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    Clinical Trial Results:
    Clinical study of the efficacy of liquid (drops) versus classic (tablets) formulations of levothyroxine in replacement therapy of adults with clinical hypothyroidism.

    Summary
    EudraCT number
    		 2017-001760-38
    Trial protocol
    		 GR  
    Global end of trial date
    31 Oct 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Nov 2021
    First version publication date
    14 Nov 2021
    Other versions
    Summary report(s)
    		 DOI: 10.1159/000508216

    Trial information

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    Trial identification
    Sponsor protocol code
    T4drops-02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Uni-Pharma Kleon Tsetis Pharmaceutical Laboratories SA
    Sponsor organisation address
    14th Km National Road 1, Kifissia, Greece, 14564
    Public contact
    Regulatory Affairs department, Uni-Pharma Kleon Tsetis Pharmaceutical Laboratories S.A., 30 2108072512374, soumelas@uni-pharma.gr
    Scientific contact
    Regulatory Affairs department, Uni-Pharma Kleon Tsetis Pharmaceutical Laboratories S.A., 2108072512 2108072512374, soumelas@uni-pharma.gr
    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
    01 Nov 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Oct 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Scope of the present study is to investigate whether there is equivalent efficacy between replacement therapy of a new LT4 formulation in liquid form (oral drops) versus the classic form (tablets) in adult patients with clinical permanent hypothyroidism.
    Protection of trial subjects
    Not Applicable
    Background therapy
    		 -
    Evidence for comparator
    		 Use of the tablet Levothyroxine formulation of the same manufacturer (T4® tablets by Uni-Pharma).
    Actual start date of recruitment
    31 Aug 2017
    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
    Greece: 50
    Worldwide total number of subjects
    50
    EEA total number of subjects
    50
    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)
    50
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first patient was admitted to the study on 19.09.2017 and the date of last visit of last patient was 31.10.2018.

    Pre-assignment
    Screening details
    		 1. Patients diagnosed with clinically permanent hypothyroidism 2. 20-60 years 3. Patients who are already receiving replacement therapy with levothyroxine tablets At the time of screening, many of the patients were taking levo tablets other than T4® so due to possible different bioequivalence between the products, patients were switched to T4®

    Period 1
    Period 1 title
    First visit
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Tablets
    Arm description
    		 The levothyroxine preparation that the patient was receiving prior to entering the study was switched to T4® tablets (group A), , in the same dose
    Arm type
    		 Active comparator

    Investigational medicinal product name
    T4 tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    At the same dosage the patients used to receive prior to entering the study

    Arm title
    		 T4 Oral drops
    Arm description
    		 The levothyroxine preparation that the patient was receiving prior to entering the study was switched either to T4® drops (group B), in the same dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    T4 100μg/ml oral drops, solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops, solution
    Routes of administration
    Oral use
    Dosage and administration details
    At the same Levothyroxine dose the patient was receiving prior to entering the study

    Number of subjects in period 1
    		Tablets T4 Oral drops
    Started
    25
    25
    Completed
    22
    22
    Not completed
    3
    3
         Lost to follow-up
    3
    3
    Period 2
    Period 2 title
    Second visit
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 T4 Tablets
    Arm description
    		 At the second visit, if the TSH levels were within the target range, the patient was switched from the tablet to the liquid form with the same dose
    Arm type
    		 Active comparator

    Investigational medicinal product name
    T4 100μg/ml oral drops, solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops, solution
    Routes of administration
    Oral use
    Dosage and administration details
    At the second visit, if the TSH levels were within the target range, the patient was switched from the tablet to the liquid form with the same dose

    Arm title
    		 T4 Oral drops
    Arm description
    		 At the second visit, if the TSH levels were within the target range, the patient was switched from the oral drops to the tablet form with the same dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    T4 tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    At the second visit, if the TSH levels were within the target range, the patient was switched from the oral drops to the tablet form with the same dose

    Number of subjects in period 2
    		T4 Tablets T4 Oral drops
    Started
    22
    22
    Completed
    21
    18
    Not completed
    1
    4
         Protocol deviation
    1
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    First visit
    Reporting group description
    		 -

    Reporting group values
    		 First visit Total
    Number of subjects
    		 50 50
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 50 50
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42.4 ± 12.5 -
    Gender categorical
    Units: Subjects
        Female
    		 41 41
        Male
    		 9 9

    End points

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    End points reporting groups
    Reporting group title
    Tablets
    Reporting group description
    		 The levothyroxine preparation that the patient was receiving prior to entering the study was switched to T4® tablets (group A), , in the same dose

    Reporting group title
    T4 Oral drops
    Reporting group description
    		 The levothyroxine preparation that the patient was receiving prior to entering the study was switched either to T4® drops (group B), in the same dose
    Reporting group title
    T4 Tablets
    Reporting group description
    		 At the second visit, if the TSH levels were within the target range, the patient was switched from the tablet to the liquid form with the same dose

    Reporting group title
    T4 Oral drops
    Reporting group description
    		 At the second visit, if the TSH levels were within the target range, the patient was switched from the oral drops to the tablet form with the same dose

    Primary: TSH-Oral drops

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    End point title
    		 TSH-Oral drops [1]
    End point description
    End point type
    Primary
    End point timeframe
    After 10±2 weeks of treatment
    Notes
    [1] - 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 was a cross-over design
    End point values
    		 Tablets T4 Oral drops
    Number of subjects analysed
    22
    18
    Units: mIU/L
        arithmetic mean (standard deviation)
    1.901 ± 0.957
    2.076 ± 1.334
    Statistical analysis title
    		 Paired samples t test
    Comparison groups
    Tablets v T4 Oral drops
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: TSH-T4 tablets

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    End point title
    		 TSH-T4 tablets [2]
    End point description
    End point type
    Primary
    End point timeframe
    After 10 ± 2 weeks of treatment
    Notes
    [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 was a cross-over design
    End point values
    		 T4 Oral drops T4 Tablets
    Number of subjects analysed
    22
    21
    Units: mIU/L
        arithmetic mean (standard deviation)
    1.901 ± 0.957
    1.759 ± 1.104
    Statistical analysis title
    		 Paired samples t test
    Comparison groups
    T4 Oral drops v T4 Tablets
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Confidence interval

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Whole study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Frequency threshold for reporting non-serious adverse events: 0%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No non-serious AEs reported

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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