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    Clinical Trial Results:
    A Single-Blind, Randomised, Parallel-Group, Single-Centre Pharmacokinetic and pH-Monitoring Study of Esomeprazole in Infants up to 24 Months of Age

    Summary
    EudraCT number
    2012-001159-37
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    15 Feb 2006

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Feb 2017
    First version publication date
    12 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SH-NEC-0001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca R&D Mölndal
    Sponsor organisation address
    Pepparedsleden 1, Mölndal, Sweden, 43183
    Public contact
    AstraZeneca Clinical Trial Transparency group, AstraZeneca R&D, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Per Lundborg, MD PhD, AstraZeneca R&D Mölndal, 46 317761000,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000331-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
    15 Feb 2006
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Feb 2006
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Feb 2006
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the pharmacokinetics of esomeprazole and its efficacy in controlling intragastric pH in infants.
    Protection of trial subjects
    The study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with ICH/Good Clinical Practice and applicable regulatory requirements and the AstraZeneca policy on Bioethics. Considerations were taken to the ICH guideline “Clinical investigation of medicinal products in the paediatric population” when developing the CSP.The study was approved by the Independent Research Ethics Committee (IEC) of the Women’s and Children’s Hospital, 72 King William Road, North Adelaide, South Australia 5006 Since all subjects in this study were infants aged 24 months or younger, informed consent could not be obtained from the subjects themselves. Therefore, the principal investigator ensured that the parent/guardian was given full and adequate oral and written information about the nature, purpose, possible risk and benefit of the study before enrolment. The parent/guardian was also notified that his/her child’s participation in the study, as well the identity, was to be treated confidentially and that he/she was free to withdraw the child from participation in the study at any time. The parent/guardian was given time for consideration and the opportunity to ask questions. The parent’s/guardian’s signed informed consent was obtained before any study specific procedure was conducted. Subjects could be withdrawn from study treatment and assessments at any time at the discretion of the investigator.
    Background therapy
    The subject population comprised outpatient infants up to 24 months of age with symptoms of GERD and diagnosis confirmed by 24-hour pH-monitoring. Medication considered necessary for the subject’s safety and well-being was to be given at the discretion of the investigator.Use of any pharmacological antireflux therapy within 24 hours prior to the first dose of investigational product, or use of any proton pump inhibitor within 72 hours of the first dose of investigational product were exclusion criteria.Mylanta or equivalent could be used for treatment of gastrointestinal symptoms, except within +/- 1 hour of the administration of investigational product .
    Evidence for comparator
    No comparator group
    Actual start date of recruitment
    06 Jun 2002
    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
    Australia: 50
    Worldwide total number of subjects
    50
    EEA total number of subjects
    0
    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)
    50
    Children (2-11 years)
    0
    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
    First subject enrolled 6 June 2002 Last subject completed 23 March 2005

    Pre-assignment
    Screening details
    107 subjects attended pre-entry visit <7 days before first study day. At pre-visit informed consent was obtained, routine lab, physical examination and 24-hour pH monitoring was performed. Out of these, 50 eligible subjects were randomised to 1 of the parallel treatment arms and given a subject number 2 days prior to first dose administered.

    Pre-assignment period milestones
    Number of subjects started
    50
    Number of subjects completed
    50

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Carer [1]

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Esomeprazole 0.25 mg/kg
    Arm description
    Esomeprazole 0.25 mg/kg
    Arm type
    Experimental

    Investigational medicinal product name
    Esomeprazole
    Investigational medicinal product code
    Other name
    NEXIUM
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    0.25 mg/kg orally od for 1 week

    Arm title
    Esomeprazole 1.0 mg/kg
    Arm description
    Esomeprazole 1.0 mg/kg
    Arm type
    Experimental

    Investigational medicinal product name
    Esomeprazole
    Investigational medicinal product code
    Other name
    NEXIUM
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1.0 mg/kg orally od for 1 week

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Individual NSAE occurring in > 1 subject in the trial (>5%) is included
    Number of subjects in period 1
    Esomeprazole 0.25 mg/kg Esomeprazole 1.0 mg/kg
    Started
    26
    24
    Completed
    23
    22
    Not completed
    3
    2
         Adverse event, non-fatal
    1
    -
         Consent withdrawn by subject
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Esomeprazole 0.25 mg/kg
    Reporting group description
    Esomeprazole 0.25 mg/kg

    Reporting group title
    Esomeprazole 1.0 mg/kg
    Reporting group description
    Esomeprazole 1.0 mg/kg

    Reporting group values
    Esomeprazole 0.25 mg/kg Esomeprazole 1.0 mg/kg Total
    Number of subjects
    26 24 50
    Age Categorical
    1 month up to 24 months of age
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    26 24 50
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    0 0 0
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
        Esomeprazole low
    0 0 0
    Age Continuous
    Study included infants aged 1 month up to 24 months
    Units: months
        arithmetic mean (full range (min-max))
    6.9 (2.3 to 22.2) 7 (2.2 to 23.8) -
    Gender Categorical
    Units: Subjects
        Female
    9 10 19
        Male
    17 14 31
    Subject analysis sets

    Subject analysis set title
    ITT population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All randomised subjects who took at least 1 dose of study medication and for whom pharmacokinetic, pharmacodynamic or symptom data post-dose are available were included in the ITT population

    Subject analysis sets values
    ITT population
    Number of subjects
    50
    Age Categorical
    1 month up to 24 months of age
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    50
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
        Esomeprazole low
    Age Continuous
    Study included infants aged 1 month up to 24 months
    Units: months
        arithmetic mean (full range (min-max))
    7 (2.2 to 23.8)
    Gender Categorical
    Units: Subjects
        Female
    19
        Male
    31

    End points

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    End points reporting groups
    Reporting group title
    Esomeprazole 0.25 mg/kg
    Reporting group description
    Esomeprazole 0.25 mg/kg

    Reporting group title
    Esomeprazole 1.0 mg/kg
    Reporting group description
    Esomeprazole 1.0 mg/kg

    Subject analysis set title
    ITT population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All randomised subjects who took at least 1 dose of study medication and for whom pharmacokinetic, pharmacodynamic or symptom data post-dose are available were included in the ITT population

    Primary: Pharmacokinetic variables AUCτ

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    End point title
    Pharmacokinetic variables AUCτ [1]
    End point description
    AUCτ
    End point type
    Primary
    End point timeframe
    1 week (7 or 8 days)
    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: For the pharmacokinetic endpoints only disscriptive statistics were used.
    End point values
    Esomeprazole 0.25 mg/kg Esomeprazole 1.0 mg/kg ITT population
    Number of subjects analysed
    17 [2]
    18 [3]
    35 [4]
    Units: µmol*h/L
        geometric mean (confidence interval 95%)
    0.24 (0.12 to 0.48)
    1.79 (0.9 to 3.56)
    7.62 (2.85 to 20.4)
    Notes
    [2] - PK total 40 subjects, in 5 of these no PK value due to too few post-dose samples or below LLQ
    [3] - PK total 40 subjects, in 5 of these no PK value due to too few post-dose samples or below LLQ
    [4] - Ratios for the Geometric means (Eso 1.0 mg/kg/Eso 0.25 mg/kg) and confidence intervals presented
    No statistical analyses for this end point

    Primary: Pharmacokinetics Cmax steady state

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    End point title
    Pharmacokinetics Cmax steady state [5]
    End point description
    End point type
    Primary
    End point timeframe
    at 1 week (day 7/8)
    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: For the pharmacokinetic endpoints only disscriptive statistics were used.
    End point values
    Esomeprazole 0.25 mg/kg Esomeprazole 1.0 mg/kg ITT population
    Number of subjects analysed
    17 [6]
    17 [7]
    34 [8]
    Units: µmol/L
        geometric mean (confidence interval 95%)
    0.17 (0.09 to 0.31)
    0.85 (0.45 to 1.6)
    5.08 (2.09 to 12.35)
    Notes
    [6] - PK total 40 subjects, in 5 of these no PK value due to too few post-dose samples or below LLQ
    [7] - PK total 40 subjects, in 5 of these no PK value due to too few post-dose samples or below LLQ
    [8] - Ratios for the Geometric means (Eso 1.0 mg/kg/Eso 0.25 mg/kg) and confidence intervals presented
    No statistical analyses for this end point

    Primary: PharmacodynamicThe percentage of time with intragastric pH above 4 during the 24-hour period

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    End point title
    PharmacodynamicThe percentage of time with intragastric pH above 4 during the 24-hour period
    End point description
    The percentage of time with intragastric pH above 4 during the 24-hour period
    End point type
    Primary
    End point timeframe
    pre-entry visit and on Day 7/8
    End point values
    Esomeprazole 0.25 mg/kg Esomeprazole 1.0 mg/kg ITT population
    Number of subjects analysed
    22 [9]
    22 [10]
    44 [11]
    Units: percentage of time
        geometric mean (confidence interval 95%)
    47.91 (39.35 to 56.47)
    69.25 (60.69 to 77.82)
    21.34 (9.23 to 33.45)
    Notes
    [9] - Subjects who had intragastric pH measurement
    [10] - Subjects who had intragastric pH measurement
    [11] - Difference between treatment groups
    Statistical analysis title
    Intragastric pH>4 after one week of treatment
    Comparison groups
    Esomeprazole 0.25 mg/kg v Esomeprazole 1.0 mg/kg v ITT population
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.0009
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    21.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    9.23
         upper limit
    33.45
    Variability estimate
    Standard error of the mean
    Dispersion value
    6

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During enrollment and randomised treatment (1 week)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    Not known
    Reporting groups
    Reporting group title
    Esomeprazole 1.0 mg/kg
    Reporting group description
    Esomeprazole 1.0 mg/kg

    Reporting group title
    Esomeprazole 0.25 mg/kg
    Reporting group description
    Esomeprazole 0.25 mg/kg

    Serious adverse events
    Esomeprazole 1.0 mg/kg Esomeprazole 0.25 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 26 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Esomeprazole 1.0 mg/kg Esomeprazole 0.25 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 24 (25.00%)
    6 / 26 (23.08%)
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 26 (3.85%)
         occurrences all number
    6
    6
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 26 (3.85%)
         occurrences all number
    6
    6
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 26 (3.85%)
         occurrences all number
    6
    6

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Dec 2001
    Addition of exclusion criteria no 2; “Current or previous evidence of liver disease and necrotising enterocolitis”.
    14 Feb 2002
    information that “At least 24 of the 40 evaluable subjects should be less than 12 months of age” was added.
    27 Feb 2002
    Clarification around antacids as rescue medication
    05 Feb 2003
    The study was changed from being double-blind to become single-blind, and prolongation of recruitment time.
    02 Apr 2003
    Change of exclusion criteria no 5a; Reflux index for subjects ≤12 months of age was change from ≥10%” to ≥5%
    14 Sep 2003
    The CSP was changed to also include infants 1 to 3 months of age in order to comply with an FDA request.
    20 Jan 2004
    The methods of drug administration for subjects ≥1 month but <3 months of age was changed (through funnel pan)
    07 Apr 2004
    The number of pharmacokinetically evaluable subjects needed in the study was changed from 40 to 30 subjects,
    09 Sep 2004
    date for last subject out was postponed until first/second quarter of 2005

    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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