Protocol for the combined immunosuppression & radiotherapy in thyroid eye disease (CIRTED) trial: A multi-centre, double-masked, factorial randomised controlled trial

Background Medical management of thyroid eye disease remains controversial due to a paucity of high quality evidence on long-term treatment outcomes. Glucocorticoids are known to be effective initially but have significant side-effects with long-term use and recrudescence can occur on cessation. Current evidence is conflicting on the efficacy of radiotherapy and non-steroid systemic immunosuppression, and the majority of previous studies have been retrospective, uncontrolled, small or poorly designed. The Combined Immunosuppression and Radiotherapy in Thyroid Eye Disease (CIRTED) trial was designed to investigate the efficacy of radiotherapy and azathioprine in combination with a standard course of oral prednisolone in patients with active thyroid eye disease. Methods/design Patients with active thyroid eye disease will be randomised to receive (i) azathioprine or oral placebo and (ii) radiotherapy or sham-radiotherapy in this multi-centre, factorial randomised control trial. The primary outcome is improvement in disease severity (assessed using a composite binary measure) at 12 months and secondary end-points include quality of life scores and health economic measures. Discussion The CIRTED trial is the first study to evaluate the role of radiotherapy and azathioprine as part of a long-term, combination immunosuppressive treatment regime for Thyroid Eye Disease. It will provide evidence for the role of radiotherapy and prolonged immunosuppression in the management of this condition, as well as pilot data on their use in combination. We have paid particular attention in the trial design to establishing (a) robust placebo controls and masking protocols which are effective and safe for both radiotherapy and the systemic administration of an antiproliferative drug; (b) constructing effective inclusion and exclusion criteria to select for active disease; and (c) selecting pragmatic outcome measures. Trial registration Current controlled trials ISRCTN22471573


Trial Medication Record -Trial Tablets & Prednisolone
Please complete this diary on a daily basis. Write the number of Trial Tablets (Azathioprine 50mg or Placebo) and the Prednisolone dose (eg '30mg') that you have taken each day in the appropriate box, and also record the date (day / month / year) for the start of each week in the top left-hand box of each table. If you have forgotten to take your tablets please write in "0", but remember to take your prescribed dose at the next scheduled time. Week

Other Medication Record
Please write down the name and dose of all tablets and medications you take (either prescribed by a doctor, or purchased over-the-counter) other than treatments we give you at the Eye Hospital. If you are taking these other medications for your thyroid eye disease (eg pain killers for discomfort around the eyes), or to counteract the side-effects of the treatment you have been given for your Thyroid Eye Disease (such as indigestion associated with steroid use), we would also like to record their cost. Medication

Health Record
It is important that we monitor all new health problems you develop during your participation in the trial. We are interested in any new symptom or illness, however minor; regardless of whether you feel this is related to your Thyroid Eye Disease and its treatment. For example, you should record if you develop heart-burn or tiredness, have a cold, or even are involved in an accident. The main reason for this is identify any potential side-effects of the medications you are taking. Please use the following

NHS / Trial Appointments
This section is a useful place to record the times and dates of your visits to hospital, GP or other healthcare services.
We would also like to use it to calculate: • How much your journeys to attend your appointments cost, •  • Days off Work = Total time taken off work to attend the appointment by you and those accompanying you (eg if you take ¼ day and your spouse takes ½ day, the total = ¾ day), • Income Lost = If you, or any of the people accompanying you, lost pay while attending your hospital appointment please estimate the total amount this cost (eg if you lost £100 and your spouse lost £50, the total = £150) • Hosp Trans = Tick this box (and leave the travel costs / mileage sections blank) if you are disabled and use the hospital's transport services • Care Costs = Complete this section if you pay for the care of dependent relatives (eg children or elderly parents) while you attend hospital appointments.
• Overnight = If you travel a long distance to each hospital visit and stay overnight to break up the journey, or to enable you to make a morning appointment, please record the cost of accommodation for you and all those accompanying you Otherwise please write a brief description of the reason for the appointment or symptoms which caused you to seek your GP's advice in the 'other' box.

RADIOTHERAPY
• Travel Costs = Total cost of return fares (eg taxi, train, bus, tube) and parking tickets for you and all those accompanying you (eg if you travel by train with your spouse to attend your appointment and the cost of your return train fare is £35 each, the total cost for the visit would be £70) • Miles = If you completed all or part of your journey by car (or motorbike) please estimate the round trip distance in miles (leave blank if you did not drive) • No. of other People = Number of people accompanying you (leave blank if you attended on your own) • Time Taken = Total number of hours taken for your round trip (eg if you left home at 09:00 and get back at 15:00, the time taken for the visit would be 6 hours) • Days off Work = Total time taken off work to attend the appointment by you and those accompanying you (eg if you take ¼ day and your spouse takes ½ day, the total = ¾ day), • Income Lost = If you, or any of the people accompanying you, lost pay while attending your hospital appointment please estimate the total amount this cost (eg if you lost £100 and your spouse lost £50, the total = £150) • Travel Costs = If you travelled to use the service what was total cost of return fares (eg taxi, train, bus, tube) and parking tickets for you and all those accompanying you (eg if you travel by train with your spouse to attend your appointment and the cost of your return train fare is £35 each, the total cost for the visit would be £70)

GENERAL PRACTITIONER
• Miles = If you travelled to use the service and completed all or part of your journey by car (or motorbike) please estimate the round trip distance in miles (leave blank if you did not drive) • Other People = Number of people accompanying you to use the service (leave blank if you attended on your own) • Days off Work = Total time taken off work to use this service by you and those accompanying you (eg if you take ¼ day and your spouse takes ½ day, the total = ¾ day) • Income Lost = If you, or any of the people accompanying you, lost pay while using this NHS service please estimate the total amount this cost (eg if you lost £100 and your spouse lost £50, the total = £150)

Use of Non-NHS Services
If you use other Non-NHS health services during your time in the CIRTED trial (such as private medical consultations, complimentary therapy or a patient support group) please record these below