Multi-centre randomised, placebo-controlled, single blind trial to investigate the efficacy of adjuvant Rituximab therapy compared to standard Anti-thyroid drug treatment of Graves’ Disease in young people with newly diagnosed disease.
Medical condition: Graves disease Medical condition in lay language: Graves Disease (autoimmune hyperthyroidism). Therapeutic areas: Diseases [C] - Immune System Diseases [C20]
Arm 1- Standard ATD therapy + Placebo: Participants will receive an intravenous (IV) infusion of saline (0.9% NaCl) over 3 hours together with antipyretic, antihistamine and steroid cover administered just prior to the infusion as follows: • Oral paracetamol (500mg 12-15 years of age or 1g ≥16 years) • Methylprednisolone 125mg IV infusion over 30 minutes • Chlorphenamine 10mg IV injection over 1 minute Arm 2- Standard ATD therapy + RTX: Patients will be managed as per the standard therapy arm, except that instead of the placebo, they will receive a single dose of 500mg RTX. RTX will be administered by slow IV infusion over approximately 3 hours with antipyretic, antihistamine and steroid cover given just prior to infusion in identical doses to arm 1: • Oral paracetamol (500mg 12-15 years of age or 1g ≥ 16 years) • Methylprednisolone 125mg IV infusion over 30 minutes • Chlorphenamine 10mg IV injection over 1 minute Treatment allocation will be performed by permuted blocks (concealed block size) stratified for sex (at birth), age at diagnosis (>16 years) and initial free T4 (FT4) level (≥50pmol/l). Visits 2-14 Follow Up Visits (years 1 & 2) • Concomitant medications (including ATD compliance check) • Clinical exam • Pregnancy test (Visit 10) • Research bloods (visits 2, 7, 10, 14, 18); Safety bloods (all visits); Additional bloods (visits 1 and 10) • Questionnaires administered (visits baseline, 2, 7, 10, 14, 18) • AEs and SAEs checked recorded/reported Visit 14 (end of year 2) • Stop ATD therapy Visits 15-18 Follow Up Visits (year 3) • Concomitant medications (including ATD extension) • Clinical exam • Bloods (Thyroid function); Research Bloods (visit 18 only) • AEs and SAEs checked recorded/reported • Questionnaires administered (visit 18)
1. Excess thyroid hormone concentrations at diagnosis: elevated FT3 and/or FT4 (based on local assay) 2. Suppressed (un-recordable) TSH (based on local assay) 3. Patients between the ages of 12-24 years inclusive who are less than 12 weeks from the initiation of ATD treatment (CBZ or PTU) for the first time 4. Elevated thyroid binding inhibitory immunoglobulin or thyroid receptor antibodies (TRAb including TSH-Binding Inhibitor Immunoglobulins (TBII)) based on local assay. Patients may or may not have a raised TPO antibody titre 5. Confirmation of no current pregnancy. Participant must be willing to undergo pregnancy testing, as stipulated in protocol section 3.2.4. 6. Willingness to use effective forms of contraception for 12 months post-treatment with RTX/placebo (for sexually active patients, see protocol section 3.2.5) 7. Able and willing to adhere to a 3-year trial period 8. Able to provide informed consent (parent/legal guardian can if <16 years of age or is an adult lacking capacity)
1. Previous episodes of autoimmune thyroid disease 2. Patients with an active, severe infection (e.g. tuberculosis, sepsis and opportunistic infections) 3. Severely immunocompromised patients 4. Patients with known allergy or contraindication to carbimazole and propylthiouracil 5. Participants with previous use of immunosuppressive or cytotoxic drugs (including RTX and methylprednisolone but excluding inhaled glucocorticoid and oral glucocorticoid for asthma or topical glucocorticoid for eczema) 6. Chromosomal disorders known to be associated with an increased risk of autoimmune thyroid disease including Downs’ syndrome and Turners’ syndrome 7. Currently pregnant or planning to become pregnant during the trial period 8. Currently breast-feeding 9. Participants with significant chronic cardiac, respiratory or renal disorder or non-autoimmune liver disease 10. Participants with known allergy or contraindication to RTX or methylprednisolone 11. Participants with evidence of Hepatitis B/C infection, assessed by determining hepatitis ‘B’ surface antigen (HBsAg) status, hepatitis ‘B’ Core antibody (HB Core antibody) status and hepatitis ‘C’ virus antibody (HCV antibody) 12. Participants with evidence of Tuberculosis infection, assessed by Quantiferon test 13. Participants in families who know they will be moving out of the United Kingdom during the 2 years following RTX treatment and thus unable to commit to attending follow-up visits 14. Participants currently involved in any other clinical trial of an IMP or who have taken an IMP within 30 days prior to trial entry 15. Absence of informed consent from parent/legal guardian for participants age <16 years