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    Clinical Trial Results:
    THYRoxine in Acute Myocardial Infarction (ThyrAMI)

    Summary
    EudraCT number
    		 2014-001369-28
    Trial protocol
    		 GB  
    Global end of trial date
    10 Dec 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 May 2020
    First version publication date
    01 May 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    880
    Additional study identifiers
    ISRCTN number
    		 ISRCTN52505169
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 University Ref: BH120110
    Sponsors
    Sponsor organisation name
    Gateshead Health NHS Foundation Trust
    Sponsor organisation address
    Queen Elizabeth Avenue, Sheriff Hill, Gateshead, United Kingdom, NE9 6SX
    Public contact
    Salman Razvi, Gateshead Health NHS Foundation Trust, 44 01914456052, salman.razvi@nhs.net
    Scientific contact
    Salman Razvi, Gateshead Health NHS Foundation Trust, 44 01914456052, salman.razvi@nhs.net
    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
    10 Dec 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Dec 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    ThyrAMI-1: whether thyroid function at the time of heart attack is related to poorer heart disease outcomes. ThyrAMI-2: to determine whether treatment of underactive thyroid with Levothyroxine following a heart attack improves heart muscle function. The proposed sample size for ThyraAMI-1 (the observational study) was 2000 to 3000 participants and for ThyrAMI-2 (the RCT) 90 to 100 participants. This report give the results for the randomised controlled trial which commenced recruitment in February 2015.
    Protection of trial subjects
    ThyrAMI-1 was an observational study. In ThyrAMI-2 any potential side effects of the IMP were described in the Participant Information Sheet and additionally explained during the consenting procedure. Levothyroxine is the treatment of choice for hypothyroidism and was not expected to cause any major side effects. Furthermore, the initial dose was low and was titrated by close monitoring of the participant's thyroid function. Patient safety was monitored throughout study participation. All adverse events were recorded in patient notes and the electronic case report form. Additionally, any serious adverse events were specifically recorded and faxed using a secure electronic system, to the Chief Investigator and appropriate Newcastle Clinical Trials Unit staff and the Sponsor. In addition, an independent Data Monitoring and Efficacy Committee had oversight of the data generated from the trial on a regular basis.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Feb 2015
    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: 95
    Worldwide total number of subjects
    95
    EEA total number of subjects
    95
    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)
    54
    From 65 to 84 years
    41
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Eligible participants were identified from acute hospitals. All individuals that matched the study criteria were approached, provided with a participant information sheet and informed consent obtained. Recruitment to ThyrAMI-2 took place between February 2015 and December 2016.

    Pre-assignment
    Screening details
    		 314 patients were screened for eligibility. 219 were excluded: TSH normalised 127; Refused 81; Contra Indication to MRI 3; Other interventional studies 8

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Assignment to either the LT4 or placebo arm was blinded to the participant as well as study team (double-blind). The principal investigator at each site had the primary right to code assignment without the requirement to discuss breaking the code with the sponsor for a patient at their site.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Levothyroxine
    Arm description
    		 Baseline
    Arm type
    		 Experimental

    Investigational medicinal product name
    Levothyroxine
    Investigational medicinal product code
    Other name
    Eltroxin, LT4
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Initial starting dose of LT4 will always be 25 mcg daily. To achieve the desired target TSH levels in the LT4 treated group (target TSH levels 0.5 – 2.5 mU/L), participants had their TSH levels checked regularly and concomitant dose of their LT4 altered by 25 mcg daily, if required. The IMP was provided as 5 week supplies of LT4 or matching placebo (dispensed separately at each visit), packaged into appropriate individual bottles (polypropylene).

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Individuals in this group were given a fresh bottle of IMP starting at 4, 8, 12, 24 +/- 7 days after blood tests, to maintain the double blind.

    Number of subjects in period 1
    		Levothyroxine Placebo
    Started
    46
    49
    Completed
    46
    49
    Period 2
    Period 2 title
    52 weeks
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Levothyroxine
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Levothyroxine
    Investigational medicinal product code
    Other name
    Eltroxin, LT4
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Initial starting dose of LT4 will always be 25 mcg daily. To achieve the desired target TSH levels in the LT4 treated group (target TSH levels 0.5 – 2.5 mU/L), participants had their TSH levels checked regularly and concomitant dose of their LT4 altered by 25 mcg daily, if required. The IMP was provided as 5 week supplies of LT4 or matching placebo (dispensed separately at each visit), packaged into appropriate individual bottles (polypropylene).

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Individuals in this group were given a fresh bottle of IMP starting at 4, 8, 12, 24 +/- 7 days after blood tests, to maintain the double blind.

    Number of subjects in period 2
    		Levothyroxine Placebo
    Started
    46
    49
    Completed
    39
    46
    Not completed
    7
    3
         High BMI
    1
    -
         Claustrophobia
    2
    1
         Poor image quality
    2
    -
         Died
    1
    1
         Withdrew
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Levothyroxine
    Reporting group description
    		 Baseline

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Levothyroxine Placebo Total
    Number of subjects
    		 46 49 95
    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
    Units: years
        arithmetic mean (standard deviation)
    		 64.1 ± 9.4 62.9 ± 9.7 -
    Gender categorical
    Units: Subjects
        Female
    		 10 13 23
        Male
    		 36 36 72
    Smoking status
    Units: Subjects
        Current smokers
    		 14 11 25
        Ex-smokers
    		 21 16 37
        Non-smokers
    		 10 22 32
        Missing
    		 1 0 1
    Diabetes mellitus
    Units: Subjects
        Yes
    		 8 10 18
        No
    		 38 39 77
    Hypercholesterolaemia
    Units: Subjects
        Yes
    		 13 14 27
        No
    		 33 35 68
    Cerebrovascular disease
    Units: Subjects
        Yes
    		 2 3 5
        No
    		 44 46 90
    Hypertension
    Units: Subjects
        Yes
    		 18 19 37
        No
    		 28 30 58
    Previous ischaemic heart disease
    Units: Subjects
        Yes
    		 8 6 14
        No
    		 38 43 81
    Coronary artery affected
    Baseline angioplasty characteristics by treatment allocation
    Units: Subjects
        Left main stem
    		 0 2 2
        LAD
    		 11 18 29
        RCA
    		 22 23 45
        Circumflex
    		 7 5 12
        Other
    		 5 1 6
        Not recorded
    		 1 0 1
    TIMI Flow pre-PCI
    Baseline angioplasty characteristics by treatment allocation
    Units: Subjects
        Grade 0
    		 10 12 22
        Grade 1
    		 5 9 14
        Grade 2
    		 17 17 34
        Grade 3
    		 13 11 24
        Not recorded
    		 1 0 1
    TIMI Flow post-PCI
    Baseline angioplasty characteristics by treatment allocation
    Units: Subjects
        Grade 2
    		 3 2 5
        Grade 3
    		 42 47 89
        Not recorded
    		 1 0 1
    Use of Glycoprotein 3b2a inhibitor
    Baseline angioplasty characteristics by treatment allocation
    Units: Subjects
        Yes
    		 21 20 41
        No
    		 25 29 54
    Subsequent staged PCI procedure
    Baseline angioplasty characteristics by treatment allocation
    Units: Subjects
        Yes
    		 5 9 14
        No
    		 41 40 81
    Drug eluting stent used during PCI
    Baseline angioplasty characteristics by treatment allocation
    Units: Subjects
        Yes
    		 40 46 86
        No
    		 6 3 9
    Systolic BP
    Units: mmHg
        arithmetic mean (standard deviation)
    		 127 ± 16.3 126.3 ± 17.5 -
    Diastolic BP
    Units: mmHg
        arithmetic mean (standard deviation)
    		 76 ± 8.6 73.8 ± 10.6 -
    Heart rate
    Units: bpm
        arithmetic mean (standard deviation)
    		 60.1 ± 9.5 62.6 ± 9.2 -
    TSH
    Units: mU/L
        median (inter-quartile range (Q1-Q3))
    		 5.75 (4.95 to 7.05) 5.7 (4.7 to 7.3) -
    FT4
    Units: pmol/L
        arithmetic mean (standard deviation)
    		 14.7 ± 2.1 14.6 ± 2.5 -
    FT3
    Units: pmol/L
        arithmetic mean (standard deviation)
    		 4.6 ± 0.8 4.4 ± 0.6 -
    Serum creatinine
    Units: umol/dl
        arithmetic mean (standard deviation)
    		 93.0 ± 36.5 96.9 ± 66.2 -
    Total cholesterol
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 4.8 ± 1.3 4.8 ± 1.2 -
    Total ischaemia time
    Total ischaemia time for STEMI patients only
    Units: minutes
        median (inter-quartile range (Q1-Q3))
    		 120 (81 to 172) 137 (72 to 209) -

    End points

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    End points reporting groups
    Reporting group title
    Levothyroxine
    Reporting group description
    		 Baseline

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

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: LVEF

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    End point title
    		 LVEF
    End point description
    Change in left ventricular ejection fraction at 52 weeks, calculated from baseline and 52 week value.
    End point type
    Primary
    End point timeframe
    52 weeks
    End point values
    		 Levothyroxine Placebo Levothyroxine Placebo
    Number of subjects analysed
    39 [1]
    46 [2]
    39 [3]
    46 [4]
    Units: percent volume/volume
        arithmetic mean (standard deviation)
    51.3 ± 9.1
    54.0 ± 7.9
    53.8 ± 9.7
    56.1 ± 7.9
    Notes
    [1] - Baseline
    [2] - Baseline
    [3] - 52 weeks
    [4] - 52 weeks
    Statistical analysis title
    		 Adjusted difference between LT4 and placebo
    Comparison groups
    Levothyroxine v Placebo
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.37
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.93
         upper limit
    		 2.46

    Secondary: LV volumes and function: EDV/BSA

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    End point title
    		 LV volumes and function: EDV/BSA
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Levothyroxine Placebo Levothyroxine Placebo
    Number of subjects analysed
    39 [5]
    46 [6]
    39 [7]
    46 [8]
    Units: ml/m2
        arithmetic mean (standard deviation)
    68.6 ± 17.2
    70.5 ± 13.8
    66.7 ± 16.6
    70.4 ± 13.1
    Notes
    [5] - Baseline
    [6] - Baseline
    [7] - 52 weeks
    [8] - 52 weeks
    Statistical analysis title
    		 Adjusted difference between LT4 and placebo
    Statistical analysis description
    Primary and secondary outcomes were compared using linear regression adjusting for age, sex type of AMI, and baseline values.
    Comparison groups
    Levothyroxine v Placebo
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.08
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -4.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.03
         upper limit
    		 0.49

    Secondary: LV volumes and function: ESV/BSA

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    End point title
    		 LV volumes and function: ESV/BSA
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Levothyroxine Placebo Levothyroxine Placebo
    Number of subjects analysed
    39 [9]
    46 [10]
    39 [11]
    46 [12]
    Units: ml/m2
        arithmetic mean (standard deviation)
    34.4 ± 14.1
    32.9 ± 9.9
    31.1 ± 12.1
    31.4 ± 10.2
    Notes
    [9] - Baseline
    [10] - Baseline
    [11] - 52 weeks
    [12] - 52 weeks
    Statistical analysis title
    		 Adjusted difference between LT4 and placebo
    Statistical analysis description
    Primary and secondary outcomes were compared using linear regression adjusting for age, sex type of AMI, and baseline values.
    Comparison groups
    Levothyroxine v Placebo
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.11
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.46
         upper limit
    		 0.58

    Secondary: LV volumes and function: Stroke volume

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    End point title
    		 LV volumes and function: Stroke volume
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Levothyroxine Placebo Levothyroxine Placebo
    Number of subjects analysed
    39 [13]
    46 [14]
    39 [15]
    46 [16]
    Units: ml
        arithmetic mean (standard deviation)
    67.2 ± 13.1
    68.7 ± 16.1
    75.4 ± 16.7
    78.9 ± 15.9
    Notes
    [13] - Baseline
    [14] - Baseline
    [15] - 52 weeks
    [16] - 52 weeks
    Statistical analysis title
    		 Adjusted difference between LT4 and placebo
    Statistical analysis description
    Primary and secondary outcomes were compared using linear regression adjusting for age, sex type of AMI, and baseline values.
    Comparison groups
    Placebo v Levothyroxine
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.45
         upper limit
    		 0.94

    Secondary: LV volumes and function: Stroke index

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    End point title
    		 LV volumes and function: Stroke index
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Levothyroxine Placebo Levothyroxine Placebo
    Number of subjects analysed
    39 [17]
    46 [18]
    39 [19]
    46 [20]
    Units: ml/m2
        arithmetic mean (standard deviation)
    34.4 ± 6.6
    37.6 ± 7.9
    34.9 ± 7.8
    38.9 ± 6.9
    Notes
    [17] - Baseline
    [18] - Baseline
    [19] - 52 weeks
    [20] - 52 weeks
    Statistical analysis title
    		 Adjusted difference between LT4 and placebo
    Statistical analysis description
    Primary and secondary outcomes were compared using linear regression adjusting for age, sex type of AMI, and baseline values.
    Comparison groups
    Levothyroxine v Placebo
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.15
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.11
         upper limit
    		 0.64

    Secondary: LV volumes and function: Cardiac output

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    End point title
    		 LV volumes and function: Cardiac output
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Levothyroxine Placebo Levothyroxine Placebo
    Number of subjects analysed
    39 [21]
    46 [22]
    39 [23]
    46 [24]
    Units: L/min
        arithmetic mean (standard deviation)
    3.9 ± 0.7
    4.6 ± 1.1
    4.1 ± 0.87
    4.6 ± 0.96
    Notes
    [21] - Baseline
    [22] - Baseline
    [23] - 52 weeks
    [24] - 52 weeks
    Statistical analysis title
    		 Adjusted difference between LT4 and placebo
    Statistical analysis description
    Primary and secondary outcomes were compared using linear regression adjusting for age, sex type of AMI, and baseline values.
    Comparison groups
    Levothyroxine v Placebo
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.38
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.47
         upper limit
    		 0.18

    Secondary: LV volumes and function: Cardiac index

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    End point title
    		 LV volumes and function: Cardiac index
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Levothyroxine Placebo Levothyroxine Placebo
    Number of subjects analysed
    39 [25]
    46 [26]
    39 [27]
    46 [28]
    Units: L/min/m2
        arithmetic mean (standard deviation)
    2.0 ± 0.3
    2.3 ± 0.5
    2.1 ± 0.43
    2.3 ± 0.38
    Notes
    [25] - Baseline
    [26] - Baseline
    [27] - 52 weeks
    [28] - 52 weeks
    Statistical analysis title
    		 Adjusted difference between LT4 and placebo
    Statistical analysis description
    Primary and secondary outcomes were compared using linear regression adjusting for age, sex type of AMI, and baseline values.
    Comparison groups
    Levothyroxine v Placebo
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.39
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.22
         upper limit
    		 0.09

    Secondary: Infarct size

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    End point title
    		 Infarct size
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Levothyroxine Placebo Levothyroxine Placebo
    Number of subjects analysed
    30 [29]
    30 [30]
    30 [31]
    30 [32]
    Units: gms
        median (inter-quartile range (Q1-Q3))
    7.9 (2.5 to 20.3)
    8.9 (1.9 to 16.1)
    5.6 (1.3 to 15.2)
    7.0 (1.0 to 13.3)
    Notes
    [29] - Baseline
    [30] - Baseline
    [31] - 52 weeks
    [32] - 52 weeks
    Statistical analysis title
    		 Adjusted difference between LT4 and placebo
    Comparison groups
    Levothyroxine v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.77
    Method
    		 Regression, Linear
    Parameter type
    		 Median difference (final values)
    Point estimate
    0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.31
         upper limit
    		 1.77

    Secondary: LV mass

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    End point title
    		 LV mass
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Levothyroxine Placebo Levothyroxine Placebo
    Number of subjects analysed
    30 [33]
    30 [34]
    30 [35]
    30 [36]
    Units: gms
        arithmetic mean (standard deviation)
    106.4 ± 33.4
    102.1 ± 22.9
    99.2 ± 29.9
    94.0 ± 18.2
    Notes
    [33] - Baseline
    [34] - Baseline
    [35] - 52 weeks
    [36] - 52 weeks
    Statistical analysis title
    		 Adjusted difference between LT4 and placebo
    Comparison groups
    Levothyroxine v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.54
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.43
         upper limit
    		 8.37

    Secondary: Infarct size

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    End point title
    		 Infarct size
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Levothyroxine Placebo Levothyroxine Placebo
    Number of subjects analysed
    30 [37]
    30 [38]
    30 [39]
    30 [40]
    Units: percentage
        median (inter-quartile range (Q1-Q3))
    7.8 (2.7 to 14.7)
    8.5 (1.7 to 16.2)
    5.8 (2.1 to 12.9)
    8.4 (1.0 to 14.8)
    Notes
    [37] - Baseline
    [38] - Baseline
    [39] - 52 weeks
    [40] - 52 weeks
    Statistical analysis title
    		 Adjusted difference between LT4 and placebo
    Comparison groups
    Levothyroxine v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.98
    Method
    		 Regression, Linear
    Parameter type
    		 Median difference (final values)
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.34
         upper limit
    		 1.38

    Secondary: SF12 Physical

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    End point title
    		 SF12 Physical
    End point description
    SF12 - Short Form Health status questionnaire. Physical: scores range from 10 to 56, with higher scores indicating better physical health.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Levothyroxine Placebo Levothyroxine Placebo
    Number of subjects analysed
    45 [41]
    49 [42]
    45 [43]
    49 [44]
    Units: Scale score
        arithmetic mean (standard deviation)
    39.9 ± 10.6
    38.5 ± 10.9
    46 ± 10.1
    45.6 ± 10.6
    Notes
    [41] - Baseline
    [42] - Baseline
    [43] - 52 weeks
    [44] - 52 weeks
    Statistical analysis title
    		 Adjusted difference between LT4 and placebo
    Comparison groups
    Levothyroxine v Placebo
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.95
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.54
         upper limit
    		 4.23

    Secondary: SF12 Mental

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    End point title
    		 SF12 Mental
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Levothyroxine Placebo Levothyroxine Placebo
    Number of subjects analysed
    45 [45]
    49 [46]
    45 [47]
    49 [48]
    Units: Scale score
        arithmetic mean (standard deviation)
    49.6 ± 10.5
    38.5 ± 10.9
    50.4 ± 11.7
    52.8 ± 7.9
    Notes
    [45] - Baseline
    [46] - Baseline
    [47] - 52 weeks
    [48] - 52 weeks
    Statistical analysis title
    		 Adjusted difference between LT4 and placebo
    Comparison groups
    Levothyroxine v Placebo
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.16
    Method
    		 Regression, Linear
    Parameter type
    		 Median difference (final values)
    Point estimate
    -3.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.3
         upper limit
    		 1.24

    Secondary: MLWHF

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    End point title
    		 MLWHF
    End point description
    MLWHF - Minnesota Living With Heart Failure Questionnaire Scores range from 0 to 105, with higher scores indicating increase in symptoms of heart failure.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Levothyroxine Placebo Levothyroxine Placebo
    Number of subjects analysed
    45 [49]
    49 [50]
    45 [51]
    49 [52]
    Units: Scale score
        median (inter-quartile range (Q1-Q3))
    27.0 (12.3 to 40)
    23.0 (11.5 to 37.5)
    13.0 (6.8 to 24.3)
    15.0 (6.0 to 30.0)
    Notes
    [49] - Baseline
    [50] - Baseline
    [51] - 52 weeks
    [52] - 52 weeks
    Statistical analysis title
    		 Adjusted difference between LT4 and placebo
    Comparison groups
    Levothyroxine v Placebo
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.28
    Method
    		 Regression, Linear
    Parameter type
    		 Median difference (final values)
    Point estimate
    -3.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.6
         upper limit
    		 3.08

    Secondary: CESD

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    End point title
    		 CESD
    End point description
    CESD: Centre for Epidemiologic Studies Depression Scale. Scores range from 0 to 60, with higher scores indicating greater depressive symptoms.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Levothyroxine Placebo Levothyroxine Placebo
    Number of subjects analysed
    45 [53]
    49 [54]
    45 [55]
    49 [56]
    Units: Scale score
        median (inter-quartile range (Q1-Q3))
    9.0 (4.0 to 16.0)
    8.0 (2.5 to 15.0)
    10.0 (2.0 to 18.0)
    5.0 (2.0 to 14.0)
    Notes
    [53] - Baseline
    [54] - Baseline
    [55] - 52 weeks
    [56] - 52 weeks
    Statistical analysis title
    		 Adjusted difference between LT4 and placebo
    Comparison groups
    Levothyroxine v Placebo
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Regression, Linear
    Parameter type
    		 Median difference (final values)
    Point estimate
    3.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 6.27

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Any serious adverse events were recorded throughout the duration of the trial until week 52 (+/- 3 days).
    Adverse event reporting additional description
    All non-serious adverse events were recorded at the follow-up visits 2 – 6.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Study specific
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Levothyroxine
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Levothyroxine Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 46 (15.22%)
    9 / 49 (18.37%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Cardiovascular events
         subjects affected / exposed
    2 / 46 (4.35%)
    5 / 49 (10.20%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Non-cardiovascular events
         subjects affected / exposed
    5 / 46 (10.87%)
    4 / 49 (8.16%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Levothyroxine Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 46 (78.26%)
    41 / 49 (83.67%)
    Cardiac disorders
    Cardiovascular events
         subjects affected / exposed
    12 / 46 (26.09%)
    17 / 49 (34.69%)
         occurrences all number
    15
    18
    General disorders and administration site conditions
    Non-cardiovascular events
         subjects affected / exposed
    24 / 46 (52.17%)
    24 / 49 (48.98%)
         occurrences all number
    32
    27

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Nov 2014
    Addition of a second Product Licence (PL) Number for Levothyroxine 50 mcg tablets (PL16201/0001) Correction of a typographical error in the PL number for Levothyroxine 25 mcg, in the IMPD: PL12672/0016, corrected to PL12762/0016 Removal of the Product Licence Numbers from the trial protocol
    13 Mar 2015
    Change of PI at the Sunderland trial site.
    30 Mar 2015
    Change to inclusion/exclusion criteria for Thyrami-2 (protocol sections 15.1 & 15.2) Clarification of pharmacy unit which holds IMP bottle number allocation list to confirm site pharmacies remain blinded (protocol section 17.2) Removal of reference to code break envelopes (protocol section 19) Clarification and a point of consistency required for one of the non-clinical procedures in section A18 of the original REC form GP information letter amended to reflect changes to inclusion/exclusion criteria ISRCTN number added to protocol CSP reference added to protocol Minor administrative changes
    08 Jun 2015
    Addition of site – Leeds General Infirmary Removal of reference to Newcastle MR centre and RVI Clincal Research Facility in the PIS/ICF and protocol, in view of the addition of Leeds Reference to procedures only carried out at Newcastle and requirement of participants who are unable to attend Newcastle or have procedures locally to sign partial withdrawal form Minor administrative changes
    17 Aug 2015
    Additional of South Tees Hospital site.
    13 Jan 2016
    • Inclusion of ThyrAMI-1 genetic sub-study • New study documents relating to ThyrAMI-1 genetic sub-study • ThyrAMI-1 GP letter • Removal of pulse oximetry as ThyrAMI-2 study procedure • Clarification the Reference Safety Information for the study • Removal of SmPCs from protocol appendix • Minor administrative amendments

    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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