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    Clinical Trial Results:
    Multi-modal effects of Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism; a randomised placebo-controlled Trial (TRUST)

    Summary
    EudraCT number
    		 2011-004554-26
    Trial protocol
    		 GB   IE   NL  
    Global end of trial date
    18 Nov 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Apr 2019
    First version publication date
    17 Apr 2019
    Other versions
    Summary report(s)
    		 TRUST summary

    Trial information

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    Trial identification
    Sponsor protocol code
    GN11GE272
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01660126
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    NHS Greater Glasgow and Clyde
    Sponsor organisation address
    Dalnair Street, Glasgow, United Kingdom,
    Public contact
    Joanne McGarry, NHS Greater Glasgow and Clyde, Joanne.McGarry@ggc.scot.nhs.uk
    Scientific contact
    Joanne McGarry, NHS Greater Glasgow and Clyde, Joanne.McGarry@ggc.scot.nhs.uk
    Sponsor organisation name
    University of Glasgow
    Sponsor organisation address
    University Avenue, Glasgow, United Kingdom, G12 8QQ
    Public contact
    Dr Debra Stuart, University of Glasgow, debra.stuart@glasgow.ac.uk
    Scientific contact
    Dr Debra Stuart, University of Glasgow, debra.stuart@glasgow.ac.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
    18 Nov 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Nov 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    i. Does thyroxine treatment for SCH give multi-modal benefits for older people with SCH? ii. Are benefits seen across a wide range of outcomes, including prevention of cardiovascular disease, and improving health-related quality of life, muscle function and cognition? iii. Are benefits seen in specific subgroups of older people with SCH, including women, very elderly and those with mild degrees of SCH (TSH 4.6-10 mU/L)? iv. Are any benefits offset by adverse effects, such as atrial fibrillation or heart failure?
    Protection of trial subjects
    To maintain levels of Thyroid Stimulating Hormone (TSH) within the reference range and avoid thyroxine overtreatment: - very low thyroxine start dose (50 micrograms) - regular Thyroid Function Tests In addition: - regular clinical review to identify and manage adverse events of special interest - cardiovascular (atrial fibrilliation, cardiac failure) and musculoskeletal (fractures and osteoporosis) - regular assessment of hyperthyroid symptoms (ThyPRO)
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Nov 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
    Netherlands: 255
    Country: Number of subjects enrolled
    United Kingdom: 150
    Country: Number of subjects enrolled
    Ireland: 115
    Country: Number of subjects enrolled
    Switzerland: 217
    Worldwide total number of subjects
    737
    EEA total number of subjects
    520
    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
    685
    85 years and over
    52

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment took place in primary care practices and academic centres in four countries (the UK, Ireland, the Netherlands and Switzerland between March 2013 and December 2015. Over 1000 General Practices agreed to take part, using clinical laboratory databases and practice records to identify potential study participants.

    Pre-assignment
    Screening details
    		 Screening according to: Inclusion: age ≥ 65 yrs; persistent subclinical hypothyroidism measured at least twice Exclusion: current levothyroxine/antithyroid drugs/amiodarone/lithium; thyroid surgery/radioactive iodine (12 mths); dementia; major illness/elective surgery/acute coronary syndrome (4 wks); terminal illness 2647 screened, 1910 excluded

    Pre-assignment period milestones
    Number of subjects started
    		 737
    Number of subjects completed
    		 737

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A mock titration was performed in the placebo group using an adaptive schedule, in which the data centre allocated (by computer algorithm) the same proportion of placebo patients to dose adjustment (up or down) as required in the levothyroxine group.

    Arm title
    		 Levothyroxine
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Levothyroxine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50 μg daily (or 25 μg in patients with a body weight of <50 kg or with known coronary heart disease [previous myocardial infarction or symptoms of angina pectoris])

    Number of subjects in period 1
    		Placebo Levothyroxine
    Started
    369
    368
    Underwent randomisation
    369
    368
    Completed
    369
    368
    Period 2
    Period 2 title
    Treatment period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    All dose adjustments were generated and executed by means of computer without the intervention of a physician. The participants, investigators, and treating physicians were unaware of the results of thyrotropin measurements throughout the course of the trial.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A mock titration was performed in the placebo group using an adaptive schedule, in which the data centre allocated (by computer algorithm) the same proportion of placebo patients to dose adjustment (up or down) as required in the levothyroxine group

    Arm title
    		 Levothyroxine
    Arm description
    		 Levothyroxine Starting dose 50 μg daily (or 25 μg in patients with a body weight of <50 kg or with known coronary heart disease [previous myocardial infarction or symptoms of angina pectoris]) with dose adjustment aimed at maintaining thyrotropin level within the reference range (0.40 to 4.59 mIU per liter).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Levothyroxine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Levothyroxine starting dose 50 μg daily (or 25 μg in patients with a body weight of <50 kg or with known coronary heart disease [previous myocardial infarction or symptoms of angina pectoris]). Dose adjustment was aimed to result in a thyrotropin level within the reference range (0.40 to 4.59 mIU per liter).

    Number of subjects in period 2
    		Placebo Levothyroxine
    Started
    369
    368
    12 month follow-up
    337
    332
    Extended follow-up
    187
    194
    Completed
    187
    194
    Not completed
    182
    174
         Physician decision
    182
    174

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Levothyroxine
    Reporting group description
    		 -

    Reporting group values
    		 Placebo Levothyroxine Total
    Number of subjects
    		 369 368 737
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Age at baseline
    Units: years
        arithmetic mean (standard deviation)
    		 74.8 ± 6.8 74.0 ± 5.8 -
    Gender categorical
    Units: Subjects
        Female
    		 198 198 396
        Male
    		 171 170 341
    Racial group
    Reported by the patient
    Units: Subjects
        White
    		 362 362 724
        Other
    		 7 6 13
    Housing
    Standard housing defined as non-sheltered community accommodation. By contrast, sheltered housing is purpose built, grouped housing for older persons, often with an on-site manager or warden.
    Units: Subjects
        Standard
    		 356 358 714
        Other
    		 13 10 23
    Ischemic heart disease
    Defined as a history of angina pectoris or previous myocardial infarction.
    Units: Subjects
        Yes
    		 50 50 100
        No or not recorded
    		 319 318 637
    Atrial fibrilliation
    Units: Subjects
        Yes
    		 44 45 89
        No or not recorded
    		 325 323 648
    Hypertension
    Units: Subjects
        Yes
    		 183 192 375
        No or Not recorded
    		 186 176 362
    Diabetes mellitus
    Units: Subjects
        Yes
    		 54 63 117
        No or Not recorded
    		 315 305 620
    Osteoporosis
    Units: Subjects
        Yes
    		 47 41 88
        No or Not recorded
    		 322 327 649
    Current smoking
    Units: Subjects
        Yes
    		 33 29 62
        No or Not recorded
    		 336 339 675
    Weight <50kg
    Units: Subjects
        Yes
    		 5 5 10
        No
    		 364 363 727
    Concomitant medicines
    Units: Number
        median (inter-quartile range (Q1-Q3))
    		 4 (2 to 6) 4 (2 to 6) -
    Mini-Mental State Examination score
    Score is on a scale from 0 to 30, with higher scores indicating better cognitive function.
    Units: Score
        median (inter-quartile range (Q1-Q3))
    		 29 (28 to 30) 29 (27 to 30) -
    Thyrotropin
    Units: mIU/L
        arithmetic mean (standard deviation)
    		 6.38 ± 2.01 6.41 ± 2.01 -
    Free thyroxine
    Units: pmol/L
        arithmetic mean (standard deviation)
    		 13.3 ± 1.9 13.4 ± 2.1 -
    Hypothyroid Symptoms score
    Assessed on a scale from 0 to 100, with a higher score indicating more symptoms
    Units: Score
        arithmetic mean (standard deviation)
    		 16.9 ± 17.9 17.5 ± 18.8 -
    Tiredness score
    From the Thyroid-Related Quality of Life Patient-Reported Outcome (ThyPRO) questionnaire. Assessed on a scale of 0 to 100, with a higher score indicating more tiredness.
    Units: Score
        arithmetic mean (standard deviation)
    		 25.5 ± 20.3 25.9 ± 20.6 -
    EQ-5D score
    The EuroQoL [EQ] Group 5-Dimension Self-Report Questionnaire (EQ-5D) descriptive index on a scale from −0.59 to 1.00; a higher score indicates better quality of life.
    Units: Score
        arithmetic mean (standard deviation)
    		 0.847 ± 0.171 0.846 ± 0.187 -
    EQ visual analogue scale score
    The EuroQoL [EQ] Group 5-Dimension Self-Report Questionnaire (EQ-5D) visual-analogue scale, on a scale from 0 to 100; a higher score indicates better quality of life.
    Units: Score
        arithmetic mean (standard deviation)
    		 76.5 ± 16.3 78.4 ± 15.3 -
    Hand grip strength
    Units: kg
        arithmetic mean (standard deviation)
    		 27.5 ± 11.3 28.0 ± 10.2 -
    Letter-digit coding test score
    The score on the letter–digit coding test (a test of executive cognitive function) indicates the speed of processing according to the number of correct responses in matching nine letters with nine digits in 90 seconds (minimum score is 0, with higher scores indicating better executive cognitive function; there is no maximum score).
    Units: Score
        arithmetic mean (standard deviation)
    		 25.2 ± 8.3 24.9 ± 7.4 -
    Systolic blood pressure
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 140.4 ± 18.9 141.2 ± 18.7 -
    Diastolic blood pressure
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 74.8 ± 11.7 74.1 ± 11.6 -
    Body Mass Index
    Weight in kilograms divided by the square of the height in meters.
    Units: score
        arithmetic mean (standard deviation)
    		 27.7 ± 4.6 28.1 ± 5.3 -
    Waist circumference
    Units: cm
        arithmetic mean (standard deviation)
    		 97.5 ± 12.8 98.5 ± 13.6 -
    Barthel Index
    The Barthel Index uses a scale from 0 to 20 points, with higher numbers indicating better performance on activities of daily living.
    Units: Score
        median (inter-quartile range (Q1-Q3))
    		 20 (14 to 20) 20 (13 to 20) -
    Instrumental Activities of Daily Living score
    The Instrumental Activities of Daily Living scale has a maximum score of 14 (range, 0 to 14), with higher scores indicating better performance in activities of daily living.
    Units: score
        median (inter-quartile range (Q1-Q3))
    		 14 (7 to 14) 14 (7 to 14) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Levothyroxine
    Reporting group description
    		 -
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group title
    Levothyroxine
    Reporting group description
    		 Levothyroxine Starting dose 50 μg daily (or 25 μg in patients with a body weight of <50 kg or with known coronary heart disease [previous myocardial infarction or symptoms of angina pectoris]) with dose adjustment aimed at maintaining thyrotropin level within the reference range (0.40 to 4.59 mIU per liter).

    Primary: Hypothyroid Symptoms score 12 months

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    End point title
    		 Hypothyroid Symptoms score 12 months
    End point description
    The range of the scale is 0 to 100, with a higher score indicating more symptoms. The minimum clinically important difference for each score has been estimated as 9 points.
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    		 Placebo Levothyroxine
    Number of subjects analysed
    320
    318
    Units: Score
        arithmetic mean (standard deviation)
    16.7 ± 17.5
    16.6 ± 16.9
    Statistical analysis title
    		 Hypothyroid Symptoms score
    Comparison groups
    Placebo v Levothyroxine
    Number of subjects included in analysis
    638
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.99
    Method
    		 Regression, Linear
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Primary: Tiredness score 12 months

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    End point title
    		 Tiredness score 12 months
    End point description
    The range of the scale is 0 to 100, with a higher score indicating more symptoms. The minimum clinically important difference for each score has been estimated as 9 points.
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    		 Placebo Levothyroxine
    Number of subjects analysed
    320
    318
    Units: Score
        arithmetic mean (standard deviation)
    28.6 ± 19.5
    28.7 ± 20.2
    Statistical analysis title
    		 Tiredness score
    Statistical analysis description
    12 months
    Comparison groups
    Placebo v Levothyroxine
    Number of subjects included in analysis
    638
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.77
    Method
    		 Regression, Linear
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Primary: Hypothyroid Symptoms score Extended follow-up

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    End point title
    		 Hypothyroid Symptoms score Extended follow-up
    End point description
    End point type
    Primary
    End point timeframe
    Extended follow-up beyond 12 months was performed in a subgroup of patients. The median duration of follow-up from baseline was [placebo] 24.2 months (interquartile range, 18.4 to 30.3) and [levothyroxine] 24.5 months (interquartile range, 18.4 to 30.5).
    End point values
    		 Placebo Levothyroxine
    Number of subjects analysed
    187
    194
    Units: Score
        arithmetic mean (standard deviation)
    15.2 ± 15.9
    17.9 ± 9.1
    Statistical analysis title
    		 Hypothyroid Symptoms score Extended follow-up
    Comparison groups
    Placebo v Levothyroxine
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5
    Method
    		 Regression, Linear
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Primary: Tiredness score Extended follow-up

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    End point title
    		 Tiredness score Extended follow-up
    End point description
    End point type
    Primary
    End point timeframe
    Extended follow-up beyond 12 months was performed in a subgroup of patients. The median duration of follow-up from baseline was [placebo] 24.2 months (interquartile range, 18.4 to 30.3) and [levothyroxine] 24.5 months (interquartile range, 18.4 to 30.5).
    End point values
    		 Placebo Levothyroxine
    Number of subjects analysed
    187
    194
    Units: Score
        arithmetic mean (standard deviation)
    31.9 ± 22.1
    30.2 ± 20.5
    Statistical analysis title
    		 Tiredness score Extended follow-up
    Comparison groups
    Placebo v Levothyroxine
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Regression, Linear
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: EQ-5D descriptive score 12 months

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    End point title
    		 EQ-5D descriptive score 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Levothyroxine
    Number of subjects analysed
    320
    318
    Units: Score
        arithmetic mean (standard deviation)
    0.853 ± 0.191
    0.833 ± 0.212
    Statistical analysis title
    		 EQ-5D descriptive score
    Comparison groups
    Placebo v Levothyroxine
    Number of subjects included in analysis
    638
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Regression, Linear
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: EQ VAS score 12 months

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    End point title
    		 EQ VAS score 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Levothyroxine
    Number of subjects analysed
    320
    318
    Units: Score
        arithmetic mean (standard deviation)
    77.4 ± 13.7
    77.3 ± 15.6
    Statistical analysis title
    		 EQ VAS score
    Statistical analysis description
    12 months
    Comparison groups
    Placebo v Levothyroxine
    Number of subjects included in analysis
    638
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.18
    Method
    		 Regression, Linear
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: Hand grip strength 12 months

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    End point title
    		 Hand grip strength 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Levothyroxine
    Number of subjects analysed
    320
    318
    Units: kg
        arithmetic mean (standard deviation)
    27.1 ± 11.2
    27.5 ± 10.5
    Statistical analysis title
    		 Hand-grip strength
    Comparison groups
    Placebo v Levothyroxine
    Number of subjects included in analysis
    638
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.84
    Method
    		 Regression, Linear
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: Systolic blood pressure 12 months

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    End point title
    		 Systolic blood pressure 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Levothyroxine
    Number of subjects analysed
    320
    318
    Units: mm Hg
        arithmetic mean (standard deviation)
    138.4 ± 17.8
    138.3 ± 18.7
    Statistical analysis title
    		 Systolic blood pressure
    Comparison groups
    Placebo v Levothyroxine
    Number of subjects included in analysis
    638
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9
    Method
    		 Regression, Linear
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: Diastolic blood pressure 12 months

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    End point title
    		 Diastolic blood pressure 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Levothyroxine
    Number of subjects analysed
    320
    318
    Units: mm Hg
        arithmetic mean (standard deviation)
    73.5 ± 11.1
    72.8 ± 11.4
    Statistical analysis title
    		 Diastolic blood pressure
    Comparison groups
    Placebo v Levothyroxine
    Number of subjects included in analysis
    638
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.93
    Method
    		 Regression, Linear
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: Body Mass Index 12 months

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    End point title
    		 Body Mass Index 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Levothyroxine
    Number of subjects analysed
    320
    318
    Units: BMI
        arithmetic mean (standard deviation)
    27.7 ± 4.6
    27.9 ± 5.1
    Statistical analysis title
    		 Body mass index
    Comparison groups
    Placebo v Levothyroxine
    Number of subjects included in analysis
    638
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.89
    Method
    		 Regression, Linear
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: Waist circumference 12 months

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    End point title
    		 Waist circumference 12 months
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Levothyroxine
    Number of subjects analysed
    320
    318
    Units: cm
        arithmetic mean (standard deviation)
    96.8 ± 13.1
    98.0 ± 13.2
    Statistical analysis title
    		 Waist circumference
    Comparison groups
    Placebo v Levothyroxine
    Number of subjects included in analysis
    638
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.34
    Method
    		 Regression, Linear
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: EQ-5D descriptive score Extended follow-up

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    End point title
    		 EQ-5D descriptive score Extended follow-up
    End point description
    End point type
    Secondary
    End point timeframe
    Extended follow-up beyond 12 months was performed in a subgroup of patients. The median duration of follow-up from baseline was [placebo] 24.2 months (interquartile range, 18.4 to 30.3) and [levothyroxine] 24.5 months (interquartile range, 18.4 to 30.5).
    End point values
    		 Placebo Levothyroxine
    Number of subjects analysed
    187
    194
    Units: Score
        arithmetic mean (standard deviation)
    0.829 ± 0.209
    0.864 ± 0.188
    Statistical analysis title
    		 EQ-5D descriptive score Extended follow-up
    Comparison groups
    Placebo v Levothyroxine
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.03
    Method
    		 Regression, Linear
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: EQ VAS score Extended follow-up

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    End point title
    		 EQ VAS score Extended follow-up
    End point description
    End point type
    Secondary
    End point timeframe
    Extended follow-up beyond 12 months was performed in a subgroup of patients. The median duration of follow-up from baseline was [placebo] 24.2 months (interquartile range, 18.4 to 30.3) and [levothyroxine] 24.5 months (interquartile range, 18.4 to 30.5).
    End point values
    		 Placebo Levothyroxine
    Number of subjects analysed
    187
    194
    Units: Score
        arithmetic mean (standard deviation)
    77.2 ± 13.5
    76.8 ± 14.2
    Statistical analysis title
    		 EQ VAS score Extended follow-up
    Comparison groups
    Placebo v Levothyroxine
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.56
    Method
    		 Regression, Linear
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: Hand grip strength Extended follow-up

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    End point title
    		 Hand grip strength Extended follow-up
    End point description
    End point type
    Secondary
    End point timeframe
    Extended follow-up beyond 12 months was performed in a subgroup of patients. The median duration of follow-up from baseline was [placebo] 24.2 months (interquartile range, 18.4 to 30.3) and [levothyroxine] 24.5 months (interquartile range, 18.4 to 30.5).
    End point values
    		 Placebo Levothyroxine
    Number of subjects analysed
    187
    194
    Units: kg
        arithmetic mean (standard deviation)
    24.9 ± 10.6
    24.4 ± 10.1
    Statistical analysis title
    		 Hand grip strength Extended follow-up
    Comparison groups
    Placebo v Levothyroxine
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.34
    Method
    		 Regression, Linear
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: Systolic blood pressure Extended follow-up

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    End point title
    		 Systolic blood pressure Extended follow-up
    End point description
    End point type
    Secondary
    End point timeframe
    Extended follow-up beyond 12 months was performed in a subgroup of patients. The median duration of follow-up from baseline was [placebo] 24.2 months (interquartile range, 18.4 to 30.3) and [levothyroxine] 24.5 months (interquartile range, 18.4 to 30.5).
    End point values
    		 Placebo Levothyroxine
    Number of subjects analysed
    187
    194
    Units: mm Hg
        arithmetic mean (standard deviation)
    137.5 ± 19.2
    136.8 ± 17.6
    Statistical analysis title
    		 Systolic blood pressure Extended follow-up
    Comparison groups
    Placebo v Levothyroxine
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.51
    Method
    		 Regression, Linear
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: Diastolic blood pressure Extended follow-up

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    End point title
    		 Diastolic blood pressure Extended follow-up
    End point description
    End point type
    Secondary
    End point timeframe
    Extended follow-up beyond 12 months was performed in a subgroup of patients. The median duration of follow-up from baseline was [placebo] 24.2 months (interquartile range, 18.4 to 30.3) and [levothyroxine] 24.5 months (interquartile range, 18.4 to 30.5).
    End point values
    		 Placebo Levothyroxine
    Number of subjects analysed
    187
    194
    Units: mm Hg
        arithmetic mean (standard deviation)
    72.3 ± 11.4
    72.0 ± 11.5
    Statistical analysis title
    		 Diastolic blood pressure Extended follow-up
    Comparison groups
    Placebo v Levothyroxine
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.59
    Method
    		 Regression, Linear
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: Body Mass Index Extended follow-up

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    End point title
    		 Body Mass Index Extended follow-up
    End point description
    End point type
    Secondary
    End point timeframe
    Extended follow-up beyond 12 months was performed in a subgroup of patients. The median duration of follow-up from baseline was [placebo] 24.2 months (interquartile range, 18.4 to 30.3) and [levothyroxine] 24.5 months (interquartile range, 18.4 to 30.5).
    End point values
    		 Placebo Levothyroxine
    Number of subjects analysed
    187
    194
    Units: BMI
        arithmetic mean (standard deviation)
    27.2 ± 4.5
    27.9 ± 4.9
    Statistical analysis title
    		 Body Mass Index Extended follow-up
    Comparison groups
    Placebo v Levothyroxine
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3
    Method
    		 Regression, Linear
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Secondary: Waist circumference Extended follow-up

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    End point title
    		 Waist circumference Extended follow-up
    End point description
    End point type
    Secondary
    End point timeframe
    Extended follow-up beyond 12 months was performed in a subgroup of patients. The median duration of follow-up from baseline was [placebo] 24.2 months (interquartile range, 18.4 to 30.3) and [levothyroxine] 24.5 months (interquartile range, 18.4 to 30.5).
    End point values
    		 Placebo Levothyroxine
    Number of subjects analysed
    187
    194
    Units: cm
        arithmetic mean (standard deviation)
    96.0 ± 13.8
    97.6 ± 13.4
    Statistical analysis title
    		 Waist circumference Extended follow-up
    Comparison groups
    Placebo v Levothyroxine
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.66
    Method
    		 Regression, Linear
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Other pre-specified: Thyrotropin 12 months

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    End point title
    		 Thyrotropin 12 months
    End point description
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    		 Placebo Levothyroxine
    Number of subjects analysed
    320
    318
    Units: mIU/L
        arithmetic mean (standard deviation)
    5.48 ± 2.48
    3.63 ± 2.11
    Statistical analysis title
    		 Thyrotropin
    Statistical analysis description
    Between group difference at 12 months
    Comparison groups
    Placebo v Levothyroxine
    Number of subjects included in analysis
    638
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Repeated measures regression
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Other pre-specified: Hyperthyroid Symptoms score 12 months

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    End point title
    		 Hyperthyroid Symptoms score 12 months
    End point description
    The score on the Hyperthyroid Symptoms scale was recorded as a measure of possible adverse effects (on a scale from 0 to 100, with higher scores indicating more symptoms; minimum clinically important difference has been estimated as 9 points).
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    		 Placebo Levothyroxine
    Number of subjects analysed
    320
    318
    Units: Score
        arithmetic mean (standard deviation)
    10.3 ± 11.3
    10.5 ± 10.8
    Statistical analysis title
    		 Hyperthyroid Symptoms score
    Comparison groups
    Placebo v Levothyroxine
    Number of subjects included in analysis
    638
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.35
    Method
    		 Regression, Linear
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Other pre-specified: Thyrotropin Extended follow-up

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    End point title
    		 Thyrotropin Extended follow-up
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Extended follow-up beyond 12 months was performed in a subgroup of patients. The median duration of follow-up from baseline was [placebo] 24.2 months (interquartile range, 18.4 to 30.3) and [levothyroxine] 24.5 months (interquartile range, 18.4 to 30.5).
    End point values
    		 Placebo Levothyroxine
    Number of subjects analysed
    187
    194
    Units: mIU/L
        arithmetic mean (standard deviation)
    5.28 ± 2.50
    3.47 ± 2.08
    Statistical analysis title
    		 Thyrotropin Extended follow-up
    Comparison groups
    Placebo v Levothyroxine
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Linear
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Other pre-specified: Hyperthyroid Symptoms score Extended follow-up

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    End point title
    		 Hyperthyroid Symptoms score Extended follow-up
    End point description
    End point type
    Other pre-specified
    End point timeframe
    Extended follow-up beyond 12 months was performed in a subgroup of patients. The median duration of follow-up from baseline was [placebo] 24.2 months (interquartile range, 18.4 to 30.3) and [levothyroxine] 24.5 months (interquartile range, 18.4 to 30.5).
    End point values
    		 Placebo Levothyroxine
    Number of subjects analysed
    187
    194
    Units: Score
        arithmetic mean (standard deviation)
    9.8 ± 11.0
    11.1 ± 11.7
    Statistical analysis title
    		 Hyperthyroid Symptoms score Extended follow-up
    Comparison groups
    Placebo v Levothyroxine
    Number of subjects included in analysis
    381
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.46
    Method
    		 Regression, Linear
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs that occur at any time after the inclusion of the subject in the study (defined as the time when the subject signs the informed consent) up to 30 days after the subject completed or discontinued the study will be reported.
    Adverse event reporting additional description
    Adverse events of special interest (atrial fibrillation, heart failure, fracture, or new diagnosis of osteoporosis)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Placebo group
    Reporting group description
    		 -

    Reporting group title
    Levothyroxine group
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo group Levothyroxine group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    103 / 369 (27.91%)
    78 / 368 (21.20%)
         number of deaths (all causes)
    5
    10
         number of deaths resulting from adverse events
    General disorders and administration site conditions
    ≥1 serious adverse event
    Additional description: All systems
         subjects affected / exposed
    103 / 369 (27.91%)
    78 / 368 (21.20%)
         occurrences causally related to treatment / all
    0 / 201
    0 / 142
         deaths causally related to treatment / all
    0 / 5
    0 / 10
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo group Levothyroxine group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 369 (8.40%)
    26 / 368 (7.07%)
    Cardiac disorders
    Atrial fibrillation
    Additional description: New onset
         subjects affected / exposed
    13 / 369 (3.52%)
    11 / 368 (2.99%)
         occurrences all number
    24
    24
    Cardiac failure
         subjects affected / exposed
    6 / 369 (1.63%)
    3 / 368 (0.82%)
         occurrences all number
    9
    9
    Musculoskeletal and connective tissue disorders
    Fracture
         subjects affected / exposed
    8 / 369 (2.17%)
    9 / 368 (2.45%)
         occurrences all number
    17
    17
    Osteoporosis
    Additional description: New diagnosis
         subjects affected / exposed
    4 / 369 (1.08%)
    3 / 368 (0.82%)
         occurrences all number
    7
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Oct 2012
    Increase of TSH monitoring Reduction of starting dose to 25ug for some participants Change to 2 questionnaires Tablets rather than capsules Other minor changes
    21 Feb 2014
    Additional question to Thyrpro Lab flag BP time changed from baseline to screen
    14 Mar 2014
    Addition of UK research site
    11 Jul 2014
    Notification of new manufacturing sites
    22 Oct 2015
    Revision to projected recruitment numbers Protocol revision to reflect updated SmPC
    19 Jan 2016
    Inclusion of ThyPRO thyroid-specific quality of life assessment tool at final study visit.
    24 Mar 2016
    Details provided of process of patient and GP unblinding, and standard format notification letters

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28402245
    For support, Contact us.
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