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    Clinical Trial Results:
    A Phase I, Open Label Study to Evaluate the Pharmacokinetics of Tezepelumab in Children ≥ 5 to 11 Years of Age with Mild, Moderate, or Severe Asthma

    Summary
    EudraCT number
    2020-000554-97
    Trial protocol
    GB   HU  
    Global end of trial date
    27 Sep 2022

    Results information
    Results version number
    v1(current)
    This version publication date
    28 Mar 2023
    First version publication date
    28 Mar 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D5180C00025
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04673630
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Karlebyhusentren, B674 Astraallen, Södertälje, Sweden, 151 85
    Public contact
    Global Clinical Lead, AstraZeneca, +1 877-240-9479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, +1 877-240-9479, information.center@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001613-PIP01-14
    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
    27 Sep 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Sep 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study was to describe the Pharmacokinetic (PK) parameters following a single subcutaneous (SC) administration of tezepelumab in children with mild, moderate, or severe asthma.
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council for Harmonisation/Good Clinical Practice, applicable regulatory requirements, and the AstraZeneca policy on Bioethics.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    23 Feb 2021
    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
    United Kingdom: 8
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    South Africa: 8
    Worldwide total number of subjects
    18
    EEA total number of subjects
    2
    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)
    18
    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
    This Phase I open-label study was conducted in pediatric participants with mild, moderate, or severe asthma at 6 investigational sites.

    Pre-assignment
    Screening details
    This study consists a screening period (14 days), and a single dose treatment (Day 1) and follow-up period (85 days). A total of 18 participants were treated in the study.

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

    Arms
    Arm title
    Tezepelumab
    Arm description
    Participants received a single dose of tezepelumab SC injection on Day 1.
    Arm type
    Experimental

    Investigational medicinal product name
    Tezepelumab
    Investigational medicinal product code
    Other name
    MEDI9929, AMG 157
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Single SC injection of tezepelumab administered by a healthcare professional on Day 1.

    Number of subjects in period 1
    Tezepelumab
    Started
    18
    Completed
    18

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tezepelumab
    Reporting group description
    Participants received a single dose of tezepelumab SC injection on Day 1.

    Reporting group values
    Tezepelumab Total
    Number of subjects
    18 18
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    7.9 ( 1.78 ) -
    Gender Categorical
    Units: Subjects
        Female
    7 7
        Male
    11 11
    Race
    Units: Subjects
        Asian
    2 2
        Black or African American
    1 1
        White
    6 6
        Other
    9 9
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    18 18

    End points

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    End points reporting groups
    Reporting group title
    Tezepelumab
    Reporting group description
    Participants received a single dose of tezepelumab SC injection on Day 1.

    Primary: Maximum Observed Serum Concentration (Cmax) of Tezepelumab

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    End point title
    Maximum Observed Serum Concentration (Cmax) of Tezepelumab [1]
    End point description
    Blood samples were collected to determine the Cmax of tezepelumab. The PK parameters were estimated using non-compartmental analysis method. The PK analysis set included participants in the Safety Analysis set that had at least 1 detectable tezepelumab serum concentration from a sample collected postdose that was assumed not to be affected by factors such as important protocol deviations (eg, incorrect dose of study drug received).
    End point type
    Primary
    End point timeframe
    Predose and within ± 1 hour of postdose on Day 1; on Days 3, 7, 11, 15, 29, 57 and 85
    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: Only descriptive statistical analysis was performed for the primary endpoint.
    End point values
    Tezepelumab
    Number of subjects analysed
    18
    Units: microgram per milliliter (mcg/mL)
        arithmetic mean (standard deviation)
    27.1 ( 11.9 )
    No statistical analyses for this end point

    Primary: Time to Achieve Maximum Observed Serum Concentration (tmax) of Tezepelumab

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    End point title
    Time to Achieve Maximum Observed Serum Concentration (tmax) of Tezepelumab [2]
    End point description
    Blood samples were collected to determine the tmax of tezepelumab. The PK parameters were estimated using non-compartmental analysis method. The PK analysis set included participants in the Safety Analysis set that had at least 1 detectable tezepelumab serum concentration from a sample collected postdose that was assumed not to be affected by factors such as important protocol deviations (eg, incorrect dose of study drug received).
    End point type
    Primary
    End point timeframe
    Predose and within ± 1 hour of postdose on Day 1; on Days 3, 7, 11, 15, 29, 57 and 85
    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: Only descriptive statistical analysis was performed for the primary endpoint.
    End point values
    Tezepelumab
    Number of subjects analysed
    18
    Units: day
        median (full range (min-max))
    3.47 (1.92 to 9.96)
    No statistical analyses for this end point

    Primary: Area Under the Concentration-Time Curve From Time Zero to The Last Measurable Concentration (AUC0-last) of Tezepelumab

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    End point title
    Area Under the Concentration-Time Curve From Time Zero to The Last Measurable Concentration (AUC0-last) of Tezepelumab [3]
    End point description
    Blood samples were collected to determine the AUC0-last of tezepelumab and calculated by linear up/log down trapezoidal summation. The PK parameters were estimated using non-compartmental analysis method. The PK analysis set included participants in the Safety Analysis set that had at least 1 detectable tezepelumab serum concentration from a sample collected postdose that was assumed not to be affected by factors such as important protocol deviations (eg, incorrect dose of study drug received).
    End point type
    Primary
    End point timeframe
    Predose and within ± 1 hour of postdose on Day 1; on Days 3, 7, 11, 15, 29, 57 and 85
    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: Only descriptive statistical analysis was performed for the primary endpoint.
    End point values
    Tezepelumab
    Number of subjects analysed
    18
    Units: day*mcg/mL
        arithmetic mean (standard deviation)
    872 ( 285 )
    No statistical analyses for this end point

    Primary: Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Tezepelumab

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    End point title
    Area Under the Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Tezepelumab [4]
    End point description
    Blood samples were collected to determine the AUC0-inf of tezepelumab and calculated by linear up/log down trapezoidal summation and extrapolated to infinity by the addition of the last quantifiable concentration divided by the terminal rate constant. The PK parameters were estimated using non-compartmental analysis method. The PK analysis set included participants in the Safety Analysis set that had at least 1 detectable tezepelumab serum concentration from a sample collected postdose that was assumed not to be affected by factors such as important protocol deviations (eg, incorrect dose of study drug received).
    End point type
    Primary
    End point timeframe
    Predose and within ± 1 hour of postdose on Day 1; on Days 3, 7, 11, 15, 29, 57 and 85
    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: Only descriptive statistical analysis was performed for the primary endpoint.
    End point values
    Tezepelumab
    Number of subjects analysed
    18
    Units: day*mcg/mL
        arithmetic mean (standard deviation)
    974 ( 320 )
    No statistical analyses for this end point

    Primary: Terminal Phase Elimination Half-Life (t1/2) of Tezepelumab

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    End point title
    Terminal Phase Elimination Half-Life (t1/2) of Tezepelumab [5]
    End point description
    Blood samples were collected to determine the t1/2 of tezepelumab and calculated as ln(2)/λZ, where λZ is the first-order rate constant associated with the terminal (log-linear) elimination phase. The PK parameters were estimated using non-compartmental analysis method. The PK analysis set included participants in the Safety Analysis set that had at least 1 detectable tezepelumab serum concentration from a sample collected postdose that was assumed not to be affected by factors such as important protocol deviations (eg, incorrect dose of study drug received).
    End point type
    Primary
    End point timeframe
    Predose and within ± 1 hour of postdose on Day 1; on Days 3, 7, 11, 15, 29, 57 and 85
    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: Only descriptive statistical analysis was performed for the primary endpoint.
    End point values
    Tezepelumab
    Number of subjects analysed
    18
    Units: day
        arithmetic mean (standard deviation)
    25.7 ( 5.94 )
    No statistical analyses for this end point

    Primary: Apparent Clearance (CL/F) of Tezepelumab

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    End point title
    Apparent Clearance (CL/F) of Tezepelumab [6]
    End point description
    Blood samples were collected to determine the CL/F of tezepelumab and estimated as dose divided by AUC0-inf. The PK parameters were estimated using non-compartmental analysis method. The PK analysis set included participants in the Safety Analysis set that had at least 1 detectable tezepelumab serum concentration from a sample collected postdose that was assumed not to be affected by factors such as important protocol deviations (eg, incorrect dose of study drug received).
    End point type
    Primary
    End point timeframe
    Predose and within ± 1 hour of postdose on Day 1; on Days 3, 7, 11, 15, 29, 57 and 85
    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: Only descriptive statistical analysis was performed for the primary endpoint.
    End point values
    Tezepelumab
    Number of subjects analysed
    18
    Units: liter per day
        arithmetic mean (standard deviation)
    0.0802 ( 0.0295 )
    No statistical analyses for this end point

    Primary: Apparent Steady-State Volume of Distribution (Vss/F) of Tezepelumab

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    End point title
    Apparent Steady-State Volume of Distribution (Vss/F) of Tezepelumab [7]
    End point description
    Blood samples were collected to determine the Vss/F of tezepelumab and estimated as CL/F*mean residence time (MRT), where MRT=Area under the moment curve of the analyte in the sampled matrix from zero (predose) extrapolated to infinite time/(AUC0-inf). The PK parameters were estimated using non-compartmental analysis method. The PK analysis set included participants in the Safety Analysis set that had at least 1 detectable tezepelumab serum concentration from a sample collected postdose that was assumed not to be affected by factors such as important protocol deviations (eg, incorrect dose of study drug received).
    End point type
    Primary
    End point timeframe
    Predose and within ± 1 hour of postdose on Day 1; on Days 3, 7, 11, 15, 29, 57 and 85
    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: Only descriptive statistical analysis was performed for the primary endpoint.
    End point values
    Tezepelumab
    Number of subjects analysed
    18
    Units: liter
        arithmetic mean (standard deviation)
    3.08 ( 1.32 )
    No statistical analyses for this end point

    Primary: Apparent Volume of Distribution (Vz/F) of Tezepelumab

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    End point title
    Apparent Volume of Distribution (Vz/F) of Tezepelumab [8]
    End point description
    Blood samples were collected to determine the Vz/F of tezepelumab and estimated as CL/F*1/ λZ. The PK parameters were estimated using non-compartmental analysis method. The PK analysis set included participants in the Safety Analysis set that had at least 1 detectable tezepelumab serum concentration from a sample collected postdose that was assumed not to be affected by factors such as important protocol deviations (eg, incorrect dose of study drug received).
    End point type
    Primary
    End point timeframe
    Predose and within ± 1 hour of postdose on Day 1; on Days 3, 7, 11, 15, 29, 57 and 85
    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: Only descriptive statistical analysis was performed for the primary endpoint.
    End point values
    Tezepelumab
    Number of subjects analysed
    18
    Units: liter
        arithmetic mean (standard deviation)
    2.98 ( 1.26 )
    No statistical analyses for this end point

    Secondary: Number of Participants With Anti-Drug Antibody (ADA) Response to Tezepelumab

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    End point title
    Number of Participants With Anti-Drug Antibody (ADA) Response to Tezepelumab
    End point description
    Blood samples were analyzed for the presence of ADAs for tezepelumab using validated assays. ADA prevalence was defined as ADA positive at baseline and/or post baseline. ADA incidence was defined as the percentage of treatment-emergent ADA positive participants in a population. Treatment induced ADA positive was defined as ADA negative at baseline and post-baseline ADA positive. Treatment-boosted ADA positive was defined as baseline positive ADA titre that was boosted to a 4-fold or higher level following study drug administration. Treatment-emergent ADA positive was defined as either treatment-induced ADA positive or treatment-boosted ADA positive. The Safety analysis set included all participants who received at least 1 dose of tezepelumab.
    End point type
    Secondary
    End point timeframe
    Predose and within ± 1 hour of postdose on Day 1; on Days 29 and 85
    End point values
    Tezepelumab
    Number of subjects analysed
    18
    Units: participants
    number (not applicable)
        ADA prevalence
    3
        Only baseline ADA positive
    2
        Baseline and at least 1 post-baseline ADA positive
    1
        Baseline ADA positive regardless of post-baseline
    3
        Any post-baseline ADA positive
    1
        Treatment-induced ADA positive
    0
        Treatment-boosted ADA positive
    0
        Treatment-emergent ADA positive
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose administration (Day 1) up to study completion (End of Study/Day 85 visit) or withdrawal date
    Adverse event reporting additional description
    The Safety analysis set included all participants who received at least 1 dose of tezepelumab.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Tezepelumab
    Reporting group description
    Participants received a single dose of tezepelumab SC injection on Day 1.

    Serious adverse events
    Tezepelumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 18 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Tezepelumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 18 (38.89%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Contusion
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Cough
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1
    Infections and infestations
    COVID-19
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Nasopharyngitis
         subjects affected / exposed
    2 / 18 (11.11%)
         occurrences all number
    2
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 18 (5.56%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Jul 2020
    Clarified that study start occur only when it is acceptable and safe to do so in accordance with local and national guidelines. Testing for Coronavirus Disease 2019 (COVID-19) and additional visits added. Addition of new exclusion criteria for participants that were positive for COVID-19 and/or had signs and/or symptoms indicative of present or past multisystem inflammatory syndrome. Screening classification for participants with a positive COVID-19 test clarified. Volume of blood clarified for severe acute respiratory syndrome coronavirus 2 serology to allow for testing of COVID 19. Details of mitigations added that could be employed to ensure study continuity in the event of a civil crisis, natural disaster or public health crisis. New section added for COVID-19 safety assessment procedure. New section added for pandemic impact assessment for COVID-19. New requirements for performing spirometry added, including the procedure for participants testing positive for COVID-19, and clarification regarding the safety of performing spirometry. New requirements for conducting the fractional exhaled nitric oxide test added, including the procedure for participants testing positive for COVID 19, and clarification regarding the safety of performing the test. Updated text to clarify that approximately 14 participants will receive a single SC dose of tezepelumab. Additional information added to clarify replacement of participants who did not receive tezepelumab or complete all required evaluations.
    13 May 2021
    The COVID-19 viral testing procedure updated to rapid test at local laboratory instead of at central laboratory at Visit 1 and Visit 2. Removed exclusion for use of systemic or intra-articular glucocorticosteroids for conditions other than asthma for 3 months prior to Visit 2 and discouraged until end of study. Change evidence of asthma by removing post-bronchodilator spirometry or historical reversibility criteria and adding to physician diagnosis of asthma as defined by regional guidelines and Investigator review of medical history. Change in participant’s pre-bronchodilator forced expiratory volume in one second criteria from ≥ 70% to ≥ 50% of predicted normal value. Updated to allow more than 1 rescreen attempt per participant, as long as the study physician had deemed the reason for rescreen was valid.
    06 Jan 2022
    Removed inclusion criteria for body mass index for age at both screening and Day 1 to include full span of growth percentiles. Updated exclusion criteria around a history of a deterioration in asthma, asthma exacerbation requiring glucocorticoids, and systemic corticosteroid use for the maintenance treatment of asthma to decrease time restriction from 3 months to 6 weeks. Updated exclusion criteria around a history of overnight hospitalisation for asthma from 6 months to 3 months prior to Visit 1, up to and including Visit 2 (Day 1). Updated location where the study was conducted to include approximately 10 study sites globally. Exclusion criteria added relating to COVID-19. Restricted medications updated to allow administration of COVID-19 vaccinations during study conduct.

    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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