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    Clinical Trial Results:
    A multicentre, open-label switch study to investigate the necessity of dose adjustment after switching from L-Thyroxine Christiaens® to the new levothyroxine sodium test formulation in (near) total thyroidectomised patients.

    Summary
    EudraCT number
    2012-005732-28
    Trial protocol
    BE  
    Global end of trial date
    23 Jun 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    LE-9999-401-BE
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01916304
    WHO universal trial number (UTN)
    U1111-1145-3526
    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)
    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
    09 Dec 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Jun 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jun 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to investigate the effect of switching participants taking levothyroxine to a new formulation.
    Protection of trial subjects
    All participants were required to read and sign an informed consent form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    02 Jul 2013
    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
    Belgium: 101
    Worldwide total number of subjects
    101
    EEA total number of subjects
    101
    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)
    78
    From 65 to 84 years
    23
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants took part in the study at 8 investigative sites in Belgium from 02 July 2013 to 23 June 2014.

    Pre-assignment
    Screening details
    Participants with a diagnosis of Primary Hypothyroidism were switched from treatment with L-Thyroxine Christiaens® to treatment with new levothyroxine sodium 25-225 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
    Arm title
    Levothyroxine sodium new formulation
    Arm description
    Levothyroxine (25-225 μg), tablets, orally, once daily for up to 12 to 20 weeks. Dose administered depends on the thyroid stimulating hormone level.
    Arm type
    Experimental

    Investigational medicinal product name
    levothyroxine sodium new formulation
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 to 225 μg once daily (dose dependent on TSH level) for 12 to 20 weeks.

    Number of subjects in period 1
    Levothyroxine sodium new formulation
    Started
    101
    Safety Set
    101
    Intent-to-Treat Set
    84
    Completed
    84
    Not completed
    17
         Screening failure
    17

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Levothyroxine sodium new formulation
    Reporting group description
    Levothyroxine (25-225 μg), tablets, orally, once daily for up to 12 to 20 weeks. Dose administered depends on the thyroid stimulating hormone level.

    Reporting group values
    Levothyroxine sodium new formulation Total
    Number of subjects
    101 101
    Age, Customized
    Units: participants
        <65 years
    78 78
        ≥ 65 years
    23 23
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    54.1 ± 12.17 -
    Gender, Male/Female
    Units: participants
        Female
    72 72
        Male
    29 29
    Region of Enrollment
    Units: Subjects
        Belgium
    101 101
    Weight
    Weight data was available for 100 participants.
    Units: kg
        arithmetic mean (standard deviation)
    76.9 ± 18.05 -
    Height
    Height data was available for 96 participants.
    Units: cm
        arithmetic mean (standard deviation)
    168.4 ± 8.57 -
    Investigator Reported Body Mass Index (BMI)
    Investigator reported BMI data was available for 93 participants.
    Units: kg/m^2
        arithmetic mean (standard deviation)
    27.2 ± 5.98 -
    Calculated BMI
    Calculated BMI data was available for 96 participants.
    Units: kg/m^2
        arithmetic mean (standard deviation)
    27.1 ± 6 -

    End points

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    End points reporting groups
    Reporting group title
    Levothyroxine sodium new formulation
    Reporting group description
    Levothyroxine (25-225 μg), tablets, orally, once daily for up to 12 to 20 weeks. Dose administered depends on the thyroid stimulating hormone level.

    Primary: Percentage of Participants that Do Not Need a Change of Dose

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    End point title
    Percentage of Participants that Do Not Need a Change of Dose [1]
    End point description
    Dose change was determined by physician according to their clinical judgement.
    End point type
    Primary
    End point timeframe
    2 months (± 2 weeks) after switch to sodium formulation.
    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: Statistical analysis is not reported for this outcome measure.
    End point values
    Levothyroxine sodium new formulation
    Number of subjects analysed
    82
    Units: percentage of participants
        number (confidence interval 95%)
    32.9 (23.7 to 43.7)
    No statistical analyses for this end point

    Secondary: Magnitude of the Change in Daily Dose Needed

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    End point title
    Magnitude of the Change in Daily Dose Needed
    End point description
    Magnitude was determined via a change table which provides the percentage of participants that needed a change in Daily Dose (μg/day) of -25 μg, -12.5 μg, -6.25 μg, -5.35 μg, 0 μg or +12.5 μg.
    End point type
    Secondary
    End point timeframe
    2 months (± 2 weeks) after switch to sodium formulation.
    End point values
    Levothyroxine sodium new formulation
    Number of subjects analysed
    82
    Units: percentage of participants
    number (not applicable)
        -25 μg change
    19.51
        -12.5 μg change
    42.68
        -6.25 μg change
    1.22
        -5.35 μg change
    1.22
        0 μg change
    32.93
        +12.5 μg change
    2.44
    No statistical analyses for this end point

    Secondary: Relative Percent Change from Baseline in Serum Thyroid Stimulating Hormone

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    End point title
    Relative Percent Change from Baseline in Serum Thyroid Stimulating Hormone
    End point description
    Blood samples were collected and samples were analyzed according to the local Quality System. A negative change from Baseline indicated improvement.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 2 (± 2 weeks) and Month 4 (± 4 weeks) after inclusion into study.
    End point values
    Levothyroxine sodium new formulation
    Number of subjects analysed
    83
    Units: percent change
    median (inter-quartile range (Q1-Q3))
        Month 2
    -74.5 (-89.5 to 50.6)
        Month 4 (n=82)
    -54 (-75.1 to -15.5)
    No statistical analyses for this end point

    Secondary: Percentage of Participants that Obtained a Thyroid Stimulating Hormone (TSH) Between 0.4-2.5 mU/L

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    End point title
    Percentage of Participants that Obtained a Thyroid Stimulating Hormone (TSH) Between 0.4-2.5 mU/L
    End point description
    Blood samples were collected and samples were analyzed according to the local Quality System.
    End point type
    Secondary
    End point timeframe
    Month 4 (± 4 weeks) after inclusion into study.
    End point values
    Levothyroxine sodium new formulation
    Number of subjects analysed
    82
    Units: percentage of participants
        number (not applicable)
    57.3
    No statistical analyses for this end point

    Secondary: Absolute Serum Thyroid Stimulating Hormone Values

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    End point title
    Absolute Serum Thyroid Stimulating Hormone Values
    End point description
    Blood samples were collected and samples were analyzed according to the local Quality System. Participants from the intent-to-treat population, all enrolled participants, with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 2 (± 2 weeks) and Month 4 (± 4 weeks) after inclusion into study.
    End point values
    Levothyroxine sodium new formulation
    Number of subjects analysed
    84
    Units: mIU/mL
    arithmetic mean (standard deviation)
        Baseline
    1.2 ± 0.59
        Month 2 (n=83)
    0.6 ± 1.69
        Month 4 (n=82)
    0.9 ± 1.09
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Study inclusion to recovery or final status is known of adverse drug reactions (ADRs) [up to 5 months]
    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
    17.0
    Reporting groups
    Reporting group title
    Levothyroxine sodium new formulation
    Reporting group description
    Levothyroxine (25-225 μg), tablets, orally, once daily for up to 12 to 20 weeks. Dose administered depends on the thyroid stimulating hormone level.

    Serious adverse events
    Levothyroxine sodium new formulation
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 101 (6.93%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural haematoma
         subjects affected / exposed
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Hysterectomy
         subjects affected / exposed
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mastectomy
         subjects affected / exposed
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Salivary gland resection
         subjects affected / exposed
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bladder catheterisation
         subjects affected / exposed
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Catheterisation cardiac
         subjects affected / exposed
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin lesion
         subjects affected / exposed
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Levothyroxine sodium new formulation
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 101 (6.93%)
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 101 (6.93%)
         occurrences all number
    9

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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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