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    Clinical Trial Results:
    A Phase 2, Multicenter, Open-label Study to Assess the Safety, Tolerability and Pharmacokinetics of Apremilast (CC-10004) in Pediatric Subjects with Moderate to Severe Plaque Psoriasis

    Summary
    EudraCT number
    		 2015-003314-24
    Trial protocol
    		 GB   DE   ES   Outside EU/EEA  
    Global end of trial date
    29 Jul 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Jan 2020
    First version publication date
    31 Jan 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CC-10004-PPSO-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02576678
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Celgene Corporation
    Sponsor organisation address
    86 Morris Avenue, Summit, United States, 07901
    Public contact
    Clinical Trial Disclosure, Celgene Corporation, 01 888-260-1599, ClinicalTrialDisclosure@Celgene.com
    Scientific contact
    Wendy Zhang, Celgene Corporation, 01 908-514-9788, WeiZhang@Celgene.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000715-PIP03-11
    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
    29 Jul 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jul 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To select a pediatric dose of apremilast based on the safety, tolerability, and pharmacokinetics (PK) of apremilast (APR) in adolescents and children with moderate to severe plaque psoriasis.
    Protection of trial subjects
    Informed Consent, Patient Confidentiality and Archiving of Essential Documents
    Background therapy
    		 Low-potency corticosteroids for treatment of the face, axillae, and groin.
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    13 Oct 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 1 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    United States: 14
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    Germany: 8
    Worldwide total number of subjects
    42
    EEA total number of subjects
    15
    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)
    21
    Adolescents (12-17 years)
    21
    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
    		 The study was conducted at 11 study centers in 4 countries, including the United States, Canada, Germany and Spain.

    Pre-assignment
    Screening details
    		 Participants were enrolled according to a staggered, stepwise approach by age range and weight starting with older and heavier participants. Dosing within and between groups was staggered based on pharmacokinetic (PK) data collected and a minimum of 2 weeks of safety data.

    Period 1
    Period 1 title
    Overall Treatment Period (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
    		 Group 1 Adolescents: Apremilast 20 mg
    Arm description
    		 Participants ages 12 to 17 years old, with a weight of ≥ 35 kg to < 70 kg received apremilast tablets 20 mg twice a day (BID) for 2 weeks followed by a 48-week extension of apremilast treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg apremilast tablets BID

    Arm title
    		 Group 1 Adolescents: Apremilast 30 mg
    Arm description
    		 Participants ages 12 to 17 years old, with a weight of ≥ 70 kg received apremilast 30 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    30 mg apremilast tablets BID

    Arm title
    		 Group 2 Children: Apremilast 20 mg
    Arm description
    		 Participants ages 6 to 11 years old, with a weight of ≥ 15 kg received apremilast 20 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CC-10004
    Investigational medicinal product code
    Other name
    Otezla
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 mg apremilast tablets BID

    Number of subjects in period 1
    		Group 1 Adolescents: Apremilast 20 mg Group 1 Adolescents: Apremilast 30 mg Group 2 Children: Apremilast 20 mg
    Started
    13
    8
    21
    Pharmacokinetic (PK) Population
    12
    8
    18
    Completed
    8
    7
    16
    Not completed
    5
    1
    5
         Consent withdrawn by subject
    3
    1
    2
         Adverse event, non-fatal
    -
    -
    2
         Miscellaneous
    2
    -
    -
         Lost to follow-up
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1 Adolescents: Apremilast 20 mg
    Reporting group description
    		 Participants ages 12 to 17 years old, with a weight of ≥ 35 kg to < 70 kg received apremilast tablets 20 mg twice a day (BID) for 2 weeks followed by a 48-week extension of apremilast treatment.

    Reporting group title
    Group 1 Adolescents: Apremilast 30 mg
    Reporting group description
    		 Participants ages 12 to 17 years old, with a weight of ≥ 70 kg received apremilast 30 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.

    Reporting group title
    Group 2 Children: Apremilast 20 mg
    Reporting group description
    		 Participants ages 6 to 11 years old, with a weight of ≥ 15 kg received apremilast 20 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.

    Reporting group values
    		 Group 1 Adolescents: Apremilast 20 mg Group 1 Adolescents: Apremilast 30 mg Group 2 Children: Apremilast 20 mg Total
    Number of subjects
    		 13 8 21 42
    Age Categorical
    Units: Participants
        6 to 11 years
    		 0 0 21 21
        12 to 17 years
    		 13 8 0 21
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 13.8 ( 1.77 ) 14.8 ( 2.05 ) 9.3 ( 1.35 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 9 1 13 23
        Male
    		 4 7 8 19
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 2 0 2 4
        Black or African American
    		 0 0 2 2
        Native Hawaiian or other Pacific Islander
    		 0 1 0 1
        White or Caucasian
    		 10 6 16 32
        Other
    		 1 1 1 3
    Baseline Weight Category (kg)
    Units: Subjects
        < 15 kg
    		 0 0 0 0
        ≥ 15 - < 35 kg
    		 0 0 13 13
        ≥ 35 - < 50 kg
    		 3 0 4 7
        ≥ 50 - < 70 kg
    		 10 0 4 14
        ≥ 70 kg
    		 0 8 0 8
    Baseline Body Mass Index (BMI) Category
    Units: Subjects
        Healthy Weight
    		 7 1 15 23
        Overweight
    		 2 1 1 4
        Obesity
    		 4 6 5 15
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 1 3 5 9
        Not Hispanic or Latino
    		 12 5 16 33
    Duration of Plaque Psoriasis
    Units: Years
        arithmetic mean (standard deviation)
    		 7.41 ( 3.190 ) 6.96 ( 4.057 ) 2.75 ( 2.057 ) -
    Psoriasis Area Severity Index (PASI)
    The PASI is a measure of psoriatic disease severity taking into account qualitative lesion characteristics (erythema, thickness, and scaling) and degree of skin surface area involvement on defined anatomical regions. PASI scores range from 0 to 72, with higher scores reflecting greater disease severity. Erythema, thickness, and scaling are scored on a scale of 0 (none) to 4 (very severe) on 4 anatomic regions of the body: head, trunk, upper limbs, and lower limbs. Degree of involvement on each of the 4 anatomic regions is scored on a scale of 0 (no involvement) to 6 (90% to 100% involvement).
    Units: Units on a scale
        arithmetic mean (standard deviation)
    		 18.78 ( 11.693 ) 15.65 ( 3.430 ) 18.09 ( 6.144 ) -

    End points

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    End points reporting groups
    Reporting group title
    Group 1 Adolescents: Apremilast 20 mg
    Reporting group description
    		 Participants ages 12 to 17 years old, with a weight of ≥ 35 kg to < 70 kg received apremilast tablets 20 mg twice a day (BID) for 2 weeks followed by a 48-week extension of apremilast treatment.

    Reporting group title
    Group 1 Adolescents: Apremilast 30 mg
    Reporting group description
    		 Participants ages 12 to 17 years old, with a weight of ≥ 70 kg received apremilast 30 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.

    Reporting group title
    Group 2 Children: Apremilast 20 mg
    Reporting group description
    		 Participants ages 6 to 11 years old, with a weight of ≥ 15 kg received apremilast 20 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.

    Primary: Number of Participants with Treatment Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of Participants with Treatment Emergent Adverse Events (TEAEs) [1]
    End point description
    A TEAE is an adverse event with a start date on or after the date of the first dose of apremilast and no later than 28 days after the last dose of apremilast. An adverse event is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the subject’s health, including laboratory test values, regardless of etiology. A serious AE is any untoward AE that results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization or in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect or constitutes an important medical event. The investigator assessment of severity/intensity of an event was defined as mild, moderate or severe. The safety population consisted of all enrolled subjects who took at least one dose of apremilast.
    End point type
    Primary
    End point timeframe
    From first dose of apremilast until 28 days after the last dose; up to 29 July 2019; median treatment duration for adolescents apremilast 20 mg and 30 mg was 50.00 and 50.57 weeks respectively and for children was 50.00 weeks.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Adverse events were analyzed using descriptive statistics based on the safety population. The safety population consisted of all participants who received at least 1 dose of apremilast.
    End point values
    		 Group 1 Adolescents: Apremilast 20 mg Group 1 Adolescents: Apremilast 30 mg Group 2 Children: Apremilast 20 mg
    Number of subjects analysed
    13
    8
    21
    Units: Participants
        Any TEAE
    13
    7
    20
        Any Drug Related TEAE
    11
    6
    17
        Any Severe TEAE
    1
    0
    1
        Any Serious TEAE
    0
    0
    1
        Any Serious Drug-Related TEAE
    0
    0
    0
        Any TEAE Leading to Drug Interruption
    1
    0
    4
        Any TEAE Leading to Drug Withdrawal
    0
    0
    2
        Any TEAE Leading to Death
    0
    0
    0
    No statistical analyses for this end point

    Primary: Maximum Observed Plasma Concentration (Cmax) of Apremilast

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of Apremilast [2]
    End point description
    Maximum observed plasma concentration (Cmax) of apremilast. PK parameters were calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule. The pharmacokinetic (PK) population consisted of all enrolled subjects who took at least one dose of apremilast and had evaluable PK data. PK data were considered evaluable if there were measurable drug levels of apremilast in plasma from at least 3 time points which extended over a minimal 5-hour period within 12 hours post a dose, eg, predose, 2 and 8 hours post a dose.
    End point type
    Primary
    End point timeframe
    For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning 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: PK parameters were calculated using non-compartmental method for plasma concentrations and actual blood sampling times from the intensive sampling schedule. Actual sampling times were used in the calculations of PK parameters. PK parameters for apremilast were summarized using descriptive statistics based on the PK population, which consisted of all participants who took at least one dose of study drug and had evaluable PK data.
    End point values
    		 Group 1 Adolescents: Apremilast 20 mg Group 1 Adolescents: Apremilast 30 mg Group 2 Children: Apremilast 20 mg
    Number of subjects analysed
    12
    8
    18
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    274.272 ( 34.3 )
    410.929 ( 39.7 )
    348.146 ( 47.4 )
    No statistical analyses for this end point

    Primary: Time to Maximum Plasma Concentration (Tmax) of Apremilast

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    End point title
    		 Time to Maximum Plasma Concentration (Tmax) of Apremilast [3]
    End point description
    Time to maximum observed plasma concentration obtained directly from the observed concentration versus time data. PK parameters were calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule. The PK population consisted of all enrolled subjects who took at least one dose of apremilast and had evaluable PK data. PK data were considered evaluable if there were measurable drug levels of apremilast in plasma from at least 3 time points which extended over a minimal 5-hour period within 12 hours post a dose, eg, predose, 2 and 8 hours post a dose.
    End point type
    Primary
    End point timeframe
    For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose.
    Notes
    [3] - 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: PK parameters were calculated using non-compartmental method for plasma concentrations and actual blood sampling times from the intensive sampling schedule. Actual sampling times were used in the calculations of PK parameters. PK parameters for apremilast were summarized using descriptive statistics based on the PK population, which consisted of all participants who took at least one dose of study drug and had evaluable PK data.
    End point values
    		 Group 1 Adolescents: Apremilast 20 mg Group 1 Adolescents: Apremilast 30 mg Group 2 Children: Apremilast 20 mg
    Number of subjects analysed
    12
    8
    18
    Units: hours
        median (full range (min-max))
    2.467 (1.00 to 3.00)
    3.000 (1.00 to 5.00)
    2.000 (1.90 to 5.00)
    No statistical analyses for this end point

    Primary: Area Under the Plasma Concentration-time Curve from Time Zero to 12 hours Post Dose of Apremilast (AUC0-12)

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    End point title
    		 Area Under the Plasma Concentration-time Curve from Time Zero to 12 hours Post Dose of Apremilast (AUC0-12) [4]
    End point description
    Area under the plasma concentration-time curve from time zero to the 12 hours post dose was calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule. The PK population consisted of all enrolled subjects who took at least one dose of apremilast and had evaluable PK data. PK data were considered evaluable if there were measurable drug levels of apremilast in plasma from at least 3 time points which extended over a minimal 5-hour period within 12 hours post a dose, eg, predose, 2 and 8 hours post a dose.
    End point type
    Primary
    End point timeframe
    For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose.
    Notes
    [4] - 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: PK parameters were calculated using non-compartmental method for plasma concentrations and actual blood sampling times from the intensive sampling schedule. Actual sampling times were used in the calculations of PK parameters. PK parameters for apremilast were summarized using descriptive statistics based on the PK population, which consisted of all participants who took at least one dose of study drug and had evaluable PK data.
    End point values
    		 Group 1 Adolescents: Apremilast 20 mg Group 1 Adolescents: Apremilast 30 mg Group 2 Children: Apremilast 20 mg
    Number of subjects analysed
    12
    8
    17
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    1799.717 ( 36.0 )
    2901.795 ( 41.2 )
    2544.874 ( 40.8 )
    No statistical analyses for this end point

    Primary: Area Under the Plasma Concentration-time Curve from Time Zero to the Last Measurable Concentration of Apremilast (AUC0-t)

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    End point title
    		 Area Under the Plasma Concentration-time Curve from Time Zero to the Last Measurable Concentration of Apremilast (AUC0-t) [5]
    End point description
    Area under the plasma concentration-time curve from time zero to the last quantifiable time point and was calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule. The PK population consisted of all enrolled subjects who took at least one dose of apremilast and had evaluable PK data. PK data were considered evaluable if there were measurable drug levels of apremilast in plasma from at least 3 time points which extended over a minimal 5-hour period within 12 hours post a dose, eg, predose, 2 and 8 hours post a dose.
    End point type
    Primary
    End point timeframe
    For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose.
    Notes
    [5] - 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: PK parameters were calculated using non-compartmental method for plasma concentrations and actual blood sampling times from the intensive sampling schedule. Actual sampling times were used in the calculations of PK parameters. PK parameters for apremilast were summarized using descriptive statistics based on the PK population, which consisted of all participants who took at least one dose of study drug and had evaluable PK data.
    End point values
    		 Group 1 Adolescents: Apremilast 20 mg Group 1 Adolescents: Apremilast 30 mg Group 2 Children: Apremilast 20 mg
    Number of subjects analysed
    12
    8
    18
    Units: ng*h/mL
        geometric mean (geometric coefficient of variation)
    1794.815 ( 35.9 )
    2900.472 ( 41.4 )
    2367.641 ( 50.2 )
    No statistical analyses for this end point

    Primary: Apparent Total Plasma Clearance when Dosed Orally (CL/F) for Apremilast

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    End point title
    		 Apparent Total Plasma Clearance when Dosed Orally (CL/F) for Apremilast [6]
    End point description
    Apparent total plasma clearance (CL/F) of apremilast was calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule. The PK population consisted of all enrolled subjects who took at least one dose of apremilast and had evaluable PK data. PK data were considered evaluable if there were measurable drug levels of apremilast in plasma from at least 3 time points which extended over a minimal 5-hour period within 12 hours post a dose, eg, predose, 2 and 8 hours post a dose.
    End point type
    Primary
    End point timeframe
    For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose.
    Notes
    [6] - 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: PK parameters were calculated using non-compartmental method for plasma concentrations and actual blood sampling times from the intensive sampling schedule. Actual sampling times were used in the calculations of PK parameters. PK parameters for apremilast were summarized using descriptive statistics based on the PK population, which consisted of all participants who took at least one dose of study drug and had evaluable PK data. .
    End point values
    		 Group 1 Adolescents: Apremilast 20 mg Group 1 Adolescents: Apremilast 30 mg Group 2 Children: Apremilast 20 mg
    Number of subjects analysed
    12
    8
    17
    Units: Liters/hour
        geometric mean (geometric coefficient of variation)
    11.113 ( 36.0 )
    10.338 ( 41.2 )
    7.859 ( 40.8 )
    No statistical analyses for this end point

    Primary: Apparent Total Volume of Distribution when Dosed Orally, Based on Study-State (Vss/F) or in the Terminal Phase (Vz/F)

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    End point title
    		 Apparent Total Volume of Distribution when Dosed Orally, Based on Study-State (Vss/F) or in the Terminal Phase (Vz/F) [7]
    End point description
    Apparent total volume of distribution when dosed orally, based on study-state (Vss/F) or in the terminal phase (Vz/F). Pharmacokinetic parameters were calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule. The PK population consisted of all enrolled subjects who took at least one dose of apremilast and had evaluable PK data. PK data were considered evaluable if there were measurable drug levels of apremilast in plasma from at least 3 time points which extended over a minimal 5-hour period within 12 hours post a dose, eg, predose, 2 and 8 hours post a dose.
    End point type
    Primary
    End point timeframe
    For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose.
    Notes
    [7] - 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: PK parameters were calculated using non-compartmental method for plasma concentrations and actual blood sampling times from the intensive sampling schedule. Actual sampling times were used in the calculations of PK parameters. PK parameters for apremilast were summarized using descriptive statistics based on the PK population, which consisted of all participants who took at least one dose of study drug and had evaluable PK data.
    End point values
    		 Group 1 Adolescents: Apremilast 20 mg Group 1 Adolescents: Apremilast 30 mg Group 2 Children: Apremilast 20 mg
    Number of subjects analysed
    12
    8
    17
    Units: Liters
        geometric mean (geometric coefficient of variation)
    86.870 ( 56.1 )
    101.049 ( 31.6 )
    55.126 ( 51.2 )
    No statistical analyses for this end point

    Primary: Terminal Phase Elimination Half-Life

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    End point title
    		 Terminal Phase Elimination Half-Life [8]
    End point description
    Terminal-phase elimination half-life (t ½). PK parameters were calculated using non-compartmental methods, plasma concentrations and actual blood sampling times from the intensive sampling schedule. The PK population consisted of all enrolled subjects who took at least one dose of apremilast and had evaluable PK data. PK data were considered evaluable if there were measurable drug levels of apremilast in plasma from at least 3 time points which extended over a minimal 5-hour period within 12 hours post a dose, eg, predose, 2 and 8 hours post a dose.
    End point type
    Primary
    End point timeframe
    For adolescents, a pre-dose sample prior to morning dose and on Day 14 as well as at hours 1, 2, 3, 5, 8 and 12 post dose; for the children, samples were collected 2 hours at predose (prior to morning dose) and at 2, 5 and 12 hours post morning dose.
    Notes
    [8] - 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: Pharmacokinetic (PK) parameters were calculated using non-compartmental method for plasma concentrations and actual blood sampling times from the intensive sampling schedule. Actual sampling times were used in the calculations of PK parameters. PK parameters for apremilast were summarized using descriptive statistics based on the PK population, which consisted of all participants who took at least one dose of study drug and had evaluable PK data.
    End point values
    		 Group 1 Adolescents: Apremilast 20 mg Group 1 Adolescents: Apremilast 30 mg Group 2 Children: Apremilast 20 mg
    Number of subjects analysed
    12
    8
    17
    Units: hours
        geometric mean (geometric coefficient of variation)
    5.418 ( 43.1 )
    6.775 ( 50.3 )
    4.862 ( 30.2 )
    No statistical analyses for this end point

    Secondary: Taste and Acceptability of Apremilast Tablets Using the Faces Likert Scale

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    End point title
    		 Taste and Acceptability of Apremilast Tablets Using the Faces Likert Scale
    End point description
    Taste and acceptability of the apremilast tablet was assessed using a faces Likert Scale on Day 1, initial dosing. The scale consists of options from 1 (dislike very much, illustrated by a frowning face) to 5 (like very much, illustrated by a smiling face). This population consisted of all enrolled subjects who took at least one dose of apremilast.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Group 1 Adolescents: Apremilast 20 mg Group 1 Adolescents: Apremilast 30 mg Group 2 Children: Apremilast 20 mg
    Number of subjects analysed
    13
    8
    21
    Units: Participants
        1 (Dislike Very Much)
    0
    0
    3
        2 (Dislike a Little)
    1
    0
    1
        3 (Not Sure)
    5
    4
    3
        4 (Like a Little)
    1
    1
    4
        5 (Like Very Much)
    6
    3
    10
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of apremilast until 28 days after the last dose; up to 198 weeks; median treatment duration for adolescents apremilast 20 mg and 30 mg was 50.00 and 50.57 weeks respectively and for children was 50.00 weeks;
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Group 1 Adolescents: Apremilast 20 mg
    Reporting group description
    		 Participants ages 12 to 17 years old, with a weight of ≥ 35 kg to < 70 kg received apremilast tablets 20 mg twice a day (BID) for 2 weeks followed by a 48-week extension of apremilast treatment.

    Reporting group title
    Group 1 Adolescents: Apremilast 30 mg
    Reporting group description
    		 Participants ages 12 to 17 years old, with a weight of ≥ 70 kg received apremilast 30 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.

    Reporting group title
    Group 2: Children Apremilast 20 mg
    Reporting group description
    		 Participants ages 6 to 11 years old, with a weight of ≥ 15 kg received apremilast 20 mg tablets BID for 2 weeks followed by a 48-week extension of apremilast treatment.

    Serious adverse events
    		 Group 1 Adolescents: Apremilast 20 mg Group 1 Adolescents: Apremilast 30 mg Group 2: Children Apremilast 20 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         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
    		 Group 1 Adolescents: Apremilast 20 mg Group 1 Adolescents: Apremilast 30 mg Group 2: Children Apremilast 20 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 13 (100.00%)
    7 / 8 (87.50%)
    19 / 21 (90.48%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Influenza like illness
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 8 (12.50%)
    2 / 21 (9.52%)
         occurrences all number
    1
    1
    3
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    8
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma exercise induced
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Cough
         subjects affected / exposed
    3 / 13 (23.08%)
    1 / 8 (12.50%)
    2 / 21 (9.52%)
         occurrences all number
    4
    1
    2
    Nasal congestion
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 8 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    3
    0
    7
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    Attention deficit/hyperactivity disorder
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Depressed mood
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Insomnia
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    0
    1
    Intentional self-injury
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Mood swings
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Blood glucose increased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    Electrocardiogram abnormal
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Eosinophil count increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    0
    3
    Monocyte count increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    Protein urine present
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    0
    2
    Weight decreased
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    White blood cells urine positive
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Injury, poisoning and procedural complications
    Dislocation of vertebra
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Ligament sprain
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Headache
         subjects affected / exposed
    7 / 13 (53.85%)
    1 / 8 (12.50%)
    11 / 21 (52.38%)
         occurrences all number
    17
    2
    21
    Syncope
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    2
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
         occurrences all number
    0
    2
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 8 (12.50%)
    3 / 21 (14.29%)
         occurrences all number
    2
    1
    3
    Abdominal pain
         subjects affected / exposed
    6 / 13 (46.15%)
    1 / 8 (12.50%)
    11 / 21 (52.38%)
         occurrences all number
    15
    1
    43
    Abdominal pain upper
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 8 (12.50%)
    4 / 21 (19.05%)
         occurrences all number
    2
    11
    5
    Change of bowel habit
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Constipation
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    Diarrhoea
         subjects affected / exposed
    6 / 13 (46.15%)
    4 / 8 (50.00%)
    5 / 21 (23.81%)
         occurrences all number
    23
    18
    7
    Dyspepsia
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
         occurrences all number
    2
    1
    1
    Flatulence
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    0
    1
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Haematemesis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Nausea
         subjects affected / exposed
    8 / 13 (61.54%)
    4 / 8 (50.00%)
    10 / 21 (47.62%)
         occurrences all number
    11
    7
    18
    Vomiting
         subjects affected / exposed
    4 / 13 (30.77%)
    1 / 8 (12.50%)
    8 / 21 (38.10%)
         occurrences all number
    8
    1
    12
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    0
    2
    Foot deformity
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Joint swelling
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Patellofemoral pain syndrome
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 8 (12.50%)
    5 / 21 (23.81%)
         occurrences all number
    2
    2
    5
    Gastroenteritis viral
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    0
    3
    Influenza
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    0
    1
    Localised infection
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    6 / 13 (46.15%)
    3 / 8 (37.50%)
    7 / 21 (33.33%)
         occurrences all number
    11
    3
    12
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    0
    Tooth infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    Urinary tract infection
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 8 (25.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    2
    0
    Viral infection
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    0
    Tonsillitis streptococcal
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
         occurrences all number
    3
    1
    1
    Obesity
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Aug 2015
    1. Primary objective was clarified to reflect that the study was being conducted to select a pediatric dose of apremilast (APR) 2. Adjusted age ranges of subject groups 3. The C-SSRS questionnaire was added at Screening, Baseline and other visits (except Week 102 follow up) 4. Exclusion criterion was added (mandated ineligibility if any question was answered YES at Screening) 4. Psychiatric Evaluation Section was updated 5. Added Tanner Staging Assessment and description 6. Added Extension Treatment Period; Optional open label was deleted in the Extension Treatment Period; 50-week Treatment Extension Period was changed to 48-week Treatment Extension Period; Length of study was shortened to 107 weeks 7. Two more visits at Week 24 and Week 40 were added to comply with safety assessments and language was updated from 5 visits to 7 additional visits 8. Added Short-term follow-up and adjusted to 4 weeks and 8 weeks after the last dose of APR; Week 56 short-term Follow-up Visit changed to Weeks 54 and 58 9. Number of subjects was changed to at least 32 and at least 16 subjects in each group 10. Daily Stool Diary was added 11. Updated Frequency of Height Measurements 12. Study Timeline Schematic was updated to reflect FDA changes; included length of Extension Treatment Period, addition of post 8-week follow-up, and adjustment to length of study 13. Two additional ECG readings were added 14. Psoriasis flare and rebound were not considered AEs 15. Canada was added as a participating country 16. Prior treatment with APR was added as an exclusion criterion 17. Pregnancy was added as reason for withdrawal 18. Added Moderate to Severe to protocol title 19. Removed text that described use of a subject pill diary 20. Added a faces Likert Scale 21. Psoriasis Flare and Rebound section title was changed to Worsening Psoriasis and Rebound Assessments 22. Added pregnancy tests to Overview of Safety Assessments 23. Two sentences were added to dosing scenario for Group 1. and Group 2.
    29 Apr 2016
    1. Revised WBC count, platelet count, and hemoglobin levels for subject eligibility; gender- and age-specific allowed for up to 10% lower than the LLN for hemoglobin and platelet count levels, and for up to 20% lower for the WBC counts 2. Added the excipients of apremilast to screen for potential sensitivity; excipients of apremilast were specified and listed in the exclusion criterion 3. Added an exclusion criterion for deficiencies in lactose metabolism; an exclusion criterion was added for subjects who may have had an allergy to lactose 4. Extended eligibility to subjects previously exposed to biologic therapy; the amendment allowed inclusion of potential subjects who had been previously exposed to a systemic biologic therapy; Inclusion Criterion #12 was modified. Exclusion Criterion #19 was added to specify required washout periods for previous biologic therapies 5. Removal of the 24-hour post-Day 14 dosing PK blood draw time point; removed the last blood draw (24 hours after the Day 14 dose) from the intensive PK assessments for Group 1; 6. A reminder to take the Day 14 dose only after the 12-hour; postdose blood draw was added for clarification 7. Modified highly effective to effective in the Option 1 description of contraception methods for females 8. A statement was added to show the percentage of subjects in Studies PSOR-008 and PSOR-009 who had prior exposure to biologic therapy 9. Additional text was included to clarify that the consenting/assenting process must be repeated for any subject who fails Screening and returns to be rescreened 10. Text was added to clarify that not all 16 subjects in Group 1 needed to have both the DBS assay and a venous blood draw if the DBS method of blood sample analysis was validated before all Group 1 subjects had blood taken using both methods 11. More sites were to be added to the study so an update of the approximate number of sites was entered 12. Text describing the shipping of PK samples was clarified

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

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