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    Clinical Trial Results:
    A Comparative Single-Dose Pharmacokinetic and Safety Study of TAK-491 Between Infants, Children, and Adolescents with Hypertension and Healthy Adults

    Summary
    EudraCT number
    		 2009-013165-25
    Trial protocol
    		 GB   Outside EU/EEA  
    Global end of trial date
    10 Jul 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Mar 2016
    First version publication date
    26 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TAK-491_109
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01078376
    WHO universal trial number (UTN)
    		 U1111-1113-4416
    Sponsors
    Sponsor organisation name
    Takeda
    Sponsor organisation address
    One Takeda Parkway, Deerfield, IL, United States, 60015
    Public contact
    Medical Director, Clinical Science, Takeda , +1 877-825-3327, trialdisclosures@takeda.com
    Scientific contact
    Medical Director, Clinical Science, Takeda , +1 877-825-3327, trialdisclosures@takeda.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000237-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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Mar 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Jun 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jul 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The objectives of this study are to determine the pharmacokinetic parameters, safety, and tolerability of a single dose of TAK-491 in pediatric subjects with hypertension, who are between the ages of 1 to 16 years (including those up to their 17th birthday) and gender matched healthy adult subjects aged 18 to 45 years, inclusive. Takeda decided to close Cohort 3 (participants between 1 and 6 years of age with hypertension) enrollment early and end this study with the agreement of both the US Food and Drug Administration (FDA) and the Pediatric Committee (PDCO) at the European Medicines Agency. Requests to the FDA and PDCO were submitted to close the study without completion of enrollment in Cohort 3 due to difficulty enrolling this particular patient population. Takeda proposed an alternative option to collect PK data in this age subset by utilizing PK modeling to determine the appropriate doses in children 1-5 years of age in lieu of completing Cohort 3.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 May 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    United States: 24
    Worldwide total number of subjects
    29
    EEA total number of subjects
    5
    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)
    11
    Adolescents (12-17 years)
    9
    Adults (18-64 years)
    9
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in the study at 6 sites in the United States and 3 sites in the United Kingdom from 10 May 2010 to 10 July 2013.

    Pre-assignment
    Screening details
    		 Children between the ages of 1 to 16 years (including up to their 17th birthday) with hypertension and gender-matched healthy adults aged 18 to 45 years, inclusive, were enrolled in 1 of 3 cohorts.

    Period 1
    Period 1 title
    Overall Study (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
    		 Cohort 1: Healthy Adults
    Arm description
    		 Azilsartan medoxomil 80 mg, tablets, orally, one day only
    Arm type
    		 Experimental

    Investigational medicinal product name
    Azilsartan medoxomil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Azilsartan medoxomil tablets

    Arm title
    		 Cohort 1: Adolescents (≥12 to <17 Years Old) 40-60 mg
    Arm description
    		 Azilsartan medoxomil 40-60 mg, tablets, orally, one day only. Dose regimen was based on body weight. Participants 40 to < 80 kg received a 40 mg dose and participants 80 to 100 kg received a 60 mg dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Azilsartan medoxomil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Azilsartan medoxomil tablets

    Arm title
    		 Cohort 2: Children (≥6 to <12 Years Old) 20-60 mg
    Arm description
    		 Azilsartan medoxomil 20-60 mg, tablets, orally, one day only. Dose regimen was based on body weight. Participants 20 to < 40 kg received a 20 mg dose, participants 40 to < 80 kg received a 40 mg dose and participants 80 to 100 kg received a 60 mg dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Azilsartan medoxomil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Azilsartan medoxomil tablets

    Arm title
    		 Cohort 3: Children (≥1 to <6 Years Old)
    Arm description
    		 Azilsartan medoxomil 0.66 mg/kg participant body weight, granules, reconstituted orally, one day only.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Azilsartan medoxomil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Azilsartan medoxomil granules for oral suspension

    Number of subjects in period 1
    		Cohort 1: Healthy Adults Cohort 1: Adolescents (≥12 to <17 Years Old) 40-60 mg Cohort 2: Children (≥6 to <12 Years Old) 20-60 mg Cohort 3: Children (≥1 to <6 Years Old)
    Started
    9
    9
    8
    3
    Completed
    9
    9
    8
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: Healthy Adults
    Reporting group description
    		 Azilsartan medoxomil 80 mg, tablets, orally, one day only

    Reporting group title
    Cohort 1: Adolescents (≥12 to <17 Years Old) 40-60 mg
    Reporting group description
    		 Azilsartan medoxomil 40-60 mg, tablets, orally, one day only. Dose regimen was based on body weight. Participants 40 to < 80 kg received a 40 mg dose and participants 80 to 100 kg received a 60 mg dose.

    Reporting group title
    Cohort 2: Children (≥6 to <12 Years Old) 20-60 mg
    Reporting group description
    		 Azilsartan medoxomil 20-60 mg, tablets, orally, one day only. Dose regimen was based on body weight. Participants 20 to < 40 kg received a 20 mg dose, participants 40 to < 80 kg received a 40 mg dose and participants 80 to 100 kg received a 60 mg dose.

    Reporting group title
    Cohort 3: Children (≥1 to <6 Years Old)
    Reporting group description
    		 Azilsartan medoxomil 0.66 mg/kg participant body weight, granules, reconstituted orally, one day only.

    Reporting group values
    		 Cohort 1: Healthy Adults Cohort 1: Adolescents (≥12 to <17 Years Old) 40-60 mg Cohort 2: Children (≥6 to <12 Years Old) 20-60 mg Cohort 3: Children (≥1 to <6 Years Old) Total
    Number of subjects
    		 9 9 8 3 29
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 0 0 8 3 11
        Adolescents (12-17 years)
    		 0 9 0 0 9
        Adults (18-64 years)
    		 9 0 0 0 9
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 28.3 ( 7.78 ) 14.2 ( 1.64 ) 9.1 ( 2.1 ) 4.7 ( 0.58 ) -
    Gender categorical
    Units: Subjects
        Female
    		 2 2 5 2 11
        Male
    		 7 7 3 1 18
    Race/Ethnicity, Customized
    Units: Subjects
        Hispanic or Latino
    		 4 0 1 0 5
        Not Hispanic or Latino
    		 5 7 5 3 20
        Not Reported
    		 0 2 2 0 4
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 0 0 1 0 1
        Black or African American
    		 1 2 2 2 7
        White
    		 8 7 5 1 21
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 172.6 ( 9.7 ) 163.1 ( 11.72 ) 138.6 ( 12.74 ) 107.7 ( 11.06 ) -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 74.64 ( 11.207 ) 71.71 ( 15.512 ) 48.5 ( 22.523 ) 18.3 ( 4.026 ) -
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 25.06 ( 3.345 ) 27.22 ( 6.611 ) 24.29 ( 8.327 ) 15.67 ( 0.551 ) -

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: Healthy Adults
    Reporting group description
    		 Azilsartan medoxomil 80 mg, tablets, orally, one day only

    Reporting group title
    Cohort 1: Adolescents (≥12 to <17 Years Old) 40-60 mg
    Reporting group description
    		 Azilsartan medoxomil 40-60 mg, tablets, orally, one day only. Dose regimen was based on body weight. Participants 40 to < 80 kg received a 40 mg dose and participants 80 to 100 kg received a 60 mg dose.

    Reporting group title
    Cohort 2: Children (≥6 to <12 Years Old) 20-60 mg
    Reporting group description
    		 Azilsartan medoxomil 20-60 mg, tablets, orally, one day only. Dose regimen was based on body weight. Participants 20 to < 40 kg received a 20 mg dose, participants 40 to < 80 kg received a 40 mg dose and participants 80 to 100 kg received a 60 mg dose.

    Reporting group title
    Cohort 3: Children (≥1 to <6 Years Old)
    Reporting group description
    		 Azilsartan medoxomil 0.66 mg/kg participant body weight, granules, reconstituted orally, one day only.

    Subject analysis set title
    Cohort 1: Healthy Adults
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Azilsartan medoxomil 80 mg, tablets, orally, one day only

    Subject analysis set title
    Cohort 1: Adolescents (≥12 to <17 Years Old) 60 mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Azilsartan medoxomil 60 mg, tablets, orally, one day only

    Subject analysis set title
    Cohort 1: Adolescents (≥12 to <17 Years Old) 40 mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Azilsartan medoxomil 40 mg, tablets, orally, one day only

    Subject analysis set title
    Cohort 2: Children (≥6 to <12 Years Old) 60 mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Azilsartan medoxomil 60 mg, tablets, orally, one day only

    Subject analysis set title
    Cohort 2: Children (≥6 to <12 Years Old) 40 mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Azilsartan medoxomil 40 mg, tablets, orally, one day only

    Subject analysis set title
    Cohort 2: Children (≥6 to <12 Years Old) 20 mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Azilsartan medoxomil 20 mg, tablets, orally, one day only

    Subject analysis set title
    Cohort 3: Children (≥1 to <6 Years Old)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Azilsartan medoxomil 0.66 mg/kg participant body weight, granules, reconstituted orally, one day only

    Primary: Area Under the Plasma Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-tlqc]) for TAK-536

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    End point title
    		 Area Under the Plasma Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-tlqc]) for TAK-536 [1]
    End point description
    AUC(0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC[0-tlqc]).
    End point type
    Primary
    End point timeframe
    Day 1
    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: No Statistical Analysis reported for this End Point.
    End point values
    		 Cohort 1: Healthy Adults Cohort 1: Adolescents (≥12 to <17 Years Old) 60 mg Cohort 1: Adolescents (≥12 to <17 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 60 mg Cohort 2: Children (≥6 to <12 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 20 mg Cohort 3: Children (≥1 to <6 Years Old)
    Number of subjects analysed
    9
    2
    6
    1 [2]
    4
    3
    3
    Units: ng.hr/mL
        arithmetic mean (standard deviation)
    40613 ( 9609.6 )
    23889 ( 5383.8 )
    17423 ( 3559.7 )
    16056 ( 0 )
    22556 ( 5792.6 )
    18691 ( 5489.9 )
    16963 ( 4948.4 )
    Notes
    [2] - Standard deviation can not be calculated for 1 participant.
    No statistical analyses for this end point

    Primary: Area Under the Plasma Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-tlqc]) for TAK-536 Metabolite M-II

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    End point title
    		 Area Under the Plasma Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC[0-tlqc]) for TAK-536 Metabolite M-II [3]
    End point description
    AUC(0-tlqc) is a measure of total plasma exposure to the drug from Time 0 to Time of the Last Quantifiable Concentration (AUC[0-tlqc]).
    End point type
    Primary
    End point timeframe
    Day 1
    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: No Statistical Analysis reported for this End Point.
    End point values
    		 Cohort 1: Healthy Adults Cohort 1: Adolescents (≥12 to <17 Years Old) 60 mg Cohort 1: Adolescents (≥12 to <17 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 60 mg Cohort 2: Children (≥6 to <12 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 20 mg Cohort 3: Children (≥1 to <6 Years Old)
    Number of subjects analysed
    9
    2
    6
    1 [4]
    4
    3
    3
    Units: ng.hr/mL
        arithmetic mean (standard deviation)
    11563 ( 3106.5 )
    7409 ( 78.6 )
    7428 ( 2120.7 )
    7392 ( 0 )
    7929 ( 3502.6 )
    9130 ( 1338.3 )
    7285 ( 3626 )
    Notes
    [4] - Standard deviation can not be calculated for 1 participant.
    No statistical analyses for this end point

    Primary: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC[0-inf]) for TAK-536

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    End point title
    		 Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC[0-inf]) for TAK-536 [5]
    End point description
    Area under the plasma concentration-time curve from time 0 to infinity, calculated as AUC(0-inf)=AUC(0-tlqc) + Clast/λz.
    End point type
    Primary
    End point timeframe
    Day 1
    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: No Statistical Analysis reported for this End Point.
    End point values
    		 Cohort 1: Healthy Adults Cohort 1: Adolescents (≥12 to <17 Years Old) 60 mg Cohort 1: Adolescents (≥12 to <17 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 60 mg Cohort 2: Children (≥6 to <12 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 20 mg Cohort 3: Children (≥1 to <6 Years Old)
    Number of subjects analysed
    9
    2
    6
    1 [6]
    4
    3
    3
    Units: ng.hr/mL
        arithmetic mean (standard deviation)
    44820 ( 11680.7 )
    26411 ( 6703.1 )
    18686 ( 3720.4 )
    16563 ( 0 )
    23792 ( 6157 )
    19543 ( 6181.1 )
    17771 ( 5263.1 )
    Notes
    [6] - Standard deviation can not be calculated for 1 participant.
    No statistical analyses for this end point

    Primary: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC[0-inf]) for TAK-536 Metabolite M-II

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    End point title
    		 Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC[0-inf]) for TAK-536 Metabolite M-II [7]
    End point description
    Area under the plasma concentration-time curve from time 0 to infinity, calculated as AUC(0-inf)=AUC(0-tlqc) + Clast/λz.
    End point type
    Primary
    End point timeframe
    Day 1
    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: No Statistical Analysis reported for this End Point.
    End point values
    		 Cohort 1: Healthy Adults Cohort 1: Adolescents (≥12 to <17 Years Old) 60 mg Cohort 1: Adolescents (≥12 to <17 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 60 mg Cohort 2: Children (≥6 to <12 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 20 mg Cohort 3: Children (≥1 to <6 Years Old)
    Number of subjects analysed
    9
    2
    6
    1 [8]
    4
    3
    3
    Units: ng.hr/mL
        arithmetic mean (standard deviation)
    19188 ( 6766 )
    10596 ( 1168.8 )
    12532 ( 3905.3 )
    8961 ( 0 )
    11387 ( 5440.7 )
    14230 ( 3419.6 )
    9477 ( 4659.6 )
    Notes
    [8] - Standard deviation can not be calculated for 1 participant.
    No statistical analyses for this end point

    Primary: Maximum Observed Plasma Concentration (Cmax) for TAK-536

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) for TAK-536 [9]
    End point description
    Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
    End point type
    Primary
    End point timeframe
    Day 1
    Notes
    [9] - 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: No Statistical Analysis reported for this End Point.
    End point values
    		 Cohort 1: Healthy Adults Cohort 1: Adolescents (≥12 to <17 Years Old) 60 mg Cohort 1: Adolescents (≥12 to <17 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 60 mg Cohort 2: Children (≥6 to <12 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 20 mg Cohort 3: Children (≥1 to <6 Years Old)
    Number of subjects analysed
    9
    2
    6
    1 [10]
    4
    3
    3
    Units: ng/mL
        arithmetic mean (standard deviation)
    5699 ( 1346.1 )
    3245 ( 106.1 )
    2512 ( 701.6 )
    2810 ( 0 )
    3858 ( 1363 )
    2960 ( 364.3 )
    3320 ( 656 )
    Notes
    [10] - Standard deviation can not be calculated for 1 participant.
    No statistical analyses for this end point

    Primary: Maximum Observed Plasma Concentration (Cmax) for TAK-536 Metabolite M-II

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) for TAK-536 Metabolite M-II [11]
    End point description
    Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
    End point type
    Primary
    End point timeframe
    Day 1
    Notes
    [11] - 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: No Statistical Analysis reported for this End Point.
    End point values
    		 Cohort 1: Healthy Adults Cohort 1: Adolescents (≥12 to <17 Years Old) 60 mg Cohort 1: Adolescents (≥12 to <17 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 60 mg Cohort 2: Children (≥6 to <12 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 20 mg Cohort 3: Children (≥1 to <6 Years Old)
    Number of subjects analysed
    9
    2
    6
    1 [12]
    4
    3
    3
    Units: ng/mL
        arithmetic mean (standard deviation)
    736 ( 241.6 )
    480 ( 74.2 )
    535 ( 200.2 )
    514 ( 0 )
    561 ( 211.7 )
    561 ( 40.3 )
    488 ( 212.2 )
    Notes
    [12] - Standard deviation can not be calculated for 1 participant.
    No statistical analyses for this end point

    Primary: Time to Reach Cmax (Tmax) for TAK-536

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    End point title
    		 Time to Reach Cmax (Tmax) for TAK-536 [13]
    End point description
    Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax, as observed on Day 1.
    End point type
    Primary
    End point timeframe
    Day 1
    Notes
    [13] - 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: No Statistical Analysis reported for this End Point.
    End point values
    		 Cohort 1: Healthy Adults Cohort 1: Adolescents (≥12 to <17 Years Old) 60 mg Cohort 1: Adolescents (≥12 to <17 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 60 mg Cohort 2: Children (≥6 to <12 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 20 mg Cohort 3: Children (≥1 to <6 Years Old)
    Number of subjects analysed
    9
    2
    6
    1 [14]
    4
    3
    3
    Units: hr
        median (full range (min-max))
    2 (2 to 4)
    2.01 (2 to 2.02)
    2 (1 to 2)
    2 (2 to 2)
    2 (1.05 to 6)
    2 (1.98 to 2)
    1 (1 to 1)
    Notes
    [14] - Standard deviation or range cannot be calculated for 1 participant.
    No statistical analyses for this end point

    Primary: Time to Reach Cmax (Tmax) for TAK-536 Metabolite M-II

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    End point title
    		 Time to Reach Cmax (Tmax) for TAK-536 Metabolite M-II [15]
    End point description
    Tmax: Time to reach the maximum plasma concentration (Cmax), equal to time (hours) to Cmax, as observed on Day 1.
    End point type
    Primary
    End point timeframe
    Day 1
    Notes
    [15] - 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: No Statistical Analysis reported for this End Point.
    End point values
    		 Cohort 1: Healthy Adults Cohort 1: Adolescents (≥12 to <17 Years Old) 60 mg Cohort 1: Adolescents (≥12 to <17 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 60 mg Cohort 2: Children (≥6 to <12 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 20 mg Cohort 3: Children (≥1 to <6 Years Old)
    Number of subjects analysed
    9
    2
    6
    1 [16]
    4
    3
    3
    Units: hr
        median (full range (min-max))
    6 (4 to 8)
    5 (4 to 6)
    6 (4 to 6.1)
    6 (6 to 6)
    4.03 (4 to 8)
    4 (4 to 8)
    6 (6 to 6)
    Notes
    [16] - Standard deviation or range cannot be calculated for 1 participant.
    No statistical analyses for this end point

    Primary: Terminal Elimination Half-life (T1/2) for TAK-536

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    End point title
    		 Terminal Elimination Half-life (T1/2) for TAK-536 [17]
    End point description
    Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.
    End point type
    Primary
    End point timeframe
    Day 1
    Notes
    [17] - 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: No Statistical Analysis reported for this End Point.
    End point values
    		 Cohort 1: Healthy Adults Cohort 1: Adolescents (≥12 to <17 Years Old) 60 mg Cohort 1: Adolescents (≥12 to <17 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 60 mg Cohort 2: Children (≥6 to <12 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 20 mg Cohort 3: Children (≥1 to <6 Years Old)
    Number of subjects analysed
    9
    2
    6
    1 [18]
    4
    3
    3
    Units: hr
        arithmetic mean (standard deviation)
    7.35 ( 1.083 )
    7.74 ( 0.621 )
    5.76 ( 1.158 )
    5.07 ( 0 )
    5.75 ( 0.76 )
    5.37 ( 0.922 )
    4.59 ( 1.627 )
    Notes
    [18] - Standard deviation can not be calculated for 1 participant.
    No statistical analyses for this end point

    Primary: Terminal Elimination Half-life (T1/2) for TAK-536 Metabolite M-II

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    End point title
    		 Terminal Elimination Half-life (T1/2) for TAK-536 Metabolite M-II [19]
    End point description
    Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.
    End point type
    Primary
    End point timeframe
    Day 1
    Notes
    [19] - 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: No Statistical Analysis reported for this End Point.
    End point values
    		 Cohort 1: Healthy Adults Cohort 1: Adolescents (≥12 to <17 Years Old) 60 mg Cohort 1: Adolescents (≥12 to <17 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 60 mg Cohort 2: Children (≥6 to <12 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 20 mg Cohort 3: Children (≥1 to <6 Years Old)
    Number of subjects analysed
    9
    2
    6
    1 [20]
    4
    3
    3
    Units: hr
        arithmetic mean (standard deviation)
    16.6 ( 6.87 )
    12.78 ( 2.915 )
    14 ( 2.414 )
    8.5 ( 0 )
    11.56 ( 3.314 )
    13.97 ( 2.983 )
    10.35 ( 2.77 )
    Notes
    [20] - Standard deviation can not be calculated for 1 participant.
    No statistical analyses for this end point

    Primary: Apparent Oral Clearance (CL/F) for TAK-536

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    End point title
    		 Apparent Oral Clearance (CL/F) for TAK-536 [21]
    End point description
    CL/F is apparent clearance of the drug from the plasma, expressed in L/hr.
    End point type
    Primary
    End point timeframe
    Day 1
    Notes
    [21] - 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: No Statistical Analysis reported for this End Point.
    End point values
    		 Cohort 1: Healthy Adults Cohort 1: Adolescents (≥12 to <17 Years Old) 60 mg Cohort 1: Adolescents (≥12 to <17 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 60 mg Cohort 2: Children (≥6 to <12 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 20 mg Cohort 3: Children (≥1 to <6 Years Old)
    Number of subjects analysed
    9
    2
    6
    1 [22]
    4
    3
    3
    Units: L/hr
        arithmetic mean (standard deviation)
    1.52 ( 0.414 )
    1.88 ( 0.477 )
    1.78 ( 0.411 )
    2.9 ( 0 )
    1.43 ( 0.427 )
    0.87 ( 0.232 )
    0.54 ( 0.134 )
    Notes
    [22] - Standard deviation can not be calculated for 1 participant.
    No statistical analyses for this end point

    Primary: Total Amount of Drug Excreted in Urine From Time 0 to 24 Hours Postdose (Ae[0-t]) (for Cohorts 1 and 2 Urine Pharmacokinetic Endpoint for TAK-536)

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    End point title
    		 Total Amount of Drug Excreted in Urine From Time 0 to 24 Hours Postdose (Ae[0-t]) (for Cohorts 1 and 2 Urine Pharmacokinetic Endpoint for TAK-536) [23]
    End point description
    End point type
    Primary
    End point timeframe
    Day 1
    Notes
    [23] - 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: No Statistical Analysis reported for this End Point.
    End point values
    		 Cohort 1: Healthy Adults Cohort 1: Adolescents (≥12 to <17 Years Old) 60 mg Cohort 1: Adolescents (≥12 to <17 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 60 mg Cohort 2: Children (≥6 to <12 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 20 mg
    Number of subjects analysed
    9
    3
    6
    1 [24]
    4
    3
    Units: mg
        arithmetic mean (standard deviation)
    10.65 ( 4.673 )
    4.56 ( 1.029 )
    2.89 ( 0.936 )
    4.59 ( 0 )
    3.63 ( 2.125 )
    1.27 ( 0.58 )
    Notes
    [24] - Standard deviation can not be calculated for 1 participant.
    No statistical analyses for this end point

    Primary: Total Amount of Drug Excreted in Urine From Time 0 to 24 Hours Postdose (Ae[0-t]) (for Cohorts 1 and 2 Urine Pharmacokinetic Endpoint for TAK-536 Metabolite M-II)

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    End point title
    		 Total Amount of Drug Excreted in Urine From Time 0 to 24 Hours Postdose (Ae[0-t]) (for Cohorts 1 and 2 Urine Pharmacokinetic Endpoint for TAK-536 Metabolite M-II) [25]
    End point description
    End point type
    Primary
    End point timeframe
    Day 1
    Notes
    [25] - 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: No Statistical Analysis reported for this End Point.
    End point values
    		 Cohort 1: Healthy Adults Cohort 1: Adolescents (≥12 to <17 Years Old) 60 mg Cohort 1: Adolescents (≥12 to <17 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 60 mg Cohort 2: Children (≥6 to <12 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 20 mg
    Number of subjects analysed
    9
    3
    6
    1 [26]
    4
    3
    Units: mg
        arithmetic mean (standard deviation)
    6.6 ( 5.149 )
    2.93 ( 0.582 )
    2.73 ( 1.528 )
    4.43 ( 0 )
    2.77 ( 1.197 )
    1.48 ( 0.284 )
    Notes
    [26] - Standard deviation can not be calculated for 1 participant.
    No statistical analyses for this end point

    Primary: Fraction of Unchanged Drug Excreted in Urine From 0 to 24 Hours Postdose (Fe%) (for Cohorts 1 and 2 Urine Pharmacokinetic Endpoint for TAK-536)

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    End point title
    		 Fraction of Unchanged Drug Excreted in Urine From 0 to 24 Hours Postdose (Fe%) (for Cohorts 1 and 2 Urine Pharmacokinetic Endpoint for TAK-536) [27]
    End point description
    Fe=[Ae(0-24)/dose]×100 (molecular weight adjusted for metabolites.
    End point type
    Primary
    End point timeframe
    Day 1
    Notes
    [27] - 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: No Statistical Analysis reported for this End Point.
    End point values
    		 Cohort 1: Healthy Adults Cohort 1: Adolescents (≥12 to <17 Years Old) 60 mg Cohort 1: Adolescents (≥12 to <17 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 60 mg Cohort 2: Children (≥6 to <12 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 20 mg
    Number of subjects analysed
    9
    3
    6
    1 [28]
    4
    3
    Units: percent
        arithmetic mean (standard deviation)
    16.65 ( 7.302 )
    9.5 ( 2.144 )
    9.04 ( 2.925 )
    9.57 ( 0 )
    11.36 ( 6.639 )
    7.94 ( 3.622 )
    Notes
    [28] - Standard deviation can not be calculated for 1 participant.
    No statistical analyses for this end point

    Primary: Fraction of Unchanged Drug Excreted in Urine From 0 to 24 Hours Postdose (Fe%) (for Cohorts 1 and 2 Urine Pharmacokinetic Endpoint for TAK-536 Metabolite M-II)

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    End point title
    		 Fraction of Unchanged Drug Excreted in Urine From 0 to 24 Hours Postdose (Fe%) (for Cohorts 1 and 2 Urine Pharmacokinetic Endpoint for TAK-536 Metabolite M-II) [29]
    End point description
    Fe=[Ae(0-24)/dose]×100 (molecular weight adjusted for metabolites.
    End point type
    Primary
    End point timeframe
    Day 1
    Notes
    [29] - 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: No Statistical Analysis reported for this End Point.
    End point values
    		 Cohort 1: Healthy Adults Cohort 1: Adolescents (≥12 to <17 Years Old) 60 mg Cohort 1: Adolescents (≥12 to <17 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 60 mg Cohort 2: Children (≥6 to <12 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 20 mg
    Number of subjects analysed
    9
    3
    6
    1 [30]
    4
    3
    Units: percent
        arithmetic mean (standard deviation)
    11.01 ( 8.581 )
    6.55 ( 1.293 )
    9.11 ( 5.094 )
    9.85 ( 0 )
    9.22 ( 3.991 )
    9.89 ( 1.896 )
    Notes
    [30] - Standard deviation can not be calculated for 1 participant.
    No statistical analyses for this end point

    Primary: Renal Clearance (CLr) From 0 to 24 Hours Postdose (for Cohorts 1 and 2 Urine Pharmacokinetic Endpoint for TAK-536)

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    End point title
    		 Renal Clearance (CLr) From 0 to 24 Hours Postdose (for Cohorts 1 and 2 Urine Pharmacokinetic Endpoint for TAK-536) [31]
    End point description
    Renal clearance, calculated as CLr=Ae(0-24)/AUC(0-24).
    End point type
    Primary
    End point timeframe
    Day 1
    Notes
    [31] - 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: No Statistical Analysis reported for this End Point.
    End point values
    		 Cohort 1: Healthy Adults Cohort 1: Adolescents (≥12 to <17 Years Old) 60 mg Cohort 1: Adolescents (≥12 to <17 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 60 mg Cohort 2: Children (≥6 to <12 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 20 mg
    Number of subjects analysed
    9
    2
    6
    1 [32]
    4
    3
    Units: L/hr
        arithmetic mean (standard deviation)
    0.28 ( 0.13 )
    0.22 ( 0.051 )
    0.17 ( 0.077 )
    0.29 ( 0 )
    0.15 ( 0.069 )
    0.07 ( 0.011 )
    Notes
    [32] - Standard deviation can not be calculated for 1 participant.
    No statistical analyses for this end point

    Primary: Renal Clearance (CLr) From 0 to 24 Hours Postdose (for Cohorts 1 and 2 Urine Pharmacokinetic Endpoint for TAK-536 Metabolite M-II)

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    End point title
    		 Renal Clearance (CLr) From 0 to 24 Hours Postdose (for Cohorts 1 and 2 Urine Pharmacokinetic Endpoint for TAK-536 Metabolite M-II) [33]
    End point description
    Renal clearance, calculated as CLr=Ae(0-24)/AUC(0-24).
    End point type
    Primary
    End point timeframe
    Day 1
    Notes
    [33] - 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: No Statistical Analysis reported for this End Point.
    End point values
    		 Cohort 1: Healthy Adults Cohort 1: Adolescents (≥12 to <17 Years Old) 60 mg Cohort 1: Adolescents (≥12 to <17 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 60 mg Cohort 2: Children (≥6 to <12 Years Old) 40 mg Cohort 2: Children (≥6 to <12 Years Old) 20 mg
    Number of subjects analysed
    9
    2
    6
    1 [34]
    4
    3
    Units: L/hr
        arithmetic mean (standard deviation)
    0.55 ( 0.309 )
    0.37 ( 0.084 )
    0.34 ( 0.146 )
    0.6 ( 0 )
    0.36 ( 0.099 )
    0.16 ( 0.022 )
    Notes
    [34] - Standard deviation can not be calculated for 1 participant.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    A treatment-emergent adverse event (TEAE) had an onset occurring after the first dose of study medication and within 14 days after the last dose of study medication or, if an SAE, within 30 days after last dose of study medication.
    Adverse event reporting additional description
    At each visit the investigator assessed whether any subjective adverse events have occurred and had to document any occurrence of adverse events and clinically significant abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Cohort 1: Healthy Adults
    Reporting group description
    		 Azilsartan medoxomil 80 mg, tablets, orally, one day only.

    Reporting group title
    Cohort 1: Adolescents (≥12 to <17 Years Old) 40-60 mg
    Reporting group description
    		 Azilsartan medoxomil 40-60 mg, tablets, orally, one day only. Dose regimen was based on body weight. Participants 40 to < 80 kg received a 40 mg dose and participants 80 to 100 kg received a 60 mg dose.

    Reporting group title
    Cohort 2: Children (≥6 to <12 Years Old) 20-60 mg
    Reporting group description
    		 Azilsartan medoxomil 20-60 mg, tablets, orally, one day only. Dose regimen was based on body weight. Participants 20 to < 40 kg received a 20 mg dose, participants 40 to < 80 kg received a 40 mg dose and participants 80 to 100 kg received a 60 mg dose.

    Reporting group title
    Cohort 3: Children (≥1 to <6 Years Old)
    Reporting group description
    		 Azilsartan medoxomil 0.66 mg/kg participant body weight, granules, reconstituted orally, one day only.

    Serious adverse events
    		 Cohort 1: Healthy Adults Cohort 1: Adolescents (≥12 to <17 Years Old) 40-60 mg Cohort 2: Children (≥6 to <12 Years Old) 20-60 mg Cohort 3: Children (≥1 to <6 Years Old)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1: Healthy Adults Cohort 1: Adolescents (≥12 to <17 Years Old) 40-60 mg Cohort 2: Children (≥6 to <12 Years Old) 20-60 mg Cohort 3: Children (≥1 to <6 Years Old)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 9 (22.22%)
    5 / 9 (55.56%)
    3 / 8 (37.50%)
    0 / 3 (0.00%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cardiac disorders
    Sinus bradycardia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Headache
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    1
    0
    Migraine
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    0
    General disorders and administration site conditions
    Infusion site pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infections and infestations
    Infected bites
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 3 (0.00%)
         occurrences all number
    0
    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
    15 Jun 2010
    • Safety endpoints were listed as additional endpoints. • Decided only safety data from pediatric subjects in Cohort 1 and 2 was required to be reviewed, and any adult subjects enrolled up to that time, prior to the commencement of Cohort 3. • Provided guidance on the continuation of subjects with emesis after dosing of study drug. • Height (or length) measurement for pediatric subjects was added.
    14 Feb 2011
    • Changed lower age limit of Cohort 3 from ≥6 months to ≥1 year. • Increased weight limit of Cohort 3 from 6.5 to 8.0 kg (17.6 lbs). • Determined that formal interim PK and safety analysis of Cohort 1 and 2 data was to be conducted.
    07 Dec 2012
    • Day 1 overnight stay was considered optional and based on investigator discretion. • Inclusion criterion 11 was updated to change the length of time that a subject must be on a stable dose of immunosuppressive therapy, after a renal transplant, from 60 days to 30 days.

    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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