Abstract
BackgroundMedical 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/designPatients 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.DiscussionThe 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 registrationCurrent controlled trials ISRCTN22471573
Highlights
Medical management of thyroid eye disease remains controversial due to a paucity of high quality evidence on long-term treatment outcomes
Particular attention in the trial design has been given to (a) establishing 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
Compliance and loss to follow-up We predict that 33% of eligible patients will choose not to take part in the study [14], 11% will be excluded because of thiopurine methyltransferase (TPMT) inactivity [53], 10% of the azathioprine treated group will be intolerant of therapy or suffer an adverse event necessitating withdrawal from the trial [54], and 5% will drop-out for other reasons
Summary
Medical management of thyroid eye disease remains controversial due to a paucity of high quality evidence on long-term treatment outcomes. A wide variety of immunosuppressive therapies have been used to target the early active inflammatory phase of the disease, including glucocorticoids (GC's), radiotherapy, antiproliferative agents, T-cell inhibitors and, more recently, biologics The goal of these interventions is to suppress the autoimmune inflammatory phase of the disease, thereby altering the course of the disease and reducing the severity of residual changes in the extraocular muscles, orbital fat and other periocular soft tissues which result in permanent visual and cosmetic dysfunction [1,4,5]. The routine use of such second-line immunosuppressive drugs in the management of TED has been limited by fears about their potential toxicity, and glucocorticoid monotherapy remains the mainstay of conventional treatment
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