A randomised trial of adjuvant rituximab in young people with Graves’ disease

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.