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    Clinical Trial Results:
    Combined Immunosuppression and Radiotherapy in Thyroid Eye Disease

    Summary
    EudraCT number
    		 2004-002547-27
    Trial protocol
    		 GB  
    Global end of trial date
    31 Dec 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Dec 2020
    First version publication date
    31 Dec 2020
    Other versions
    Summary report(s)
    		 Summary key variables
    Notes on CIRTED summary

    Trial information

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    Trial identification
    Sponsor protocol code
    OP/CD001
    Additional study identifiers
    ISRCTN number
    		 ISRCTN22471573
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Bristol
    Sponsor organisation address
    1 Cathedral Square, Bristol, United Kingdom, BS1 5DD
    Public contact
    Richard Lee, University of Bristol, +44 01173312020, richard.lee@bristol.ac.uk
    Scientific contact
    Richard Lee, University of Bristol, +44 01173312020, richard.lee@bristol.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
    01 Jun 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Test the hypotheses that in patients being treated with prednisolone for active Thyroid Eye Disease:1.RADIOTHERAPY (compared with placebo) induces early remission and reduces long-term disease severity.2.COMBINED SYSTEMIC IMMUNOSUPPRESSION WITH ORAL AZATHIOPRINE (compared with placebo) reduces long-term disease severity.
    Protection of trial subjects
    All treatments and assessments are used in routine NHS care, although substantial benefits of treatments were unclear. This trial was to assess whether either was superior and refine our knowledge of the potential benefits
    Background therapy
    		 Oral steroids in a reducing regime, given to all participants
    Evidence for comparator
    		 Factorial 2x2 design for radiotherapy and azathioprine. So radiotherapy was assessed against those not receiving radiotherapy. Azathioprine was assessed against those not receiving it. Interaction between azathioprine and radiotherapy was also assessed
    Actual start date of recruitment
    02 Jan 2006
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Scientific research, Efficacy
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 126
    Worldwide total number of subjects
    126
    EEA total number of subjects
    126
    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)
    113
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 People were recruited from London, Bristol, Manchester, Glasgow and Cardiff from NHS clinics.

    Pre-assignment
    Screening details
    		 Eligibility was clarified using Clinical Activity Score and other factors including proptosis. Pregnancy, previous use of radio-iodine or dysthyroid optic neuropathy as well as FBC or liver abnormalities were also reasons for exclusion

    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, Carer, Assessor
    Blinding implementation details
    Sham radiotherapy was used. Individuals in the placebo group also had random dose changes to maintain

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Radiotherapy
    Arm description
    		 Twenty gray (Gy) of radiation was administered to the retrobulbar orbit in 10-12 fractions over 2 to 3 weeks. Subjects receiving sham radiotherapy also attended and underwent all the same procedures other than no radiation being delivered.
    Arm type
    		 Factorial intervention

    Investigational medicinal product name
    Radiotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Radiopharmaceutical precursor
    Routes of administration
    Route of administration not applicable
    Dosage and administration details
    Twenty gray (Gy) of radiation was administered to the retrobulbar orbit in 10-12 fractions over 2 to 3 weeks.

    Arm title
    		 Azathioprine
    Arm description
    		 Treatment dose varied between 100mg and 200mg daily (dispensed as 50 mg tablets), depending on body weight. Matched placebo tablets and packaging were used and the dose was adjusted according to a standard algorithm dependent on patient’s blood test results. Again, extensive effort was taken to ensure participants were unaware if they were receiving placebo, including identical blood tests and random placebo dose adjustments. To reduce the risk of serious adverse events, patients with abnormal TPMT activity who are at increased risk of developing bone marrow suppression (low activity) or hepatotoxicity (high activity) with azathioprine were not enrolled.
    Arm type
    		 factorial intervention

    Investigational medicinal product name
    Azathioprine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    See other section

    Number of subjects in period 1
    		Radiotherapy Azathioprine
    Started
    126
    126
    Completed
    126
    126
    Period 2
    Period 2 title
    Completed
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    As before

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Radiotherapy
    Arm description
    		 Twenty gray (Gy) of radiation was administered to the retrobulbar orbit in 10-12 fractions over 2 to 3 weeks. Subjects receiving sham radiotherapy also attended and underwent all the same procedures other than no radiation being delivered.
    Arm type
    		 Factorial intervention

    Investigational medicinal product name
    Radiotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Radiopharmaceutical precursor
    Routes of administration
    Route of administration not applicable
    Dosage and administration details
    Twenty gray (Gy) of radiation was administered to the retrobulbar orbit in 10-12 fractions over 2 to 3 weeks.

    Arm title
    		 Azathioprine
    Arm description
    		 Treatment dose varied between 100mg and 200mg daily (dispensed as 50 mg tablets), depending on body weight. Matched placebo tablets and packaging were used and the dose was adjusted according to a standard algorithm dependent on patient’s blood test results. Again, extensive effort was taken to ensure participants were unaware if they were receiving placebo, including identical blood tests and random placebo dose adjustments. To reduce the risk of serious adverse events, patients with abnormal TPMT activity who are at increased risk of developing bone marrow suppression (low activity) or hepatotoxicity (high activity) with azathioprine were not enrolled.
    Arm type
    		 Factorial intervention

    Investigational medicinal product name
    Azathioprine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment dose varied between 100mg and 200mg daily (dispensed as 50 mg tablets), depending on body weight. Matched placebo tablets and packaging were used and the dose was adjusted according to a standard algorithm dependent on patient’s blood test results. Again, extensive effort was taken to ensure participants were unaware if they were receiving placebo, including identical blood tests and random placebo dose adjustments. To reduce the risk of serious adverse events, patients with abnormal TPMT activity who are at increased risk of developing bone marrow suppression (low activity) or hepatotoxicity (high activity) with azathioprine were not enrolled.

    Number of subjects in period 2
    		Radiotherapy Azathioprine
    Started
    126
    126
    Completed
    103
    103
    Not completed
    23
    23
         Protocol deviation
    23
    23

    Baseline characteristics

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

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 126 126
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 113 113
        From 65-84 years
    		 13 13
        85 years and over
    		 0 0
    Age continuous
    49.2 (SD 11.0)
    Units: years
        arithmetic mean (standard deviation)
    		 42.9 ± 11.0 -
    Gender categorical
    Units: Subjects
        Female
    		 93 93
        Male
    		 33 33

    End points

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    End points reporting groups
    Reporting group title
    Radiotherapy
    Reporting group description
    		 Twenty gray (Gy) of radiation was administered to the retrobulbar orbit in 10-12 fractions over 2 to 3 weeks. Subjects receiving sham radiotherapy also attended and underwent all the same procedures other than no radiation being delivered.

    Reporting group title
    Azathioprine
    Reporting group description
    		 Treatment dose varied between 100mg and 200mg daily (dispensed as 50 mg tablets), depending on body weight. Matched placebo tablets and packaging were used and the dose was adjusted according to a standard algorithm dependent on patient’s blood test results. Again, extensive effort was taken to ensure participants were unaware if they were receiving placebo, including identical blood tests and random placebo dose adjustments. To reduce the risk of serious adverse events, patients with abnormal TPMT activity who are at increased risk of developing bone marrow suppression (low activity) or hepatotoxicity (high activity) with azathioprine were not enrolled.
    Reporting group title
    Radiotherapy
    Reporting group description
    		 Twenty gray (Gy) of radiation was administered to the retrobulbar orbit in 10-12 fractions over 2 to 3 weeks. Subjects receiving sham radiotherapy also attended and underwent all the same procedures other than no radiation being delivered.

    Reporting group title
    Azathioprine
    Reporting group description
    		 Treatment dose varied between 100mg and 200mg daily (dispensed as 50 mg tablets), depending on body weight. Matched placebo tablets and packaging were used and the dose was adjusted according to a standard algorithm dependent on patient’s blood test results. Again, extensive effort was taken to ensure participants were unaware if they were receiving placebo, including identical blood tests and random placebo dose adjustments. To reduce the risk of serious adverse events, patients with abnormal TPMT activity who are at increased risk of developing bone marrow suppression (low activity) or hepatotoxicity (high activity) with azathioprine were not enrolled.

    Primary: Binary Clinical composite outcome measure

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    End point title
    		 Binary Clinical composite outcome measure
    End point description
    Major criteria* • Improvement of ≥1 grade in diplopia score • Improvement of >8° of eye movement in any direction • Reduction of ≥2 mm in proptosis Minor criteria* • Reduction of ≥2 mm in lid aperture • Improvement of ≥1 grade in soft tissue involvement • Improvement in best-corrected visual acuity of ≥1 line on the Snellen chart • Patient-judged subjective improvement Calculation of response • Improved: improvement in ≥1 major criteria or ≥2 minor criteria • No change: improvement or deterioration in ≤1 minor criterion • Worse: deterioration in ≥1 major or ≥2 minor criteria (even if other criteria improve) *All items refer to the worst eye.
    End point type
    Primary
    End point timeframe
    48 weeks
    End point values
    		 Radiotherapy Azathioprine
    Number of subjects analysed
    123
    123
    Units: 0 1
        number (not applicable)
    123
    123
    Attachments
    		 BCCOM ITT APP
    Statistical analysis title
    		 Logistic regression
    Statistical analysis description
    Note it was a factorial analysis so all on azathioprine vs those who did not receive azathioprine and radiotherapy was done in a similar fashion
    Comparison groups
    Azathioprine v Radiotherapy
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.054
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.98
         upper limit
    		 6.66
    Variability estimate
    Standard deviation
    Notes
    [1] - For Azathioprine

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During the trial so data is up to 48 weeks.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Radiotherapy
    Reporting group description
    		 Twenty gray (Gy) of radiation was administered to the retrobulbar orbit in 10-12 fractions over 2 to 3 weeks. Subjects receiving sham radiotherapy also attended and underwent all the same procedures other than no radiation being delivered.

    Reporting group title
    Azathioprine
    Reporting group description
    		 Treatment dose varied between 100mg and 200mg daily (dispensed as 50 mg tablets), depending on body weight. Matched placebo tablets and packaging were used and the dose was adjusted according to a standard algorithm dependent on patient’s blood test results. Again, extensive effort was taken to ensure participants were unaware if they were receiving placebo, including identical blood tests and random placebo dose adjustments. To reduce the risk of serious adverse events, patients with abnormal TPMT activity who are at increased risk of developing bone marrow suppression (low activity) or hepatotoxicity (high activity) with azathioprine were not enrolled.

    Serious adverse events
    		 Radiotherapy Azathioprine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 62 (1.61%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Endocrine disorders
    Any
         subjects affected / exposed
    1 / 63 (1.59%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Radiotherapy Azathioprine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    49 / 63 (77.78%)
    46 / 62 (74.19%)
    Blood and lymphatic system disorders
    ANY
         subjects affected / exposed
    49 / 63 (77.78%)
    46 / 62 (74.19%)
         occurrences all number
    115
    118

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    There is some complexity to analysis in comparing the outcomes be it APP or ITT.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29396245
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