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    Clinical Trial Results:
    A Randomised Controlled Trial of the Efficacy and Mechanism of Levothyroxine Treatment on Pregnancy and Neonatal Outcomes in Women with Thyroid Antibodies. (TABLET: Thyroid AntiBodies and LEvoThyroxine Study)

    Summary
    EudraCT number
    2011-000719-19
    Trial protocol
    GB  
    Global end of trial date
    14 Jan 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    30 Jun 2019
    First version publication date
    30 Jun 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    09/100/10
    Additional study identifiers
    ISRCTN number
    ISRCTN15948785
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Birmingham
    Sponsor organisation address
    Room 119, Aston Webb Building, Edgbaston, Birmingham, United Kingdom, B15 2TT
    Public contact
    Prof Arri Coomarasamy, University of Birmingham, +44 (0)121 627 2775, a.coomarasamy@bham.ac.uk
    Scientific contact
    Prof Arri Coomarasamy, University of Birmingham, +44 (0)121 627 2775, a.coomarasamy@bham.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
    27 Sep 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To test the hypothesis that in women with normal thyroid function but with thyroid peroxidase antibodies (TPO), levothyroxine (50mcg, oral, once daily), started pre-conceptually and continued to the end of pregnancy, compared with placebo, increases the proportion of women who attain a live birth beyond 34 completed weeks of gestation by at least 10%.
    Protection of trial subjects
    No special measures were required to minimise pain or distress in this patient population.
    Background therapy
    A systematic review of 31 studies involving euthyroid women showed a strong association between the presence of thyroid peroxidase antibodies and miscarriage (odds ratio, 3.90; 95% confidence interval [CI], 2.48 to 6.12; P<0.001) and preterm birth (odds ratio, 2.07; 95% CI, 1.17 to 3.68; P = 0.01). Studies included in the systematic review involved women with recurrent miscarriage, infertile women, and unselected populations. The 2017 guidelines of the American Thyroid Association stated that “insufficient evidence exists to conclusively determine whether LT4 [levothyroxine] therapy decreases pregnancy loss risk in TPOAb-positive [thyroid peroxidase antibody–positive] euthyroid women who are newly pregnant” and recommended that “administration of LT4 to TPOAb-positive euthyroid pregnant women with a . . . history of loss may be considered given its potential benefits in comparison with its minimal risk.” The guideline task force drew attention to our ongoing trial. We designed the multicenter, randomized, placebo-controlled Thyroid Antibodies and Levothyroxine (TABLET) trial to investigate whether the use of levothyroxine would increase the rates of live births after at least 34 weeks of gestation among euthyroid women with thyroid peroxidase antibodies.
    Evidence for comparator
    Participants were randomly assigned in a 1:1 ratio to receive oral capsules containing either 50 μg of levothyroxine or matched placebo once a day. Administration of the trial agents began immediately after randomization. The appearance, route, and timing of the administration of the trial agents were identical in the two groups. Throughout the duration of the trial, the participants, clinicians, and trial nurses were unaware of the trial-group assignments.
    Actual start date of recruitment
    01 Sep 2011
    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: 952
    Worldwide total number of subjects
    952
    EEA total number of subjects
    952
    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)
    952
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The participants were recruited from 49 hospitals across the United Kingdom. 1420 were eligible for enrollment in the trial, of whom 952 consented to participate and were randomly assigned to receive either levothyroxine (476 women) or placebo (476 women).

    Pre-assignment
    Screening details
    A total of 19,556 women underwent tests to detect thyroid peroxidase antibodies and thyroid-function tests between December 2011 and January 2016. Of these women, 1420 were eligible for enrollment in the trial, of whom 952 consented to participate and were randomly assigned to receive either levothyroxine (476 women) or placebo (476 women).

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Levothyroxine
    Arm description
    50 μg of levothyroxine once a day.
    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
    oral capsules containing 50 μg of levothyroxine taken once a day.

    Arm title
    Placebo
    Arm description
    Oral placebo taken once a day.
    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
    Oral placebo capsules taken once a day.

    Number of subjects in period 1
    Levothyroxine Placebo
    Started
    476
    476
    Completed
    470
    470
    Not completed
    6
    6
         Lost to follow-up
    6
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Levothyroxine
    Reporting group description
    50 μg of levothyroxine once a day.

    Reporting group title
    Placebo
    Reporting group description
    Oral placebo taken once a day.

    Reporting group values
    Levothyroxine Placebo Total
    Number of subjects
    476 476 952
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    476 476 952
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    32.5 ± 4.9 32.7 ± 4.9 -
    Gender categorical
    Units: Subjects
        Female
    476 476 952
        Male
    0 0 0
    Ethnic group
    Units: Subjects
        White
    328 337 665
        Chinese
    4 4 8
        South Asian
    110 94 204
        Black
    16 23 39
        Other
    18 18 36
    Nulliparous
    Units: Subjects
        Nulliparous
    141 131 272
        Parous
    335 342 677
        Not recorded
    0 3 3
    Previous miscarriages
    Units: Subjects
        Zero
    166 165 331
        One or Two
    219 213 432
        Three or more
    91 95 186
        Not recorded
    0 3 3
    Previous preterm births at <34 wk
    Units: Subjects
        Yes
    11 10 21
        No
    465 463 928
        Not recorded
    0 3 3
    Current treatment for infertility
    Units: Subjects
        Yes
    216 213 429
        No
    260 263 523
    Serum thyrotropin level
    Units: Subjects
        ≤2.5 mIU/liter
    329 330 659
        >2.5 mIU/liter
    147 146 293
    BMI
    Units: BMI
        arithmetic mean (standard deviation)
    26.4 ± 5.6 26.5 ± 5.5 -
    No. of previous miscarriages in women with ≥1 miscarriage
    Units: No. of previous miscarriages
        median (inter-quartile range (Q1-Q3))
    2 (1 to 3) 2 (1 to 3) -
    No. of previous miscarriages - first-trimester miscarriage (<14 wk) in women with ≥1 miscarriage
    Units: No. of previous miscarriages
        median (inter-quartile range (Q1-Q3))
    2 (1 to 3) 2 (1 to 3) -
    Serum thyrotropin level
    Units: mIU/liter
        median (inter-quartile range (Q1-Q3))
    2.10 (1.51 to 2.74) 2.01 (1.45 to 2.70) -
    Serum thyrotropin level (level on Log scale)
    Units: mIU/liter
        arithmetic mean (standard deviation)
    0.674 ± 0.422 0.652 ± 0.418 -
    Mean serum free thyroxine level
    Units: pmol/liter
        arithmetic mean (standard deviation)
    14.6 ± 1.9 14.5 ± 2.0 -
    Median serum thyroid peroxidase antibody level
    Units: IU/ml
        median (inter-quartile range (Q1-Q3))
    170 (83 to 428) 202 (94 to 417) -

    End points

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    End points reporting groups
    Reporting group title
    Levothyroxine
    Reporting group description
    50 μg of levothyroxine once a day.

    Reporting group title
    Placebo
    Reporting group description
    Oral placebo taken once a day.

    Primary: Live birth ≥ 34 weeks

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    End point title
    Live birth ≥ 34 weeks
    End point description
    End point type
    Primary
    End point timeframe
    From randomization to pregnancy end
    End point values
    Levothyroxine Placebo
    Number of subjects analysed
    470
    470
    Units: Subjects
    176
    178
    Statistical analysis title
    Log-binomial regression
    Statistical analysis description
    For the primary outcome (live birth at ≥34 weeks of gestation), the trial population consisted of all participants who underwent randomization (intention-to-treat population). Log-binomial regression was used to generate relative risks, with adjustment for the minimization variable for all binary outcomes.
    Comparison groups
    Levothyroxine v Placebo
    Number of subjects included in analysis
    940
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.74
    Method
    Regression, Logistic
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.97
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.83
         upper limit
    1.14
    Variability estimate
    Standard deviation

    Secondary: Pregnancy at ≤12 mo after enrollment

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    End point title
    Pregnancy at ≤12 mo after enrollment
    End point description
    End point type
    Secondary
    End point timeframe
    Randomization to confirmation of pregnancy
    End point values
    Levothyroxine Placebo
    Number of subjects analysed
    470
    470
    Units: Subjects
    266
    274
    No statistical analyses for this end point

    Secondary: Clinical pregnancy at 7 wk

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    End point title
    Clinical pregnancy at 7 wk
    End point description
    End point type
    Secondary
    End point timeframe
    Randomization to pregnancy end
    End point values
    Levothyroxine Placebo
    Number of subjects analysed
    266
    274
    Units: Subjects
    237
    248
    No statistical analyses for this end point

    Secondary: Ongoing pregnancy at 12 wk

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    End point title
    Ongoing pregnancy at 12 wk
    End point description
    End point type
    Secondary
    End point timeframe
    Randomization to pregnancy end
    End point values
    Levothyroxine Placebo
    Number of subjects analysed
    266
    274
    Units: Subjects
    194
    200
    No statistical analyses for this end point

    Secondary: Miscarriage at <24 wk

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    End point title
    Miscarriage at <24 wk
    End point description
    End point type
    Secondary
    End point timeframe
    Randomization to pregnancy end
    End point values
    Levothyroxine Placebo
    Number of subjects analysed
    266
    274
    Units: Subjects
    75
    81
    No statistical analyses for this end point

    Secondary: Stillbirth: intrauterine death at ≥24 wk

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    End point title
    Stillbirth: intrauterine death at ≥24 wk
    End point description
    End point type
    Secondary
    End point timeframe
    Randomization to pregnancy end
    End point values
    Levothyroxine Placebo
    Number of subjects analysed
    266
    274
    Units: Subjects
    1
    0
    No statistical analyses for this end point

    Secondary: Ectopic pregnancy

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    End point title
    Ectopic pregnancy
    End point description
    End point type
    Secondary
    End point timeframe
    Randomization to pregnancy end
    End point values
    Levothyroxine Placebo
    Number of subjects analysed
    266
    274
    Units: Subjects
    3
    6
    No statistical analyses for this end point

    Secondary: Termination of pregnancy

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    End point title
    Termination of pregnancy
    End point description
    End point type
    Secondary
    End point timeframe
    Randomization to pregnancy end
    End point values
    Levothyroxine Placebo
    Number of subjects analysed
    266
    274
    Units: Subjects
    1
    0
    No statistical analyses for this end point

    Secondary: Live birth

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    End point title
    Live birth
    End point description
    End point type
    Secondary
    End point timeframe
    Randomization to pregnancy end
    End point values
    Levothyroxine Placebo
    Number of subjects analysed
    266
    274
    Units: Subjects
        At <34 wk
    10
    10
        At ≥34 wk
    176
    178
    No statistical analyses for this end point

    Secondary: Gestational age at delivery

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    End point title
    Gestational age at delivery
    End point description
    End point type
    Secondary
    End point timeframe
    Date of conception to pregnancy end
    End point values
    Levothyroxine Placebo
    Number of subjects analysed
    186
    188
    Units: Days
        arithmetic mean (standard deviation)
    272 ± 17
    273 ± 18
    No statistical analyses for this end point

    Secondary: Birth weight

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    End point title
    Birth weight
    End point description
    End point type
    Secondary
    End point timeframe
    Randomization to pregnancy end
    End point values
    Levothyroxine Placebo
    Number of subjects analysed
    187
    188
    Units: Grams
        arithmetic mean (standard deviation)
    3226 ± 660
    3262 ± 668
    No statistical analyses for this end point

    Secondary: Apgar score @ 1 minute

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    End point title
    Apgar score @ 1 minute
    End point description
    End point type
    Secondary
    End point timeframe
    Randomization to pregnancy end
    End point values
    Levothyroxine Placebo
    Number of subjects analysed
    179
    178
    Units: score
        median (inter-quartile range (Q1-Q3))
    9 (9 to 9)
    9 (8 to 9)
    No statistical analyses for this end point

    Secondary: Apgar score @ 5 minutes

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    End point title
    Apgar score @ 5 minutes
    End point description
    End point type
    Secondary
    End point timeframe
    Randomization to pregnancy end
    End point values
    Levothyroxine Placebo
    Number of subjects analysed
    178
    178
    Units: score
        median (inter-quartile range (Q1-Q3))
    9 (9 to 10)
    9 (9 to 10)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From randomisation to pregnancy end or from randomisation to the end of 12 months of attempted conception
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14
    Reporting groups
    Reporting group title
    Levothyroxine
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: No non-serious adverse events were reported at a rate greater than 5%.
    Serious adverse events
    Levothyroxine Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    29 / 470 (6.17%)
    18 / 470 (3.83%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Congenital, familial and genetic disorders
    Anencephaly
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 470 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Edward's syndrome
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 470 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neonatal tongue tie
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neonatal left sided duplex collecting system
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 470 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Anxiety
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 470 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain and vomiting
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest, back and stomach pains; shortness of breath
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 470 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Exacerbation of asthma
         subjects affected / exposed
    2 / 470 (0.43%)
    0 / 470 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Facial weakness and numbness
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 470 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache and rash
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 470 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache, vomiting and tachycardia
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 470 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Insomnia and anxiety
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 470 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 470 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abdominal pain
         subjects affected / exposed
    0 / 470 (0.00%)
    4 / 470 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abnormal antenatal scan
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back and epigastric pain
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Placenta pracina
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 470 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Missed miscarriage
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 470 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Per vaginal bleeding
         subjects affected / exposed
    1 / 470 (0.21%)
    2 / 470 (0.43%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post-partum haemorrhage
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right Iliac Fossa pain
         subjects affected / exposed
    1 / 470 (0.21%)
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Single fetal demise in twin pregnancy
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spontaneous rupture of membranes
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain and dysuria
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 470 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter infection
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 470 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    High blood pressure, nausea and vomiting
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 470 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 470 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 470 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgery
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 470 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Enlarged thyroid and thyroid cysts
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stage 1 papillary thyroid cancer
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 470 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Groin abscess
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 470 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 470 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Maternal sepsis
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neonatal sepsis
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    0 / 470 (0.00%)
    1 / 470 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post-caesaerean infection
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 470 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis and neonatal hypogycaemia
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 470 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 470 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound tenderness, pyrexia and malaise
         subjects affected / exposed
    1 / 470 (0.21%)
    0 / 470 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Levothyroxine Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 470 (0.00%)
    0 / 470 (0.00%)

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Jul 2011
    1. Protocol Version 2.0 Addition of members to steering committee and DMC. 2. Protocol Version 2.0 Addition of two further exclusion criteria. a) Women who intend to conceive using ovulation stimulation therapy. Women with ovulation stimulation treatment will have a very different hormonal milieu to those without ovarian stimulation. Thus the endocrinologists (and in fact one of the EME reviewers) suggested excluding these patients.b) Women with previous or current cardiac disease. Thyroxine has the effect of increasing heart rate, and will need to be carefully titrated in patients with cardiac disease. Thus this trial will not be suitable for them. 3. Protocol Version 2.0 Addition of Roche Cobas Analyser to specified Analysers for trial participation. 4. Protocol version 2.0 Additional appointment at 9 months post randomisation and pre-pregnancy to dispense a further 3 month supply of trial medication. This was previously covered by an appointment at 3 months post randomisation and pre pregnancy, where 6 months of medication was dispensed in one appointment. This extra appointment will overcome any potential problems involving drug expiry date of the IMP or Placebo and would also enable the trial investigators to meet with the participant and discuss any trial related issues. 5. Protocol version 2.0 Addition of collection of anonymised excess serum to be used for quality control purposes, and possible future analyses of other biomarkers, which we understand will require separate ethical approval. 6. Protocol Version 2.0 Minor changes in spelling, typos and table/section references.
    24 Nov 2011
    1. Protocol version 3.0 section 4.2 page 10 - In a double blind study there is no risk of foreknowledge, and therefore the sentence has been revised to read more clearly. 2. Protocol version 3.0 Section 5.1.4 page 11 - Revision of word "given" to "taken" as the capsule will be self-administered. The following sentence "A sheet giving instructions on how to take the capsules, and what to do if a capsule is missed, will be given to the participant at the randomisation appointment." has been inserted to inform of instructions sheet to take medication included in this submission. Deletion of sentence referring to attending clinician, as participant will be outpatient. 3. Protocol Version 3.0 section 5.3 page 12 re-arrangement of sentence - The Trial coordinator will monitor drug compliance with help from Pharmacy Accountability logs. 4. Protocol Version 3.0 section 8.3.1 Page 22 - removal of sentences "The Trial Statistician may be unblinded to the level of groups A and B. A and B will be made know to the DMC if appropriate" In section 5.5.3 the Trial Protocol does not specify statistician in the list of blinded people. In order to produce DMC reports at the A/B level, the trial Statistician would not be blinded. The following sentence has also been removed in line with this change.
    04 Apr 2012
    1.Target the Infertility population for screening and recruitment. 2.To increase the range of TFT analysers which are permitted for the trial. These are broadly the most frequently used analysers in the country. This will enable us to recruit from a wider range of centres. We have found that restricting to the Roche Analysers very limiting, meaning that other keen hospitals are not been given an opportunity to participate in the trial. The reference ranges for each analyser will be determined by the thyroid experts on the TMG. We feel that this change presents an opportunity to reflect the general UK population in the trial.To account for the variation in analysers we have also widened the Free T4 range Inclusion Criteria range to be between 10.0 to 21.0 pmol/L. 3.To allow for blood for screening to be taken at the first approach to the patient. (This is mainly at the request of the patients who would prefer their blood sample to be taken immediately with other bloods rather than having to return for a blood sample). 4.Removal of a DMC Member who has resigned from the trial DMC due to increasing trial commitments. (A replacement is being sought). 5.Listing specific examples of conditions which are not required to report an SAE.
    25 Sep 2014
    As timeframes for initial patient contact are short, and patients may be distressed, there are times when the patient is discharged before contact is made, even though they are aware of the trial. We wish to be able to contact the patient following discharge. We must exclude women with a current thyroid disorder, but do not want to exclude all women who have required only short-term treatment a significant time ago. It would be difficult to propose criteria for inclusion, so we propose that the small number of women who fall into this category are considered on a case by case basis, with discussion between the local PI and chief investigator. There is no safety reason to exclude these women. Patients who are initially screened for the trial are sometimes not contactable by telephone or will not answer calls from private numbers on their mobile phones. We wish to introduce a letter,to have the ability to contact patients with normal blood results by letter. We have introduced Patient Normal Results Letter v1.0 16/2/15 and amended the word "telephone" to "contact" in the Patient Screening Leaflet so it is now v5.0 16/2/15. Clarification that a trial number and treatment bottle are not allocated until all essential information is entered on to the randomisation database. We are explicitly mentioning that the randomisation algorithm will be minimised by centre. Given the study is double blind we do not believe this will be an issue. Adding the term pregnancy loss to clarify that all forms of pregnancy loss constitute an outcome of trial and that trial participation and trial drug use cease at this point. In a measure to gather good compliance data we are asking the trial participant a question on estimated percentage of time the IMP is taken, in addition to pill counting To clarify the clinical management of thyroid problems which are identified within the trial, we have re-worded some sections of the protocol and refer clinicians to guidance agreed by the TMG.
    24 Jun 2015
    Contents page amended to list Appendix I Summary of Product Characteristics. Section 6.1.4 changed wording. Appendix I changed wording to replace page on expected toxicities. Non Substantial Changes SmPC v3.0 24th June 2015 SmPC v4.0 25th June 2015 SmPC v5.0 26th June 2015
    13 Apr 2016
    Update the SmPC for the trial IMP Levothyroxine to 6.0
    31 Oct 2016
    Section: 4.2 update to the stratification variables. Sections: 5.1.3 clarification of the manufacturing authorisation holder to reflect the changes submitted in SA21.
    04 Oct 2017
    1.Update to the Trial Management Group. 2.Section 3.4.2 –Clarification to the exclusion criteria. 3.Section 5.1.1 -Clarification of safety assessments. 4.Section 5.1.3-Clarification on storage of IMP. 5.Section 5.2.1 –Clarification of treatment duration. 6.Section 5.3 –Clarification of compliance monitoring. 7.Section 5.5 –Clarification of withdrawal process. 8.Section 6.1.2/6.1.3/6.3/6.4 –Clarification of reporting SUSARs. 9.Section 7 –Clarification of follow up and secondary measures. 10.Section 8.1 –Clarification of primary outcome measure. 11.Section 8.3 –Clarification of statistical analysis. 12.Section 9.4 –Clarification of Date Monitoring and Ethics Committee. 13.Appendix I –updated SmPC for Levothyoxine.

    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/30907987
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