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    Clinical Trial Results:
    A Multicentre, International, Adaptive, Open-label, Repeated Administration Pharmacokinetic Study of Bilastine in Children from 2 to <12 Years of age with Allergic Rhinoconjunctivitis or Chronic Urticaria

    Summary
    EudraCT number
    		 2009-012013-22
    Trial protocol
    		 DE   ES   SE  
    Global end of trial date
    12 Jun 2012

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Jul 2022
    First version publication date
    01 Jul 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BILA-3009/PED
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01081574
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ClinicalTrials.gov identifier: NCT01081574
    Sponsors
    Sponsor organisation name
    FAES FARMA S.A.
    Sponsor organisation address
    Avda Autonomía, 10, Leioa, Spain,
    Public contact
    Cristina Campo, FAES FARMA S.A., +34 94 481 83 00 , ccampo@faes.es
    Scientific contact
    Cristina Campo, FAES FARMA S.A., +34 94 481 83 00 , ccampo@faes.es
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000347-PIP01-08
    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
    10 Mar 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Jun 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jun 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to assess the pharmacokinetics of bilastine in children (aged 2 to <12 years) with allergic rhinoconjunctivitis (seasonal allergic rhinitis and/or perennial allergic rhinitis [SAR/PAR]) or chronic urticaria (CU) in order to ascertain whether the proposed dose (10 mg/day or lower) matches the systemic exposure seen in adults with the 20 mg/day dose.
    Protection of trial subjects
    - Only children with symptomatic AR or chronic urticaria were enrolled in this study, thus avoiding unnecessary dosing of healthy children not in need of any medication -To minimise the potential risk of overexposure to bilastine for younger children (2 to <6 years), the study design, includes an ongoing implementation of the PK/PD model with pharmacokinetic data obtained from children 6 to <12 years old, to allow to choose an adequate bilastine dose to be administered to younger children (2 to <6 years) before enrolling this group of children in this study. This model also reduces any risk or discomfort associated with blood sampling, to be drawn from children to a minimum. In addition, appropriate safety monitoring of patients enrolled in the study is conducted throughout the treatment period. - Given the lower incidence of somnolence due to bilastine compared to cetirizine and levocetirizine, bilastine is expected to show some advantages for the children enrolled in the study, in terms of side effects such as somnolence/drowsiness which represent a common concern for this class of drugs particularly in children where it can negatively affect their school performance and social life.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Apr 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 10
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    Australia: 2
    Worldwide total number of subjects
    31
    EEA total number of subjects
    29
    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)
    31
    Adolescents (12-17 years)
    0
    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
    		 41 patients were screened in 8 sites: Australia (2), Germany (3), Sweden (2) and Spain (1). 31 patients were recruited and randomized: 24 in Group A (6-12 years) and 7 in Group B (2-6 years) between April 15, 2010 - June 12, 2012. These 31 patients completed the study.

    Pre-assignment
    Screening details
    		 An adaptive design was followed to minimize testing in children and achieve adequate characterization of the PK model. Study recruitment was terminated early based on the results of the second interim analysis, in accordance with pre-specified rules in the protocol, only 31 subjects were included (instead of the initially planned 44 subjects).

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Final analysis children group
    Arm description
    		 31 children from groups A (6 to < 12 years ol) and B (2 to 6 years old) treated with Bilastine 10 mg orodispersible tablet, once daily for 7 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bilastine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Orodispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Bilastine 10 mg once daily, administered orally, for 7 days

    Arm title
    		 Group A (children 6 to < 12 years)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bilastine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Orodispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Bilastine 10 mg once daily, administered orally, for 7 days

    Arm title
    		 Group B (Children 2 to 6 years)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bilastine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Orodispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Bilastine 10 mg once daily, administered orally, for 7 days

    Number of subjects in period 1
    		Final analysis children group Group A (children 6 to < 12 years) Group B (Children 2 to 6 years)
    Started
    31
    25
    9
    Completed
    31
    25
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 All children in this study received bilastine 10 mg orodispersible tablet, once daily for 7 days, administered orally under fasting conditions. The blood-sampling was performed after 7 days.

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 31 31
    Age categorical
    Group A: 6 to <12 years, subgroups A1 (6-8 years), A2 (8-10 years), A3 (10- <12 years) Group B: 2 to < 6 years
    Units: Subjects
        Children (2-11 years)
    		 31 31
    Gender categorical
    Units: Subjects
        Female
    		 11 11
        Male
    		 20 20
    Subject analysis sets

    Subject analysis set title
    First Interim analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Pharmacokinetic analysis of 16 subjects from group A (6 to 12 years old) treated with bilastine 10 mg

    Subject analysis set title
    Second Interim analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    9 children (6 from group A + 3 from group B) + 16 chidren from the first interim analysis

    Subject analysis set title
    Final model analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Total group of 31 children from 4 to <12 years: Groups A (25 children from 6 to < 12 years) + Group B (7 children from 4 to 5 years). For the final model 2 outliers subjects were removed from the analysis.

    Subject analysis sets values
    		 First Interim analysis set Second Interim analysis set Final model analysis
    Number of subjects
    16
    25
    31
    Age categorical
    Group A: 6 to <12 years, subgroups A1 (6-8 years), A2 (8-10 years), A3 (10- <12 years) Group B: 2 to < 6 years
    Units: Subjects
        Children (2-11 years)
    16
    25
    29
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    Final analysis children group
    Reporting group description
    		 31 children from groups A (6 to < 12 years ol) and B (2 to 6 years old) treated with Bilastine 10 mg orodispersible tablet, once daily for 7 days.

    Reporting group title
    Group A (children 6 to < 12 years)
    Reporting group description
    		 -

    Reporting group title
    Group B (Children 2 to 6 years)
    Reporting group description
    		 -

    Subject analysis set title
    First Interim analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Pharmacokinetic analysis of 16 subjects from group A (6 to 12 years old) treated with bilastine 10 mg

    Subject analysis set title
    Second Interim analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    9 children (6 from group A + 3 from group B) + 16 chidren from the first interim analysis

    Subject analysis set title
    Final model analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Total group of 31 children from 4 to <12 years: Groups A (25 children from 6 to < 12 years) + Group B (7 children from 4 to 5 years). For the final model 2 outliers subjects were removed from the analysis.

    Primary: Maximum plasma concentration (Cmax)

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    End point title
    		 Maximum plasma concentration (Cmax)
    End point description
    Pharmacokinetics (PK) of bilastine in children (aged 2 to <12 years) with allergic rhinoconjunctivitis (AR) (seasonal allergic rhinitis [SAR] and/or perennial allergic rhinitis [PAR]) or chronic urticaria in order to ascertain that the systemic exposure attained with a dose of 10 mg every day or lower is comparable to that achieved in adults and adolescents administered with a dose of 20 mg/every day.
    End point type
    Primary
    End point timeframe
    Group A, prior to dose administration, and at 0.25, 0.5, 0.8, 1.0, 1.2, 1.5, 3.0, 4.0, 6.0, 8.0, 10.0, 12.0, and 24.0 hours Group B, prior to dose administration, and at0.25, 0.5, 1.0, 1.5, 3.0, 6.0, 8.0, 10.0, and 12.0 hours
    End point values
    		 First Interim analysis set Second Interim analysis set
    Number of subjects analysed
    16
    25
    Units: ng/mL
        arithmetic mean (standard deviation)
    241 ( 109 )
    347 ( 109 )
    Statistical analysis title
    		 Nonlinear mixed-effects modelling (NONMEM)
    Statistical analysis description
    Pharmacokinetic analysis was performed. The paediatric PK dataset of N=31 (Group A and Group B) was analysed by nonlinear mixed-effects modelling methods as implemented in NONMEM® VI (GloboMax LLC, Hanover, MD, USA) (FOCE method). Data exploration, statistical testing external to NONMEM and graphics were performed using S-PLUS version 8 (Insightful Corp, Seattle, WA).
    Comparison groups
    First Interim analysis set v Second Interim analysis set
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [1] - Pharmacokinetic characterization of the IMP in a population of children

    Secondary: Safety and tolerability

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    End point title
    		 Safety and tolerability
    End point description
    Describe the safety and tolerability of a repeated administration of bilastine in the aforementioned paediatric subset with allergic rhinoconjunctivitis (SAR/PAR) or chronic urticaria in terms of the number of subjects who presented Adverse Events during the study
    End point type
    Secondary
    End point timeframe
    Period from the signature of the Informed Consent to the end of the study
    End point values
    		 Final analysis children group Group A (children 6 to < 12 years) Group B (Children 2 to 6 years)
    Number of subjects analysed
    31 [2]
    25 [3]
    9 [4]
    Units: number
    15
    12
    3
    Notes
    [2] - 31 children (total safety population)
    [3] - Group A (Children 6 to < 12 y)
    [4] - Group B (2 to 6 y)
    Statistical analysis title
    		 S-plus software
    Statistical analysis description
    S-plus software. Descriptive analysis
    Comparison groups
    Group A (children 6 to < 12 years) v Group B (Children 2 to 6 years)
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 indiviual Bayes parameters
    Confidence interval
         level
    		 95%
    Variability estimate
    Standard deviation
    Notes
    [5] - P < 0.05 indicates statistical significance between two values

    Other pre-specified: Pharmacokinetic final model - Absorption constant

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    End point title
    		 Pharmacokinetic final model - Absorption constant
    End point description
    This parameter was estimated in 29 pediatric patients. Two patients from Group A3 (10-11 years) were eliminated due to atypical statistical behavior (outliers), probably due to protocol deviations. The absorption constant (Ka) is measured in h -1, we present the estimated value and the standard error of the estimate as a percentage (%)
    End point type
    Other pre-specified
    End point timeframe
    After collecting blood-samples from 31 children included in the study (from Groups A + B).
    End point values
    		 First Interim analysis set Second Interim analysis set Final model analysis
    Number of subjects analysed
    16 [6]
    25
    29
    Units: h -1
        arithmetic mean (standard error)
    1.28 ( 0.000 )
    1.49 ( 0.214 )
    1.29 ( 0.286 )
    Attachments
    		 Population pK parameter estimates
    Notes
    [6] - Group A 6-12 years
    No statistical analyses for this end point

    Other pre-specified: Pharmacokinetic final model - Clearance

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    End point title
    		 Pharmacokinetic final model - Clearance
    End point description
    This parameter was estimated in 29 pediatric patients. Two patients from Group A3 (10-11 years) were eliminated due to atypical statistical behavior (outliers). The Clearance (Cl/F) is measured in L/h, we present the estimated value and the standard error of the estimate as a percentage (%)
    End point type
    Other pre-specified
    End point timeframe
    After collecting blood-samples from 31 children included in the study (from Groups A + B).
    End point values
    		 First Interim analysis set Second Interim analysis set Final model analysis
    Number of subjects analysed
    16
    25
    29
    Units: L/h
        arithmetic mean (standard error)
    13.2 ( 1.20 )
    13.8 ( 1.23 )
    12.5 ( 0.74 )
    No statistical analyses for this end point

    Other pre-specified: Pharmacokinetic final model - Volume of distribution (Vd/F)

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    End point title
    		 Pharmacokinetic final model - Volume of distribution (Vd/F)
    End point description
    This parameter was estimated in 29 pediatric patients. Two patients from Group A3 (10-11 years) were eliminated due to atypical statistical behavior (outliers). The Volume of distribution (Vd/F) is measured in L, we present the estimate and the standard error of the estimate as a percentage (%)
    End point type
    Other pre-specified
    End point timeframe
    At the end of the sutdy, after collecting blood-samples from 31 children included in the study (from Groups A + B).
    End point values
    		 First Interim analysis set Second Interim analysis set Final model analysis
    Number of subjects analysed
    16
    25
    29
    Units: L
        arithmetic mean (standard error)
    19.0 ( 4.34 )
    24.6 ( 3.78 )
    19.7 ( 2.53 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From informed consent signature till end of trial
    Adverse event reporting additional description
    Safety statistical analyses were performed by inVentiv Health Clinical, (formerly PharmaNet/i3, company name change in US only). A safety population was included with all participant children who received at least 1 dose of protocol treatment. The Medical Dictionary for Regulatory Activities (MedDRA), Version 13.0, was used
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Safety population (Group A + B)
    Reporting group description
    		 No deaths, SAEs, severe events, or discontinuations due to AEs were reported.

    Serious adverse events
    		 Safety population (Group A + B)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 31 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety population (Group A + B)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 31 (48.39%)
    Investigations
    Blood glucose descreased
         subjects affected / exposed
    3 / 31 (9.68%)
         occurrences all number
    3
    Nervous system disorders
    Headache
    Additional description: 5 children from Group A and 1 kid from group B
         subjects affected / exposed
    6 / 31 (19.35%)
         occurrences all number
    6
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    4 / 31 (12.90%)
         occurrences all number
    4
    Abdominal pain upper
         subjects affected / exposed
    3 / 31 (9.68%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    2 / 31 (6.45%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Dec 2009
    made the following changes based on the request from EC/CA involved in the study protocol evaluation: One inclusion and one exclusion criterion amended for clarification, and 2 exclusion criteria added to exclude mentally disabled minors or those minors who explicitly refuse to take part in the study. In the withdrawal of subjects section, respect of minor’s volition was added for emphasis and clarity. Information regarding withdrawing subjects based on abnormal lab results or ECG change from baseline of greater than 30 msec was added to provide the investigator with clear instructions to protect the safety of the subject. A few general changes were made apart from EC/CA request including the deletion of carbon dioxide test in the blood chemistry panel, as this parameter is not required, minor changes in the shipping of sampling information, and a note added to the pharmacokinetic sampling tables for Groups A and B for clarity.
    10 Nov 2010
    changed the inclusion criterion #2 from a majority range of the 25th through 75th percentile to the 10th to 90th percentile.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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