
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Habitual WBC differential status within a six months retrospective data collection period was assessed. Chronic blood dyscrasia was defined as a minimum of 50% of the retrospective observations, for a given cell line, located either under or above the normal reference range. Only subjects with three or more WBC differential observations, within the retrospective period, were included for chronic blood dyscrasia evaluation.

    Subject analysis sets values
    		 Chronic blood dyscrasia
    Number of subjects
    42
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        median (full range (min-max))
    Gender categorical
    Units: Subjects
        Female
        Male
    Smoking status
    Units: Subjects
        Smokers
        Non-smoker
    CRP status
    Units: Subjects
        CRP > 5 mg/L
        CRP < 5 mg/L
    Chronic blood dyscrasia
    Habitual WBC differential status within a six months retrospective data collection period was assessed. Chronic blood dyscrasia was defined as a minimum of 50% of the retrospective observations, for a given cell line, located either under or above the normal reference range. Only subjects with three or more WBC differential observations, within the retrospective period, were included for chronic blood dyscrasia evaluation. See up-loaded Table 1 and manuscript for clarification.
    Units: Subjects
        Chronic blood dyscrasia
    31
        No chronic blood dyscrasia
    11
    Number of daily clozapine administrations
    Units: Subjects
        1 daily administration
        2 daily administratio2
        3 daily administrations
        4 daily administrations
    Co-medications of relevance
    Relevant co-administrations was defined as drug-groups with known affecters of clozapine concentration. See up-loaded Table 1 and manuscript for clarification.
    Units: Subjects
        Relevantly co-medicated
        Not relevantly co-medicted
    Study specific age
    Units: Subjects
        Age > 45 years
        Age < 45 years
    BMI
    Units: kg/cm2
        median (full range (min-max))
    Daily caffeine consumption
    Units: mg
        median (full range (min-max))
    Clozapine evening dose
    Units: mg
        median (full range (min-max))
    Clozapine day doses
    Units: mg
        median (full range (min-max))

    End points

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    End points reporting groups
    Reporting group title
    Included subjects
    Reporting group description
    		 Subjects are patients in stable treatment with clozapine
    Reporting group title
    Final inclusion
    Reporting group description
    		 Included subjects are patients in stable treatment with clozapine

    Subject analysis set title
    Chronic blood dyscrasia
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Habitual WBC differential status within a six months retrospective data collection period was assessed. Chronic blood dyscrasia was defined as a minimum of 50% of the retrospective observations, for a given cell line, located either under or above the normal reference range. Only subjects with three or more WBC differential observations, within the retrospective period, were included for chronic blood dyscrasia evaluation.

    Primary: Differences in clozapine concentrations within a four-hour time span, 10-14 hours post-dose.

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    End point title
    		 Differences in clozapine concentrations within a four-hour time span, 10-14 hours post-dose. [1]
    End point description
    End point type
    Primary
    End point timeframe
    10-14 hours post-dose
    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: Primary end-point was a observational record of percentage difference in clozapine serum concentrations, between 2 time-points. No statistical analysis was pre-specified. See article-manuscript and up-loaded Table 2 for clarification.
    End point values
    		 Final inclusion
    Number of subjects analysed
    46
    Units: percentages
    median (full range (min-max))
        12-hour values vs. 10-hour values
    8.4 (-32.2 to 52.6)
        12-hour values vs. 11-hour values
    8 (-37.5 to 50.8)
        12-hour values vs. 13-hour values
    -3.4 (-30.5 to 25.9)
        12-hour values vs. 14-hour values
    -1.5 (-31.1 to 44)
        11-hour values vs. 13-hour values
    -8.6 (-39.1 to 23.5)
        10-hour values vs. 14-hour values
    -8.4 (-42.8 to 20.4)
    No statistical analyses for this end point

    Primary: Differences in norclozapine concentrations within a four-hour time span, 10-14 hours post-dose.

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    End point title
    		 Differences in norclozapine concentrations within a four-hour time span, 10-14 hours post-dose. [2]
    End point description
    End point type
    Primary
    End point timeframe
    10-14 hours post-dose
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Primary end-point was a observational record of percentage difference in norclozapine serum concentrations, between 2 time-points. No statistical analysis was pre-specified. See article-manuscript and up-loaded Table 2 for clarification.
    End point values
    		 Final inclusion
    Number of subjects analysed
    46
    Units: Percentages
    median (full range (min-max))
        12-hour values vs. 10-hour values
    6.2 (-28.1 to 105)
        12-hour values vs. 11-hour values
    0.8 (-24.8 to 53)
        12-hour values vs. 13-hour values
    4.2 (-16.3 to 31.3)
        12-hour values vs. 14-hour values
    7.3 (-25.6 to 37.5)
        11-hour values vs. 13-hour values
    2.7 (-23.6 to 31.3)
        10-hour values vs. 14-hour values
    1.2 (-38.4 to 35.5)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From last clozapine night ingestion the night before trial blood sampling until ended sampling time at inclusion day.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Directive 2001/20/EC
    Dictionary version
    2011/C 172
    Reporting groups
    Reporting group title
    Primary inclusion
    Reporting group description
    		 -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Only 1 adverse event occured during the trial, and this was a serious adverse event. See article-manuscript for clarification.
    Serious adverse events
    		 Primary inclusion
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 48 (2.08%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Primary inclusion
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 48 (0.00%)

    More information

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

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27922183
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