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    Clinical Trial Results:
    An Open-Label, Phase 2a Study to Evaluate the Pharmacodynamics of Different Dosing Regimens of TAK-448, a Kisspeptin Agonist, in Male Overweight/Obese Participants With Hypogonadotropic Hypogonadism

    Summary
    EudraCT number
    2014-002155-25
    Trial protocol
    GB  
    Global end of trial date
    03 Nov 2015

    Results information
    Results version number
    v3(current)
    This version publication date
    01 Mar 2017
    First version publication date
    17 Nov 2016
    Other versions
    v1 , v2
    Version creation reason
    • Correction of full data set
    Updates to the Primary endpoint data will be corrected.

    Trial information

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    Trial identification
    Sponsor protocol code
    TAK-448-2001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02369796
    WHO universal trial number (UTN)
    U1111-1162-4892
    Sponsors
    Sponsor organisation name
    Takeda Development Center Americas, Inc.
    Sponsor organisation address
    One Takeda Parkway, Deerfield, United States, IL 60015
    Public contact
    Medical Director, Clinical Science, Takeda, +1 +18778253327, clinicaltrialregistry@tpna.com
    Scientific contact
    Medical Director, Clinical Science, Takeda, +1 +18778253327, trialdisclosures@takeda.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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
    03 Nov 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Oct 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Nov 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the effects on serum testosterone (ST) after 4 weeks of subcutaneous (SC) dose administration, with different doses and dosing frequencies of TAK-448 to overweight/obese subjects with hypogonadotropic hypogonadism.
    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 Feb 2015
    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: 15
    Worldwide total number of subjects
    15
    EEA total number of subjects
    15
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    15
    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 1 investigative site in the United Kingdom from 10 February 2015 to 3 November 2015.

    Pre-assignment
    Screening details
    Overweight/obese male participants with a diagnosis of hypogonadotropic hypogonadism were enrolled in 1 of 5 treatment groups: once weekly TAK-448 3 µg, 1 µg or 0.3 µg or twice weekly TAK-448 0.3 µg or 0.1 µg.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    TAK-448 3 µg once weekly
    Arm description
    TAK-448 3 µg, subcutaneous injection, once weekly on Days 1, 8, 15 and 22.
    Arm type
    Experimental

    Investigational medicinal product name
    TAK-448
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    TAK-448 solution for subcutaneous injection

    Arm title
    TAK-448 1 µg once weekly
    Arm description
    TAK-448 1 µg, subcutaneous injection, once weekly on Days 1, 8, 15 and 22.
    Arm type
    Experimental

    Investigational medicinal product name
    TAK-448
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    TAK-448 solution for subcutaneous injection.

    Arm title
    TAK-448 0.3 µg once weekly
    Arm description
    TAK-448 0.3 µg, subcutaneous injection, once weekly on Days 1, 8, 15 and 22.
    Arm type
    Experimental

    Investigational medicinal product name
    TAK-448
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    TAK-448 solution for subcutaneous injection.

    Arm title
    TAK-448 0.3 µg twice weekly
    Arm description
    TAK-448 0.3 µg, subcutaneous injection, twice weekly on Days 1, 4, 8, 11, 15, 18, 22, and 25.
    Arm type
    Experimental

    Investigational medicinal product name
    TAK-448
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    TAK-448 solution for subcutaneous injection.

    Arm title
    TAK-448 0.1 µg twice weekly
    Arm description
    TAK-448 0.1 µg, subcutaneous injection, twice weekly on Days 1, 4, 8, 11, 15, 18, 22, and 25.
    Arm type
    Experimental

    Investigational medicinal product name
    TAK-448
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    TAK-448 solution for subcutaneous injection.

    Number of subjects in period 1
    TAK-448 3 µg once weekly TAK-448 1 µg once weekly TAK-448 0.3 µg once weekly TAK-448 0.3 µg twice weekly TAK-448 0.1 µg twice weekly
    Started
    3
    3
    3
    3
    3
    Completed
    3
    3
    3
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TAK-448 3 µg once weekly
    Reporting group description
    TAK-448 3 µg, subcutaneous injection, once weekly on Days 1, 8, 15 and 22.

    Reporting group title
    TAK-448 1 µg once weekly
    Reporting group description
    TAK-448 1 µg, subcutaneous injection, once weekly on Days 1, 8, 15 and 22.

    Reporting group title
    TAK-448 0.3 µg once weekly
    Reporting group description
    TAK-448 0.3 µg, subcutaneous injection, once weekly on Days 1, 8, 15 and 22.

    Reporting group title
    TAK-448 0.3 µg twice weekly
    Reporting group description
    TAK-448 0.3 µg, subcutaneous injection, twice weekly on Days 1, 4, 8, 11, 15, 18, 22, and 25.

    Reporting group title
    TAK-448 0.1 µg twice weekly
    Reporting group description
    TAK-448 0.1 µg, subcutaneous injection, twice weekly on Days 1, 4, 8, 11, 15, 18, 22, and 25.

    Reporting group values
    TAK-448 3 µg once weekly TAK-448 1 µg once weekly TAK-448 0.3 µg once weekly TAK-448 0.3 µg twice weekly TAK-448 0.1 µg twice weekly Total
    Number of subjects
    3 3 3 3 3 15
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    3 3 3 3 3 15
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    50.7 ± 8.02 50.7 ± 4.62 51.7 ± 3.79 56 ± 3.61 45 ± 19.16 -
    Gender, Male/Female
    Units: participants
        Female
    0 0 0 0 0 0
        Male
    3 3 3 3 3 15
    Race
    Units: Subjects
        Asian
    2 0 0 0 0 2
        White
    1 3 3 3 3 13
    Smoking Classification
    Units: Subjects
        Has never smoked
    3 0 0 1 1 5
        Is current smoker
    0 0 1 0 0 1
        Is an ex-smoker
    0 3 2 2 2 9
    Alcohol Classification
    Units: Subjects
        Has never drunk
    0 0 1 0 0 1
        Is current drinker
    3 2 1 2 2 10
        Is an ex-drinker
    0 1 1 1 1 4
    Caffeine Consumption
    Units: Subjects
        Yes
    3 3 3 2 3 14
        No
    0 0 0 1 0 1
    Region of Enrollment: United Kingdom
    Units: Subjects
        Subjects
    3 3 3 3 3 15
    Study Specific Characteristic | Height
    Units: cm
        arithmetic mean (standard deviation)
    168 ± 7 174 ± 6 181 ± 18 178 ± 6 178 ± 12 -
    Study Specific Characteristic | Weight
    Units: kg
        arithmetic mean (standard deviation)
    104 ± 30 113 ± 10 119 ± 26 115 ± 7 110 ± 26 -
    Study Specific Characteristic | Body Mass Index
    Units: kg/m^2
        arithmetic mean (standard deviation)
    36 ± 8 37 ± 1 36 ± 2 36 ± 2 34 ± 4 -

    End points

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    End points reporting groups
    Reporting group title
    TAK-448 3 µg once weekly
    Reporting group description
    TAK-448 3 µg, subcutaneous injection, once weekly on Days 1, 8, 15 and 22.

    Reporting group title
    TAK-448 1 µg once weekly
    Reporting group description
    TAK-448 1 µg, subcutaneous injection, once weekly on Days 1, 8, 15 and 22.

    Reporting group title
    TAK-448 0.3 µg once weekly
    Reporting group description
    TAK-448 0.3 µg, subcutaneous injection, once weekly on Days 1, 8, 15 and 22.

    Reporting group title
    TAK-448 0.3 µg twice weekly
    Reporting group description
    TAK-448 0.3 µg, subcutaneous injection, twice weekly on Days 1, 4, 8, 11, 15, 18, 22, and 25.

    Reporting group title
    TAK-448 0.1 µg twice weekly
    Reporting group description
    TAK-448 0.1 µg, subcutaneous injection, twice weekly on Days 1, 4, 8, 11, 15, 18, 22, and 25.

    Primary: Percent Change from Baseline in Mean Area Under the Effect Curve from Time 0 to 72 hours (AUEC72) of Total Serum Testosterone for Once Weekly Dosing Groups

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    End point title
    Percent Change from Baseline in Mean Area Under the Effect Curve from Time 0 to 72 hours (AUEC72) of Total Serum Testosterone for Once Weekly Dosing Groups [1] [2]
    End point description
    Area under the pharmacodynamic (PD) total serum testosterone (ST) concentration-time curve from the time 0 to 72 hours, calculated using the linear trapezoidal rule for baseline profile and those obtained after first and last dose. PD set included all participants who received at least one dose of study drug and had at least 1 valid PD measure.
    End point type
    Primary
    End point timeframe
    Baseline and Day 22 pre-dose and multiple time points (up to 72 hours) post dose
    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: This endpoint was planned to be assessed on baseline and Day 22 pre-dose and multiple time points (up to 72 hours) post dose in once weekly arm group.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be assessed on baseline and Day 22 pre-dose and multiple time points (up to 72 hours) post dose in once weekly arm group.
    End point values
    TAK-448 3 µg once weekly TAK-448 1 µg once weekly TAK-448 0.3 µg once weekly
    Number of subjects analysed
    3
    3
    3
    Units: percent change
        arithmetic mean (standard deviation)
    1.9 ± 11.3
    13.5 ± 24.9
    14.9 ± 16.3
    No statistical analyses for this end point

    Primary: Percent Change from Baseline in Mean Area Under the Effect Curve from Time 0 to 72 hours (AUEC72) of Total Serum Testosterone for Twice Weekly Dosing Groups

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    End point title
    Percent Change from Baseline in Mean Area Under the Effect Curve from Time 0 to 72 hours (AUEC72) of Total Serum Testosterone for Twice Weekly Dosing Groups [3] [4]
    End point description
    Area under the PD total ST concentration-time curve from the time 0 to 72 hours, calculated using the linear trapezoidal rule for baseline profile and those obtained after first and last dose. PD set included all participants who received at least one dose of study drug and had at least 1 valid PD measure.
    End point type
    Primary
    End point timeframe
    Baseline and Day 25 pre-dose and multiple time points (up to 72 hours) post dose
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This endpoint was planned to be assessed on baseline and Day 22 pre-dose and multiple time points (up to 72 hours) post dose in once weekly arm group.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be assessed on baseline and Day 25 pre-dose and multiple time points (up to 72 hours) post dose in twice weekly arm group.
    End point values
    TAK-448 0.3 µg twice weekly TAK-448 0.1 µg twice weekly
    Number of subjects analysed
    3
    3
    Units: percent change
        arithmetic mean (standard deviation)
    -2.8 ± 3.7
    6 ± 12.3
    No statistical analyses for this end point

    Primary: Percent Change from Baseline in Mean Area Under the Effect Curve from Time 0 to 72 hours (AUEC72) of Free Serum Testosterone for Once Weekly Dosing Groups

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    End point title
    Percent Change from Baseline in Mean Area Under the Effect Curve from Time 0 to 72 hours (AUEC72) of Free Serum Testosterone for Once Weekly Dosing Groups [5] [6]
    End point description
    Area under the PD free ST concentration-time curve from the time 0 to 72 hours, calculated using the linear trapezoidal rule for baseline profile and those obtained after first and last dose. PD set included all participants who received at least one dose of study drug and had at least 1 valid PD measure.
    End point type
    Primary
    End point timeframe
    Baseline and Day 22 pre-dose and multiple time points (up to 72 hours) post dose
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This endpoint was planned to be assessed on baseline and Day 22 pre-dose and multiple time points (up to 72 hours) post dose in once weekly arm group.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be assessed on baseline and Day 22 pre-dose and multiple time points (up to 72 hours) post dose in once weekly arm group.
    End point values
    TAK-448 3 µg once weekly TAK-448 1 µg once weekly TAK-448 0.3 µg once weekly
    Number of subjects analysed
    3
    3
    3
    Units: percent change
        arithmetic mean (standard deviation)
    3.55 ± 9.08
    11.1 ± 28
    7.92 ± 8.88
    No statistical analyses for this end point

    Primary: Percent Change from Baseline in Mean Area Under the Effect Curve from Time 0 to 72 hours (AUEC72) of Free Serum Testosterone for Twice Weekly Dosing Groups

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    End point title
    Percent Change from Baseline in Mean Area Under the Effect Curve from Time 0 to 72 hours (AUEC72) of Free Serum Testosterone for Twice Weekly Dosing Groups [7] [8]
    End point description
    Area under the PD free ST concentration-time curve from the time 0 to 72 hours, calculated using the linear trapezoidal rule for baseline profile and those obtained after first and last dose. PD set included all participants who received at least one dose of study drug and had at least 1 valid PD measure.
    End point type
    Primary
    End point timeframe
    Baseline and Day 25 pre-dose and multiple time points (up to 72 hours) post dose
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This endpoint was planned to be assessed on baseline and Day 25 pre-dose and multiple time points (up to 72 hours) post dose in twice weekly arm group.
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be assessed on baseline and Day 25 pre-dose and multiple time points (up to 72 hours) post dose in twice weekly arm group.
    End point values
    TAK-448 0.3 µg twice weekly TAK-448 0.1 µg twice weekly
    Number of subjects analysed
    3
    3
    Units: percent change
        arithmetic mean (standard deviation)
    -9 ± 4.232
    20.48 ± 5.329
    No statistical analyses for this end point

    Primary: Trough Serum Concentration (Ctrough) of Total Serum Testosterone for Once Weekly Dosing Groups

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    End point title
    Trough Serum Concentration (Ctrough) of Total Serum Testosterone for Once Weekly Dosing Groups [9] [10]
    End point description
    Trough serum concentration of total ST, defined as lowest baseline concentration compared to pre-dose of the last dose. PD set included all participants who received at least one dose of study drug and had at least 1 valid PD measure.
    End point type
    Primary
    End point timeframe
    Day 22 pre-dose
    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: Only descriptive statistics were planned for this endpoint.
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be assessed on baseline and Day 22 pre-dose and multiple time points (up to 72 hours) post dose in once weekly arm group.
    End point values
    TAK-448 3 µg once weekly TAK-448 1 µg once weekly TAK-448 0.3 µg once weekly
    Number of subjects analysed
    3
    3
    3
    Units: nmol/L
        arithmetic mean (standard deviation)
    5.4 ± 1.3
    4.4 ± 3.1
    8.7 ± 1.3
    No statistical analyses for this end point

    Primary: Trough Serum Concentration (Ctrough) of Total Serum Testosterone for Twice Weekly Dosing Group

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    End point title
    Trough Serum Concentration (Ctrough) of Total Serum Testosterone for Twice Weekly Dosing Group [11] [12]
    End point description
    Trough serum concentration of total ST, defined as lowest baseline concentration compared to pre-dose of the last dose. PD set included all participants who received at least one dose of study drug and had at least 1 valid PD measure.
    End point type
    Primary
    End point timeframe
    Day 25 pre-dose
    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: This endpoint was planned to be assessed on baseline and Day 25 pre-dose and multiple time points (up to 72 hours) post dose in twice weekly arm group.
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be assessed on baseline and Day 25 pre-dose and multiple time points (up to 72 hours) post dose in twice weekly arm group.
    End point values
    TAK-448 0.3 µg twice weekly TAK-448 0.1 µg twice weekly
    Number of subjects analysed
    3
    3
    Units: nmol/L
        arithmetic mean (standard deviation)
    4.7 ± 2.8
    6.9 ± 2.1
    No statistical analyses for this end point

    Primary: Trough Serum Concentration (Ctrough) of Free Serum Testosterone for Once Weekly Dosing Groups

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    End point title
    Trough Serum Concentration (Ctrough) of Free Serum Testosterone for Once Weekly Dosing Groups [13] [14]
    End point description
    Trough serum concentration of free ST, defined as lowest baseline concentration compared to pre-dose of the last dose. PD set included all participants who received at least one dose of study drug and had at least 1 valid PD measure. Number of participants analyzed is number of participants evaluated for this endpoint.
    End point type
    Primary
    End point timeframe
    Day 22 pre-dose
    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: This endpoint was planned to be assessed on baseline and Day 22 pre-dose and multiple time points (up to 72 hours) post dose in once weekly arm group.
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be assessed on baseline and Day 22 pre-dose and multiple time points (up to 72 hours) post dose in once weekly arm group.
    End point values
    TAK-448 3 µg once weekly TAK-448 1 µg once weekly TAK-448 0.3 µg once weekly
    Number of subjects analysed
    3
    3
    2
    Units: nmol/L
        arithmetic mean (standard deviation)
    0.16 ± 0.03
    0.12 ± 0.07
    0.21 ± 0.004
    No statistical analyses for this end point

    Primary: Trough Serum Concentration (Ctrough) of Free Serum Testosterone for Twice Weekly Dosing Groups

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    End point title
    Trough Serum Concentration (Ctrough) of Free Serum Testosterone for Twice Weekly Dosing Groups [15] [16]
    End point description
    Trough serum concentration of free ST, defined as lowest baseline concentration compared to pre-dose of the last dose. PD set included all participants who received at least one dose of study drug and had at least 1 valid PD measure.
    End point type
    Primary
    End point timeframe
    Day 25 pre-dose
    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: Only descriptive statistics were planned for this endpoint.
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be assessed on baseline and Day 25 pre-dose and multiple time points (up to 72 hours) post dose in twice weekly arm group.
    End point values
    TAK-448 0.3 µg twice weekly TAK-448 0.1 µg twice weekly
    Number of subjects analysed
    3
    3
    Units: nmol/L
        arithmetic mean (standard deviation)
    0.12 ± 0.09
    0.2 ± 0.06
    No statistical analyses for this end point

    Secondary: Cmax: Mean Maximum Observed Plasma Concentration for TAK-448 Free Base Form (TAK-448F)

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    End point title
    Cmax: Mean Maximum Observed Plasma Concentration for TAK-448 Free Base Form (TAK-448F) [17]
    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. 99999=NA (data was not estimable as plasma concentration was below the lower level of quantification [LLOQ]). Pharmacokinetic (PK) set included all participants who received at least one dose of study drug and had at least 1 measurable concentration of TAK-448F.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 22 pre-dose and at multiple time points (up to 8 hours) post-dose
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: PK endpoints were conducted in PK population (once weekly arm group).
    End point values
    TAK-448 3 µg once weekly TAK-448 1 µg once weekly TAK-448 0.3 µg once weekly
    Number of subjects analysed
    3
    3
    1
    Units: pg/mL
    arithmetic mean (standard deviation)
        Day 1
    39.5 ± 4.943
    10.46 ± 1.484
    99999 ± 99999
        Day 22
    40.1 ± 6.344
    12.27 ± 3.618
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: AUC(0-∞): Mean Area Under the Plasma Concentration-time Curve from Time 0 to Infinity for TAK-448F

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    End point title
    AUC(0-∞): Mean Area Under the Plasma Concentration-time Curve from Time 0 to Infinity for TAK-448F [18]
    End point description
    AUC(0-∞) is a measure of total plasma exposure to the drug from time zero extrapolated to infinity. 9999 = NA (No participant was analysed at this time point.), 999999 = NA (Only 1 participant was analysed at this time point) and 99999=NA (data was not estimable as plasma concentration was below LLOQ). PK set included all participants who received at least one dose of study drug and had at least 1 measurable concentration of TAK-448F. Here, 'n' is the participants who were analyzed at specific time point.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 22 pre-dose and at multiple time points (up to 8 hours) post-dose
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: PK endpoints were conducted in PK population (once weekly arm group).
    End point values
    TAK-448 3 µg once weekly TAK-448 1 µg once weekly TAK-448 0.3 µg once weekly
    Number of subjects analysed
    3
    1
    1
    Units: pg*hr/mL
    arithmetic mean (standard deviation)
        Day 1 (n=3, 0, 1)
    112 ± 5.686
    9999 ± 9999
    99999 ± 99999
        Day 22 (n=3, 1, 1)
    122.33 ± 10.477
    33.3 ± 999999
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: AUC(0-tlqc): Mean Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-448F

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    End point title
    AUC(0-tlqc): Mean Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-448F [19]
    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]). 99999 = NA (data was not estimable as plasma concentration was below LLOQ). PK set included all participants who received at least one dose of study drug and had at least 1 measurable concentration of TAK-448F.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 22 pre-dose and at multiple time points (up to 8 hours) post-dose
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pharmacokinetic (PK) endpoints were conducted in PK population (once weekly arm group).
    End point values
    TAK-448 3 µg once weekly TAK-448 1 µg once weekly TAK-448 0.3 µg once weekly
    Number of subjects analysed
    3
    3
    1
    Units: pg*hr/mL
    arithmetic mean (standard deviation)
        Day 1
    92.23 ± 6.732
    19 ± 3.47
    99999 ± 99999
        Day 22
    95.2 ± 11.914
    18.37 ± 3.069
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: Mean Terminal Phase Elimination Half-life (T1/2) for TAK-448F

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    End point title
    Mean Terminal Phase Elimination Half-life (T1/2) for TAK-448F [20]
    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. 9999 = NA (No participant was analysed at this time point.), 999999 = NA (Only 1 participant was analysed at this time point) and 99999=NA (data was not estimable as plasma concentration was below LLOQ). PK set included all participants who received at least one dose of study drug and had at least 1 measurable concentration of TAK-448F. Here, 'n' is the participants who were analyzed at specific time point.
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 22 pre-dose and at multiple time points (up to 8 hours) post-dose
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: PK endpoints were conducted in PK population (once weekly arm group).
    End point values
    TAK-448 3 µg once weekly TAK-448 1 µg once weekly TAK-448 0.3 µg once weekly
    Number of subjects analysed
    3
    1
    1
    Units: hr
    arithmetic mean (standard deviation)
        Day 1 (n=3, 0 , 1)
    1.8 ± 0.0751
    9999 ± 9999
    99999 ± 99999
        Day 22 (n=3, 1, 1)
    2.073 ± 0.192
    1.15 ± 999999
    99999 ± 99999
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 up to Day 39
    Adverse event reporting additional description
    At each visit the investigator had to document any occurrence of adverse events and 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
    18.0
    Reporting groups
    Reporting group title
    TAK-448 3 µg once weekly
    Reporting group description
    TAK-448 3 µg, subcutaneous injection, once weekly on Days 1, 8, 15 and 22.

    Reporting group title
    TAK-448 1 µg once weekly
    Reporting group description
    TAK-448 1 µg, subcutaneous injection, once weekly on Days 1, 8, 15 and 22.

    Reporting group title
    TAK-448 0.3 µg once weekly
    Reporting group description
    TAK-448 0.3 µg, subcutaneous injection, once weekly on Days 1, 8, 15 and 22.

    Reporting group title
    TAK-448 0.3 µg twice weekly
    Reporting group description
    TAK-448 0.3 µg, subcutaneous injection, twice weekly on Days 1, 4, 8, 11, 15, 18, 22, and 25.

    Reporting group title
    TAK-448 0.1 µg twice weekly
    Reporting group description
    TAK-448 0.1 µg, subcutaneous injection, twice weekly on Days 1, 4, 8, 11, 15, 18, 22, and 25.

    Serious adverse events
    TAK-448 3 µg once weekly TAK-448 1 µg once weekly TAK-448 0.3 µg once weekly TAK-448 0.3 µg twice weekly TAK-448 0.1 µg twice weekly
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    TAK-448 3 µg once weekly TAK-448 1 µg once weekly TAK-448 0.3 µg once weekly TAK-448 0.3 µg twice weekly TAK-448 0.1 µg twice weekly
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    3 / 3 (100.00%)
    1 / 3 (33.33%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    0
    1
    1
    Dizziness
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Eye disorders
    Eye haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Sep 2014
    The purpose of this amendment was to update the protocol regarding addition of clinical laboratory testing.
    29 Sep 2014
    The purpose of this amendment was to update the protocol regarding frequency of vital signs, electrocardiograms (ECG), and the addition of a Data Monitoring Committee (DMC).
    19 Jun 2015
    The purpose of this amendment was to allow greater flexibility with dose levels of TAK-448 and the frequency of administration based on available data from dosed subjects, to remove the requirement that subjects should be diagnosed with type 2 diabetes mellitus and to remove the requirement for an Independent Monitoring Committee.
    22 Oct 2015
    The primary purpose of this amendment was to update the details of the new Chief Investigator for the study.

    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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