A single dose of the antibody drug rituximab, given shortly after diagnosis, could nearly double the chance that a young person with Graves’ disease will recover without needing lifelong treatment. Graves’ disease is the most common cause of an overactive thyroid in adolescents, affecting about 1 in 10,000 teenagers each year. Standard treatment with antithyroid drugs leads to remission in only around 24% of young patients after two to three years. Most who relapse must either restart medication or undergo thyroid removal or radioactive iodine ablation, both of which require lifelong levothyroxine replacement—a regimen linked to reduced quality of life. This phase III trial will recruit 124 newly diagnosed patients aged 12 to 24 across 26 UK centres. Half will receive standard antithyroid drugs plus a single infusion of rituximab; the other half will receive drugs plus a placebo. The primary measure is remission at three years, defined as no need for antithyroid drugs for 12 months. A proof-of-concept study found that adding rituximab raised remission rates to 48%, with no serious side effects. If successful, this would be the first new treatment strategy for Graves’ disease in over 60 years, sparing many young people a lifetime of thyroid hormone replacement.
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Research Question Does a single dose of rituximab administered shortly after diagnosis, in addition to a 2-year course of thionamide antithyroid drug treatment, increase remission rate when compared to antithyroid drug alone in young people with newly-diagnosed Graves’ disease? Background Graves’ disease (GD) is the commonest cause of hyperthyroidism in young people with an annual incidence of 1 in 10,000 adolescents. GD is an autoimmune disease that develops when thyroid-stimulating hormone receptor autoantibodies (TRAbs) stimulate the thyroid-stimulating hormone receptor on the thyroid gland. This causes excess thyroid hormone secretion and a detrimental impact on health and academic performance. Conventional therapy is with anti-thyroid drugs (ATD), but the remission rate after two to three years is only around 24%. This is lower than in adults and most patients who relapse need to restart ATD or undergo total thyroidectomy or thyroid ablation using radioiodine (RAI). Thyroidectomy and RAI result in a requirement for lifelong levothyroxine replacement, which has been linked to a reduced quality of life. Increasing remission rates by targeting the immune response is a logical strategy and in a phase II trial a single dose of the monoclonal antibody rituximab (RTX) improved remission rates to 48%. RTX and ATD was well-tolerated with no serious side-effects. Aims and objectives This randomised phase III trial will determine whether adjuvant RTX increases remission rate when compared to standard ATD treatment in young people with GD. The primary endpoint will be a comparison of the proportion of subjects in remission at 3 years (subjects not requiring ATD for 12 months) following a 2-year course of ATD +/- RTX in the two treatment arms. Secondary outcomes include an analysis of lymphocyte subsets, cytokines, chemokines and immunological and genetic markers of B lymphocyte activity compared to outcome as well as quality of life. Methods including justification of study design A UK, multi-centre randomised, placebo controlled, single-blinded (to participants) trial will investigate the efficacy of adjuvant RTX compared to standard ATD treatment. Newly diagnosed GD patients (12 to 24 years) will be recruited and randomised 1:1 to ATD or ATD + RTX. Treatment allocation will be performed by stratification for sex, age at diagnosis and initial free T4 level. Assuming 90% power to detect a 24% difference in remission rate (24% remission with ATD alone to 48% from proof-of-concept study) 124 participants will be recruited to take into consideration a 10% drop out figure. We will use regional networks and work with the British Thyroid Foundation and British Society for Endocrinology and Diabetes to ensure that the 26 tertiary centres within the UK (13 paediatric and 13 adult sites) recruit to target. Timelines for delivery This project will be conducted over 6 years, with a 9-month set-up period, an 18-month recruitment period, a 3-year period of treatment/ follow-up and a 9-month analysis/close-down period. Anticipated impact and dissemination This treatment strategy, if efficacious, would increase the proportion of GD patients not requiring long-term medication and improve quality of life. This would be the first new treatment strategy for GD patients for >60 years and the results will be disseminated in paediatric and adult endocrine circles, the national media and published in high impact journals.
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