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    Clinical Trial Results:
    Study of Optimal Replacement of Thyroxine in the ElDerly (SORTED) A Randomised Controlled Trial (Feasibility study)

    Summary
    EudraCT number
    		 2011-004425-27
    Trial protocol
    		 GB  
    Global end of trial date
    15 Oct 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Aug 2016
    First version publication date
    11 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    5863
    Additional study identifiers
    ISRCTN number
    		 ISRCTN16043724
    US NCT number
    		 NCT01647750
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Newcastle Upon Tyne Hospitals NHS Foundation Trust
    Sponsor organisation address
    Joint Research Office, Regent Point (Level 1), Gosforth, Newcastle upon Tyne, United Kingdom, NE3 3HD
    Public contact
    Dr Salman Razvi, Gateshead Health NHS Foundation Trust, 0044 1914456052, salman.razvi@ghnt.nhs.uk
    Scientific contact
    Dr Salman Razvi, Gateshead Health NHS Foundation Trust, 0044 1914456052, salman.razvi@ghnt.nhs.uk
    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 Apr 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Oct 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Oct 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of this trial were: • To assess participant’s willingness to enter the trial • To gauge participant’s acceptability of study design. • To study length of time required to complete recruitment. • To assess the dose titration strategy, described above, and length of time required to achieve desired TSH levels. • To gauge medication compliance. There was also a qualitative study and a retrospective cohort study combined in the protocol for this study.
    Protection of trial subjects
    Blood samples may cause discomfort and/or bruising (this should be transient), or rarely infection. Venepuncture was routinely performed in these patient's to assess L-thyroxine dose. Multiple questionnaires were required to furnish a larger RCT. The order of completion was carefully considered (as documented in the current protocol), such that the most important study information was gathered first prior to any patient fatigue. The common side effects of under treatment of hypothyroidism are tiredness, increased awareness of the cold, difficulty in concentrating, dry skin and hair, and weight gain. If the dose of levothyroxine is too high, common symptoms may include diarrhoea, vomiting, chest pain, fast heart rate, insomnia, flushing, sweating, weight loss, palpitations and muscle weakness. Participants may be familiar with the side effects of LT4 they currently take (although brand may be different). We saw participants regularly and assessed their symptoms. Participants were provided with a telephone helpline number to ring in case of concern. They were also provided with a "patient alert card" containing emergency numbers if required.
    Background therapy
    		 none
    Evidence for comparator
    		 The IMP for the randomised controlled trial (RCT) is routinely used in patients with hypothyroidism.
    Actual start date of recruitment
    17 Oct 2012
    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: 48
    Worldwide total number of subjects
    48
    EEA total number of subjects
    48
    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)
    0
    From 65 to 84 years
    29
    85 years and over
    19

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial opened for recruitment in the UK only on 17th October 2012 and the first patient was randomised on 9th November 2012. The trial closed to recruitment on 10th July 2013. 48 patients were randomised. The last patient to enter the study was randomised on 10th July 2013.

    Pre-assignment
    Screening details
    		 Subjects were screened via either GP practices using an eligibility proforma provided by the PCRN research team or via secondary care using a medical record review at routine clinics at Gateshead Health NHS Foundation Trust and the Newcastle upon Tyne Hospital NHS Foundation Trust. For detailed Inclusion/Exclusion criteria please refer to protocol.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject
    Blinding implementation details
    Single-blind will be achieved by de-blistering and over-encapsulation, using a capsule filler of Lactose BP. For doses that are multiples of 50mcg, we will over-encapsulate Eltroxin/Levothyroxine 50 mcg tablets; for the remaining 25mcg, 75mcg and 125mcg dose increments, we will over-encapsulate Eltroxin/Levothyroxine 25mcg tablets. Capsules will be re-packaged into an appropriate bottle container (polypropylene) and labelled in accordance with Annex 13.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard dose
    Arm description
    		 Participants will be randomised to usual dose LT4 (their current dose) to be taken once daily. For participants randomised to usual dose and who have a TSH level between 4.1 – 4.7 at the screening visit, their dose of LT4 will be increased by 25mcgs daily so that they are within the desired TSH range for this group.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Levothyroxine
    Investigational medicinal product code
    Other name
    Eltroxin
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Participants will be randomised to usual dose LT4 (their current dose) or lower dose LT4 to be taken once daily. For participants randomised to usual dose and who have a TSH level between 4.1 – 4.7 at the screening visit, their dose of LT4 will be increased by 25mcgs daily so that they are within the desired TSH range for this group. On the other hand, to achieve the desired target TSH levels for the lower dose LT4 (target TSH levels 4.1 – 8.0 mU/L), participants in the lower dose LT4 arm are likely to have their LT4 medication reduced by 25mcgs once a day at visit 1. IMP will be provided as two separate 13 week supplies of LT4 (dispensed separately at visits 1 and 2), packaged into appropriate individual bottles (polypropylene). The container will be labelled in accordance with Annex 13 but will not indicate details of the arm of the study the participants have been randomised to. The Annex 13 label will instead contain a pack number, which will be the link to relevant packaged dose.

    Arm title
    		 Reduced Dose
    Arm description
    		 Participants will be randomised to lower dose LT4 to be taken once daily. For participants randomised to lower dose LT4 (target TSH levels 4.1 – 8.0 mU/L), participants in the lower dose LT4 arm are likely to have their LT4 medication reduced by 25mcgs once a day at visit 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Levothyroxine
    Investigational medicinal product code
    Other name
    Eltroxin
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Participants will be randomised to usual dose LT4 (their current dose) or lower dose LT4 to be taken once daily. For participants randomised to usual dose and who have a TSH level between 4.1 – 4.7 at the screening visit, their dose of LT4 will be increased by 25mcgs daily so that they are within the desired TSH range for this group. On the other hand, to achieve the desired target TSH levels for the lower dose LT4 (target TSH levels 4.1 – 8.0 mU/L), participants in the lower dose LT4 arm are likely to have their LT4 medication reduced by 25mcgs once a day at visit 1. IMP will be provided as two separate 13 week supplies of LT4 (dispensed separately at visits 1 and 2), packaged into appropriate individual bottles (polypropylene). The container will be labelled in accordance with Annex 13 but will not indicate details of the arm of the study the participants have been randomised to. The Annex 13 label will instead contain a pack number, which will be the link to relevant packaged dose.

    Number of subjects in period 1
    		Standard dose Reduced Dose
    Started
    24
    24
    Completed
    24
    24
    Period 2
    Period 2 title
    Follow Up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject
    Blinding implementation details
    Single-blind will be achieved by de-blistering and over-encapsulation, using a capsule filler of Lactose BP. For doses that are multiples of 50mcg, we will over-encapsulate Eltroxin/Levothyroxine 50 mcg tablets; for the remaining 25mcg, 75mcg and 125mcg dose increments, we will over-encapsulate Eltroxin/Levothyroxine 25mcg tablets. Capsules will be re-packaged into an appropriate bottle container (polypropylene) and labelled in accordance with Annex 13.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard Dose
    Arm description
    		 Participants will be randomised to usual dose LT4 (their current dose) to be taken once daily. For participants randomised to usual dose and who have a TSH level between 4.1 – 4.7 at the screening visit, their dose of LT4 will be increased by 25mcgs daily so that they are within the desired TSH range for this group.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Levothyroxine
    Investigational medicinal product code
    Other name
    Eltroxin
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Participants will be randomised to usual dose LT4 (their current dose) or lower dose LT4 to be taken once daily. For participants randomised to usual dose and who have a TSH level between 4.1 – 4.7 at the screening visit, their dose of LT4 will be increased by 25mcgs daily so that they are within the desired TSH range for this group. On the other hand, to achieve the desired target TSH levels for the lower dose LT4 (target TSH levels 4.1 – 8.0 mU/L), participants in the lower dose LT4 arm are likely to have their LT4 medication reduced by 25mcgs once a day at visit 1. IMP will be provided as two separate 13 week supplies of LT4 (dispensed separately at visits 1 and 2), packaged into appropriate individual bottles (polypropylene). The container will be labelled in accordance with Annex 13 but will not indicate details of the arm of the study the participants have been randomised to. The Annex 13 label will instead contain a pack number, which will be the link to relevant packaged dose.

    Arm title
    		 Reduced Dose
    Arm description
    		 Participants will be randomised to lower dose LT4 to be taken once daily. For participants randomised to the lower dose LT4 (target TSH levels 4.1 – 8.0 mU/L), participants in the lower dose LT4 arm are likely to have their LT4 medication reduced by 25mcgs once a day at visit 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Levothyroxine
    Investigational medicinal product code
    Other name
    Eltroxin
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Participants will be randomised to usual dose LT4 (their current dose) or lower dose LT4 to be taken once daily. For participants randomised to usual dose and who have a TSH level between 4.1 – 4.7 at the screening visit, their dose of LT4 will be increased by 25mcgs daily so that they are within the desired TSH range for this group. On the other hand, to achieve the desired target TSH levels for the lower dose LT4 (target TSH levels 4.1 – 8.0 mU/L), participants in the lower dose LT4 arm are likely to have their LT4 medication reduced by 25mcgs once a day at visit 1. IMP will be provided as two separate 13 week supplies of LT4 (dispensed separately at visits 1 and 2), packaged into appropriate individual bottles (polypropylene). The container will be labelled in accordance with Annex 13 but will not indicate details of the arm of the study the participants have been randomised to. The Annex 13 label will instead contain a pack number, which will be the link to relevant packaged dose.

    Number of subjects in period 2
    		Standard Dose Reduced Dose
    Started
    24
    24
    Completed
    21
    19
    Not completed
    3
    5
         Consent withdrawn by subject
    3
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Standard dose
    Reporting group description
    		 Participants will be randomised to usual dose LT4 (their current dose) to be taken once daily. For participants randomised to usual dose and who have a TSH level between 4.1 – 4.7 at the screening visit, their dose of LT4 will be increased by 25mcgs daily so that they are within the desired TSH range for this group.

    Reporting group title
    Reduced Dose
    Reporting group description
    		 Participants will be randomised to lower dose LT4 to be taken once daily. For participants randomised to lower dose LT4 (target TSH levels 4.1 – 8.0 mU/L), participants in the lower dose LT4 arm are likely to have their LT4 medication reduced by 25mcgs once a day at visit 1.

    Reporting group values
    		 Standard dose Reduced Dose Total
    Number of subjects
    		 24 24 48
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 14 15 29
        85 years and over
    		 10 9 19
    Age continuous
    Units: years
        median (full range (min-max))
    		 83 (80 to 91) 82.5 (80 to 93) -
    Gender categorical
    Units: Subjects
        Female
    		 18 16 34
        Male
    		 6 8 14
    TPO Antibodies
    Units: Subjects
        <35 IU/ml
    		 12 16 28
        ≥35 IU/ml
    		 12 8 20
    Blood Pressure Systolic
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    		 154.5 (140 to 176) 155 (142.5 to 166.5) -
    Blood Pressure Diastolic
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    		 86.5 (76 to 94) 83 (77 to 89) -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 159.2 ( 9.1 ) 158.4 ( 8.7 ) -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 68.7 ( 13.2 ) 68.3 ( 13.3 ) -
    BMI
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 27.1 ( 4.8 ) 27.2 ( 4.6 ) -
    Pulse
    Units: bpm
        arithmetic mean (standard deviation)
    		 67.8 ( 9.9 ) 68.1 ( 10 ) -
    Blood Result TSH
    Units: mU/L
        median (inter-quartile range (Q1-Q3))
    		 1.05 (0.76 to 1.69) 2.05 (1.12 to 2.75) -
    Blood Result FT3
    Units: ppmol/L
        median (inter-quartile range (Q1-Q3))
    		 3.85 (3.75 to 4.15) 3.7 (3.4 to 4.15) -
    Blood Results FT4
    omitting patient 412 (usual dose arm) with FT4=36.0 pmol/L as this patient has a genetic condition whereby measured level of FT4 appears to be higher than it actually is
    Units: pmol/L
        median (inter-quartile range (Q1-Q3))
    		 18.8 (17 to 20.2) 18.75 (16.55 to 19.35) -
    Blood Results Total Cholesterol
    Units: mmol/L
        median (inter-quartile range (Q1-Q3))
    		 4.9 (4.35 to 6.4) 5 (4.5 to 5.85) -
    Blood Results HDL
    Units: mmol/L
        median (inter-quartile range (Q1-Q3))
    		 1.6 (1.4 to 2) 1.7 (1.45 to 1.9) -
    Blood Results Triglycerides
    Units: mmol/L
        median (inter-quartile range (Q1-Q3))
    		 1.35 (1.05 to 2.2) 1.25 (1 to 1.8) -
    Serum CTX
    Units: pg/mL
        median (inter-quartile range (Q1-Q3))
    		 0.25 (0.18 to 0.34) 0.32 (0.14 to 0.47) -

    End points

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    End points reporting groups
    Reporting group title
    Standard dose
    Reporting group description
    		 Participants will be randomised to usual dose LT4 (their current dose) to be taken once daily. For participants randomised to usual dose and who have a TSH level between 4.1 – 4.7 at the screening visit, their dose of LT4 will be increased by 25mcgs daily so that they are within the desired TSH range for this group.

    Reporting group title
    Reduced Dose
    Reporting group description
    		 Participants will be randomised to lower dose LT4 to be taken once daily. For participants randomised to lower dose LT4 (target TSH levels 4.1 – 8.0 mU/L), participants in the lower dose LT4 arm are likely to have their LT4 medication reduced by 25mcgs once a day at visit 1.
    Reporting group title
    Standard Dose
    Reporting group description
    		 Participants will be randomised to usual dose LT4 (their current dose) to be taken once daily. For participants randomised to usual dose and who have a TSH level between 4.1 – 4.7 at the screening visit, their dose of LT4 will be increased by 25mcgs daily so that they are within the desired TSH range for this group.

    Reporting group title
    Reduced Dose
    Reporting group description
    		 Participants will be randomised to lower dose LT4 to be taken once daily. For participants randomised to the lower dose LT4 (target TSH levels 4.1 – 8.0 mU/L), participants in the lower dose LT4 arm are likely to have their LT4 medication reduced by 25mcgs once a day at visit 1.

    Primary: Participants’ acceptability of study design

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    End point title
    		 Participants’ acceptability of study design [1]
    End point description
    as measured by the completion rate of participants in each randomised group
    End point type
    Primary
    End point timeframe
    Baseline and follow up
    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 is a feasibility study and therefore is not powered to perform inferential statistical analysis
    End point values
    		 Standard Dose Reduced Dose
    Number of subjects analysed
    24
    24
    Units: percentage
        number (not applicable)
    87.5
    79.2
    No statistical analyses for this end point

    Primary: Dose Titration Strategy ITT

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    End point title
    		 Dose Titration Strategy ITT [2]
    End point description
    Dose titration strategy:
    End point type
    Primary
    End point timeframe
    follow up
    Notes
    [2] - 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 is a feasibility study and therefore is not powered to perform inferential statistical analysis
    End point values
    		 Standard Dose Reduced Dose
    Number of subjects analysed
    24
    24
    Units: percent
    number (not applicable)
        Percent achieving target TSH range at week 12 (vi
    75
    25
        Percent achieving target TSH range at week 24 (vi
    79.2
    41.7
    No statistical analyses for this end point

    Primary: Dose titration strategy: Completers

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    End point title
    		 Dose titration strategy: Completers [3]
    End point description
    Dose titration strategy: Completers
    End point type
    Primary
    End point timeframe
    follow up
    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 is a feasibility study and therefore is not powered to perform inferential statistical analysis
    End point values
    		 Standard Dose Reduced Dose
    Number of subjects analysed
    21
    19
    Units: percent
    number (not applicable)
        Percent achieving target TSH range at week 12 (vi
    85.7
    31.6
        Percent achieving target TSH range at week 24 (vi
    90.5
    52.6
    No statistical analyses for this end point

    Primary: Compliance (based on tablet count): ITT

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    End point title
    		 Compliance (based on tablet count): ITT [4]
    End point description
    Compliance (based on tablet count): ITT
    End point type
    Primary
    End point timeframe
    follow up
    Notes
    [4] - 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 is a feasibility study and therefore is not powered to perform inferential statistical analysis
    End point values
    		 Standard Dose Reduced Dose
    Number of subjects analysed
    24
    24
    Units: percent
    number (not applicable)
        week 12 (visit 2)
    87.5
    79.2
        week 24 (visit 3)
    87.5
    75
    No statistical analyses for this end point

    Secondary: Mean change from baseline ThyDQoL (qu. II)

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    End point title
    		 Mean change from baseline ThyDQoL (qu. II)
    End point description
    End point type
    Secondary
    End point timeframe
    follow up
    End point values
    		 Standard Dose Reduced Dose
    Number of subjects analysed
    21
    19
    Units: score
        arithmetic mean (standard deviation)
    -0.44 ( 0.78 )
    -0.47 ( 1.07 )
    No statistical analyses for this end point

    Secondary: Mean change from baseline ThyDQol (AWI-18)

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    End point title
    		 Mean change from baseline ThyDQol (AWI-18)
    End point description
    End point type
    Secondary
    End point timeframe
    follow up
    End point values
    		 Standard Dose Reduced Dose
    Number of subjects analysed
    21
    19
    Units: score
        arithmetic mean (standard deviation)
    -0.95 ( 1.67 )
    -0.17 ( 1.01 )
    No statistical analyses for this end point

    Secondary: Mean change from baseline EQ-5D (VAS)

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    End point title
    		 Mean change from baseline EQ-5D (VAS)
    End point description
    End point type
    Secondary
    End point timeframe
    follow up
    End point values
    		 Standard Dose Reduced Dose
    Number of subjects analysed
    21
    19
    Units: score
        arithmetic mean (standard deviation)
    4.9 ( 13.4 )
    -1.1 ( 10.5 )
    No statistical analyses for this end point

    Secondary: Mean change from baseline Falls Risk Assessment Test score

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    End point title
    		 Mean change from baseline Falls Risk Assessment Test score
    End point description
    End point type
    Secondary
    End point timeframe
    follow up
    End point values
    		 Standard Dose Reduced Dose
    Number of subjects analysed
    21
    19
    Units: score
        arithmetic mean (standard deviation)
    0.8 ( 2.2 )
    0 ( 1.2 )
    No statistical analyses for this end point

    Secondary: Mean change from baseline TUG (time in seconds)

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    End point title
    		 Mean change from baseline TUG (time in seconds)
    End point description
    End point type
    Secondary
    End point timeframe
    follow up
    End point values
    		 Standard Dose Reduced Dose
    Number of subjects analysed
    21
    19
    Units: score
        arithmetic mean (standard deviation)
    0.1 ( 3.1 )
    -0.2 ( 3.8 )
    No statistical analyses for this end point

    Secondary: Mean change from baseline Total Cholesterol

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    End point title
    		 Mean change from baseline Total Cholesterol
    End point description
    End point type
    Secondary
    End point timeframe
    follow up
    End point values
    		 Standard Dose Reduced Dose
    Number of subjects analysed
    21
    19
    Units: mmol/L
        arithmetic mean (standard deviation)
    -0.17 ( 0.49 )
    0.08 ( 0.45 )
    No statistical analyses for this end point

    Secondary: Mean change from baseline HDL

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    End point title
    		 Mean change from baseline HDL
    End point description
    End point type
    Secondary
    End point timeframe
    follow up
    End point values
    		 Standard Dose Reduced Dose
    Number of subjects analysed
    21
    19
    Units: mmol/L
        arithmetic mean (standard deviation)
    0.05 ( 0.24 )
    0.06 ( 0.18 )
    No statistical analyses for this end point

    Secondary: Mean change from baseline Triglycerides

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    End point title
    		 Mean change from baseline Triglycerides
    End point description
    End point type
    Secondary
    End point timeframe
    follow up
    End point values
    		 Standard Dose Reduced Dose
    Number of subjects analysed
    21
    19
    Units: mmol/L
        arithmetic mean (standard deviation)
    -0.24 ( 0.55 )
    0.06 ( 0.63 )
    No statistical analyses for this end point

    Secondary: Mean change from baseline Systolic Blood Pressure

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    End point title
    		 Mean change from baseline Systolic Blood Pressure
    End point description
    End point type
    Secondary
    End point timeframe
    follow up
    End point values
    		 Standard Dose Reduced Dose
    Number of subjects analysed
    21
    19
    Units: mmHg
        arithmetic mean (standard deviation)
    -16 ( 22.5 )
    -7 ( 27 )
    No statistical analyses for this end point

    Secondary: Mean change from baseline blood pressure diastolic

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    End point title
    		 Mean change from baseline blood pressure diastolic
    End point description
    End point type
    Secondary
    End point timeframe
    follow up
    End point values
    		 Standard Dose Reduced Dose
    Number of subjects analysed
    21
    19
    Units: mmHg
        arithmetic mean (standard deviation)
    -5.3 ( 9.28 )
    -3.3 ( 12 )
    No statistical analyses for this end point

    Secondary: Mean change from baseline Weight

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    End point title
    		 Mean change from baseline Weight
    End point description
    End point type
    Secondary
    End point timeframe
    follow up
    End point values
    		 Standard Dose Reduced Dose
    Number of subjects analysed
    21
    19
    Units: kg
        arithmetic mean (standard deviation)
    -0.1 ( 1.76 )
    0.9 ( 2.2 )
    No statistical analyses for this end point

    Secondary: Mean change from baseline serum type 1 telopeptide

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    End point title
    		 Mean change from baseline serum type 1 telopeptide
    End point description
    End point type
    Secondary
    End point timeframe
    follow up
    End point values
    		 Standard Dose Reduced Dose
    Number of subjects analysed
    21
    19
    Units: score
        arithmetic mean (standard deviation)
    0.02 ( 0.16 )
    -0.08 ( 0.2 )
    No statistical analyses for this end point

    Secondary: Underactive Thyroid Symptom Rating Questionnaire (ThySRQ)

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    End point title
    		 Underactive Thyroid Symptom Rating Questionnaire (ThySRQ)
    End point description
    Have you felt tired in recent weeks?, percentage tired.
    End point type
    Secondary
    End point timeframe
    baseline and follow up
    End point values
    		 Standard Dose Standard dose Reduced Dose Reduced Dose
    Number of subjects analysed
    21
    21
    19
    19
    Units: percentage
        number (not applicable)
    81
    95
    78
    83
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During Follow Up
    Adverse event reporting additional description
    Adverse events were reported at wk 24
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 As Reported
    Dictionary version
    n/a
    Reporting groups
    Reporting group title
    Standard dose
    Reporting group description
    		 Participants will be randomised to usual dose LT4 (their current dose) to be taken once daily. For participants randomised to usual dose and who have a TSH level between 4.1 – 4.7 at the screening visit, their dose of LT4 will be increased by 25mcgs daily so that they are within the desired TSH range for this group.

    Reporting group title
    Reduced Dose
    Reporting group description
    		 Participants will be randomised to lower dose LT4 to be taken once daily. For participants randomised to lower dose LT4 (target TSH levels 4.1 – 8.0 mU/L), participants in the lower dose LT4 arm are likely to have their LT4 medication reduced by 25mcgs once a day at visit 1.

    Serious adverse events
    		 Standard dose Reduced Dose
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 24 (4.17%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Overdose on levothyroxine
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Mild Stroke
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    VF arrest due to acute myocardial infarction
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Standard dose Reduced Dose
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 24 (66.67%)
    21 / 24 (87.50%)
    General disorders and administration site conditions
    Balance Problems
         subjects affected / exposed
    4 / 24 (16.67%)
    4 / 24 (16.67%)
         occurrences all number
    4
    4
    Brittle Nails
         subjects affected / exposed
    1 / 24 (4.17%)
    2 / 24 (8.33%)
         occurrences all number
    1
    2
    Dizzy
         subjects affected / exposed
    2 / 24 (8.33%)
    2 / 24 (8.33%)
         occurrences all number
    2
    2
    Dry Hair
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Memory Problems
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Slow
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Tired
         subjects affected / exposed
    9 / 24 (37.50%)
    14 / 24 (58.33%)
         occurrences all number
    9
    14
    Weight Gain
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    Chest Pain
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Feeling Unwell
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 24 (4.17%)
         occurrences all number
    2
    1
    Sore Throat
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    0
    Cold sweat
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    Confusional state
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Dry mouth
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Raised Temperature
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Hayfever
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Heat Intolerance
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Lack of motivation
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Restless leg
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Hypertension
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Immune system disorders
    Common Cold
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Left Ear blocked and bleeding
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 24 (4.17%)
    4 / 24 (16.67%)
         occurrences all number
    1
    4
    Loss of appetite
         subjects affected / exposed
    1 / 24 (4.17%)
    2 / 24 (8.33%)
         occurrences all number
    1
    2
    Nausea
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Abdominal colic
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Dysphagia
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Loose Stools
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Breathless
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Cough
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Palpatations
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Shortness of Breath
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Dry Skin
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Bruised Face
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Skin discolouration (breast)
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Skin Lesions
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    swollen top half of face, itchy blotches
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Depressed
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 24 (4.17%)
         occurrences all number
    2
    1
    Stress
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Brown urine
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Incontinence
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Kidney dysfunction
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 24 (4.17%)
         occurrences all number
    2
    1
    Joint Pain
         subjects affected / exposed
    2 / 24 (8.33%)
    3 / 24 (12.50%)
         occurrences all number
    3
    3
    Muscle Ache
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 24 (4.17%)
         occurrences all number
    2
    1
    Swollen Ankes
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Bilateral ankle oedema
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    Gout
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Left Leg/Ankle Swollen
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Numbness in hands and legs
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    oedematous right foot
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Osteoarthritis flare up
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Pain in neck
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Infected Right Foot
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Vaginal Thrush
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jul 2012
    - The addition of the ISRCTN number and the Clinicaltrials.gov Number, as this study been registered for both since the approval of the last protocol. - The Trial Manager’s details have been amended from Dr Catherine Watson to Ms Melinda Jeffels, due to a change in study management. - The protocol version number and date has been updated to ensure version control is kept. - The abbreviation of RfPB (Research for Patient Benefit) has been added to the abbreviation section of the protocol. - The name of the manufacturer of Eltroxin to be used in this study was changed from Goldsheild Group Limited to Mercury Pharma Group Limited, due to a change in the name of the Manufacturer (it should be noted that the marketing authorization of the product PL number remains unchanged) - The web address details for the online randomization system, as well as the availability details, have been added to the protocol as they have now been confirmed. - The SAE fax and telephone numbers have been added to the protocol as these have been confirmed as well.
    29 Apr 2013
    - The inclusion criteria regarding required TSH levels to be eligible for the study (originally 0.4 – 4 mU/L) has been amended in order to reflect the local laboratory reference ranges (0.3 – 4.7 mU/L) in order to ensure that all patients with normal TSH levels can be enrolled on the study. - The protocol version number and date has been updated to ensure version control is kept.
    14 Jun 2013
    Update the status of Newcastle PCT to a site from a PIC.
    30 Oct 2013
    Due to the limited availability of trial IMP Eltroxin. Current stock of Eltroxin expires on the 14th of November, so we request the flexibility to use the generic medication Levothyroxine instead.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/23522096
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