Welcome to the Health Professionals section where you will find all relevant information concerning the trial. Use the 'Trial Information' bar to select the various documents.

1. Why do we need another trial?

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There is great controversy about the best treatment for TED. Traditionally, it was managed conservatively during the inflammatory phase, and the residual deformity was then corrected surgically (including orbital decompression, strabismus correction and eyelid repositioning) when the disease had burnt out. In addition to the surgical burden for patients and ophthalmologists, this approach did not address the underlying pathology and outcomes were frequently imperfect.

Systemic immunosuppression and radiotherapy, directed at the initial inflammatory response in the active phase of the disease, might be expected to modify the subsequent disease course and reduce the severity of residual orbital fibrosis; thereby improving long-term function and reducing the need for rehabilitative surgery. However, confusion has arisen over the role of these treatments for the following reasons:

Limitations in the quality of evidence:

• The majority of previous reports on radiotherapy in TED are retrospective and / or uncontrolled.
• Most studies have involved small sample sizes.
• Few trials have evaluated long-term results (1 year or more) Several studies have not distinguished between inactive and active disease in their analysis of treatment outcome.
• Recent randomised controlled trials on radiotherapy in TED have produced conflicting results.
• Concern about the side-effects caused by systemic immunosuppressants.

A large randomised controlled trial with adequate placebos such as the CIRTED trial is needed to provide good quality of evidence.

For further information or to receive a summary protocol please contact the CIRTED investigators.

2. Trials Summary.

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This randomised controlled trial of azathioprine and radiotherapy (with prednisolone) will be the first to establish the role of these interventions as part of a long-term, combination immunosuppressive treatment regime for TED. Such a definitive study is required to resolve the debate which currently surrounds these treatments and to provide evidence for authoritative management guidelines. Only patients with active orbital inflammation will be enrolled and follow-up will continue for 12 months. A factorial design is used to allow the efficacy of both interventions to be assessed in a single study with efficient use of patients; and the involvement of a number of trial centres will ensure adequate patient numbers for statistical power. Health economic and carefully designed quality of life/disfigurement analyses in collaboration with the Division of Primary Care (University of Bristol) and the Centre for Appearance Research (University of West of England) will accompany the trial.

3. Trial Intervention & Design.

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TRIAL INTERVENTIONS:

All trial patients will receive a six month course of high dose steroids tailing down to lower dose rapidly (see oral prednisolone treatment protocol for details). Patients will be randomised to one of the following treatment groups:

• Sham radiotherapy and azathioprine
• Sham radiotherapy and placebo tablet
• Radiotherapy and placebo tablet
• Radiotherapy and azathioprine

TRIAL DESIGN:

This trial has a factorial design. Factorial randomised trials allow two interventions to be evaluated in a single study. This has particular advantages for the assessment of combined treatment regimes, especially when considering relatively uncommon conditions with a limited number of potential recruits, such as TED. They are the most valid means of establishing whether the combination of two or more therapies achieves incremental benefits.

Application to CIRTED - Trial Arm:

As there are a number of factors that are known to affect thyroid eye disease response to treatment and outcome (eg smoking, age, gender, disease duration, initial disease activity) we are using a statistical process called minimisation to ensure the factors are distributed throughout the four trial treatment arms.

4. Trial Objectives.

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Primary

Test the hypotheses that in patients being treated with prednisolone for active TED

• RADIOTHERAPY (compared with placebo) induces early remission and reduces long-term disease severity.
• COMBINED SYSTEMIC IMMUNOSUPPRESSION WITH ORAL AZATHIOPRINE (compared with placebo) reduces long-term disease severity.

Secondary

• To test the hypotheses that in patients being treated with prednisolone for active TED, RADIOTHERAPY and COMBINED SYSTEMIC IMMUNOSUPPRESSION WITH ORAL AZATHIOPRINE improve patient-centred outcomes, including quality of life scores. To validate the use of a new TED specific Quality of Life score in the UK population.
• To improve understanding of the extent and type of psychosocial distress experienced by TED patients.
• To conduct an economic evaluation of the cost of TED and its treatment to patients, the NHS and Society.
• To compare treatments using health-economic analyses.
• To report the safety and tolerability of COMBINED SYSTEMIC IMMUNOSUPPRESSION WITH ORAL AZATHIOPRINE in TED patients.

5. Inclusion & Exclusion Criteria.

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Subject Inclusion Criteria

• Mourits' Clinical Activity Score > 4 (worst eye) OR = 2 (worst eye) with a history of proptosis* or motility restriction** of less than 6 months duration
• Past or present history of abnormal Thyroid Gland Function OR a clinical diagnosis of TED made and confirmed by > 2 muscle involvement on CT or MRI scan plus a history of recent onset motility restriction** and / or proptosis*

Subject Exclusion Criteria

• Age <20 or >75 yrs
• Optic neuropathy
• Mourits’ Clinical Activity Score > 4 without proptosis * or motility restriction**
• Pre-existing glaucoma with a characteristic optic disc appearance and associated visual field defect
• Use of radioiodine within the last 3 months
• Pre-existing Diabetes Mellitus (not simply steroid induced disease from recent therapy)
• Previous adverse event associated with, or contraindication to, either prednisolone or azathioprine
• Within 6/12 of pregnancy, women planning pregnancy
• Lactation
• Haemoglobin Concentration, Total White Cell Count or Platelet Count below the local laboratory's reference range
• Low, intermediate or high Thiopurine Methyltransferase (TPMT) activity
• Lymphocyte Count < 0.8 x 109 / L
• Abnormal renal function (assessed by urea and creatinine levels above the local laboratory’s reference range)
• Abnormal liver function, specifically: bilirubin, alanine aminotransferase or alkaline phosphatase concentrations above the local laboratory’s reference range
• Malignant or pre-malignant (dysplastic) condition within the past 5 years
• Previous tuberculosis
• Shingles within the past 3/12
• HIV / AIDS
• Concurrent use of:
• other immunosuppressive or cytotoxic agents
• allopurinol
• Live vaccines within the past 3 months
• Previous orbital irradiation

* Definition of proptosis = EITHER subjective unilateral proptosis confirmed by asymmetry in exophthalmometry of > 2mm OR subjective bilateral proptosis.

** Definition of motility restriction = intermittent, inconstant or constant diplopia grade54

6. Timeline.

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Proposed Trial Start

January 2006

Projected Trial End

December 2011

Duration of Each Patient's Participation

12 months

Frequency of Follow-up

Trial subjects will be seen twice in the first month after enrolment to determine their response to, and tolerability of, steroids. Thereafter they will have 12-weekly assessments until trial exit 11 months post-randomisation. In addition they will have multiple frequent visits for radiotherapy over a 3 week period at the start of the trial. Regular blood tests will also be required after randomisation to monitor the potential adverse effects of azathioprine treatment. Additional reviews can be arranged at the trial centres for any reason at the patient or investigators' request.

7. Safety of the Trial.

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Data Monitoring Committee (DMC)

There will be data monitoring committee interim analyses. The data monitoring committee will be presented the interim results and adverse events every nine months. Randomisation codes may be broken prior to trial completion at the request of the DMC. Randomisation codes for individual patients may be broken for withdrawn subjects.

Withdrawal Criteria

• Development of Dysthyroid-associated Optic Neuropathy (DON), defined as

EITHER

• a significant visual field defect
• a relative afferent pupilary defect,

OR

• an unexplainable best corrected visual acuity of less than 6/12 (with or without a swollen optic disc)
• Patient withdrawal of consent
• Trial subjects who have had TED for more than 6 months and whose Clinical Activity Score (CAS) has not improved by at least one point 2 weeks after starting high-dose steroids, are unlikely to benefit from Radiotherapy and / or Azathioprine. They will be withdrawn from the trial - ie they will not be randomised.
• Increasing Clinical Activity Score (CAS) by =2 points, confirmed on repeat examination (within 14 days).
• Azathioprine toxicity *
• A Serious Adverse Event potentially attributable to radiotherapy or azathioprine.

Treatment of Withdrawn Subjects

The patient, Consultant Ophthalmologist and Consultant Radiotherapist responsible for their care, will be informed of their treatment allocation on withdrawal from the trial. If the patient received sham-radiotherapy or placebo tablets (or both) they will be offered the active treatments (if appropriate). Withdrawn patients will also have access to alternative therapies, such as other immunosuppressive agents or surgery. The investigators conducting trial assessments will not be informed of the withdrawn patient's treatment allocation until the trial as a whole and its data analysis is complete. Final outcome data for withdrawn subjects will be imputed using the principle of last observation carried forward. They will not be 'replaced'.

8. Funding & Sponsorship.

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Support for this trial has been granted by the following charitable bodies:

• The National Eye Research Centre
• Moorfield's Eye Hospital Special Trustees
• Above & Beyond Charities

The University of Bristol has arranged clinical research insurance to cover the legal liability of the University for both negligent and non-negligent harm. In addition the study doctors hold substantive or honorary NHS contracts, giving them the protection of the NHS clinical negligence arrangements.