Graves' hyperthyroidism
Conditions
Interventions
Trade Name: Mabthera Infusion
Product Name: Mabthera Infusion
Product Code: Rituximab
Pharmaceutical Form: Concentrate for solution for injection/infusion
Sponsors
Newcastle upon Tyne Hospitals NHS Foundation Trust
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Excess thyroid hormone concentrations at diagnosis: elevated free tri-iodothyronine (FT3) and / or free thyroxine (based on local assay). • Suppressed (un-recordable) TSH (based on local assay). • Patients between the ages of 12-20 years inclusive that are less than 6 weeks from first diagnosis of Graves’ hyperthyroidism • Elevated thyroid binding inhibitory immunoglobulin or thyroid receptor antibodies (TRAb including TBII) based on local assay. Patients may or may not have a raised TPO antibody titre. • Willingness to travel to the regional centres in Birmingham, Doncaster, Edinburgh, Leeds, Newcastle-upon-Tyne or Sheffield. • If females are of childbearing potential, must have a negative serum pregnancy test at screening. • Willingness to use 2 forms of contraception for 12 months post-treatment with rituximab (all females of childbearing potential). • Able and willing to adhere to a 2 year study period. Are the trial subjects under 18? yes Number of subjects for this age range: 12 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 15 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range 0
Exclusion criteria
Exclusion criteria: • Previous episodes of autoimmune thyroid disease • Other concurrent immunomodulatory treatment apart from inhaled steroids for asthma (such as beclomethasone) or topical steroids for skin disorders such as eczema. • Pregnancy, planned pregnancy during the study period or current breast-feeding • Absence of informed consent from parent/legal guardian for participants age <16 years. • Participants with previous use of immunosuppressive or cytotoxic drugs (including rituximab and methylprednisolone but excluding inhaled glucocorticoid and oral glucocorticoid for asthma or topical glucocorticoid for eczema). • Participants with active viral illness including HIV, Hepatitis B or C, shingles/Zoster. • Participants with significant chronic cardiac, respiratory or renal disorder or non-autoimmune liver disease. • Participants with known allergy or contraindication to rituximab or methylprednisolone. • 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) status. • Participants in families who know they will be moving out of the catchment areas during the 2 years following RTX treatment. • Participants currently involved in any other clinical trial of an IMP or who have taken an IMP within 30 days prior to trial entry.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The principal question is to establish whether a single 500mg dose of RTX, when administered together with a short 12 month course of 'conventional' anti-thyroid drug (ATD), is likely to result in a meaningful improvement in the proportion of young people with Graves' hyperthyroidism entering disease remission.;Secondary Objective: • To examine whether there is a relationship between thyrotropin receptor antibody (TRAb) titre in recruited subjects and thyroid hormone status (TSH, FT4 and FT3) at the beginning and end of the trial. This will help to establish whether there is a biologically compelling relationship between disease severity, as assessed by autoantibody status, and biochemical outcome following the proposed treatment regimen. • To examine whether the immune cellular response is related to disease outcome by examining the relationship between time to recovery of immune cell numbers (CD 19+ cells) to within the local normal reference range and thyroid hormone status at the end of the trial. • To examine whether the total dose of ATD is related to disease outcome by examining the nature of the relationship between the cumulative dose of ATD (mg/kg) in relation to thyroid hormone status at the end of the trail. • To examine the time taken for TSH concentrations to normalise post Rituximab and to;Primary end point(s): The number of patients in remission at 24 months will be compared to the critical number. Formal justification to proceed to a larger randomised trial is based upon observing a minimum number achieving remission, referred to as the critical number (35). The critical number depends upon the desired and unacceptable remission rates, set at 40% and 20%, respectively, and the error levels set at 10% alpha (type I) and 20% beta (type II). The remission rate corresponding to the critical number will lie between 40% and 20% and will be specified in the Statistical Analysis Plan. If the true remission rate is 40% there is an 80% chan | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1). The distribution of TRAb titres will be compared between patients in and out of remission by graphical summary, numerical summary statistics (median and interquartile range) and a Mann-Whitney test. 2). Time to recovery of B cell lymphocyte numbers (CD 19+ cells) to the normal range in relation to thyroid hormone status. This will be compared between patients in and out of remission by graphical summary, numerical summary statistics (median and interquartile range) and a Mann-Whitney test. 3). Cumulative dose of ATD (Carbimazole) in mg/kg in relation to thyroid hormone status. This will be compared between patients in and out of remission by graphical summary, numerical summary statistics (median and interquartile range) and a Mann-Whitney test. 4). We will assess the time taken for TSH concentrations to normalise (increase above 0.1mU/l) post Rituximab and describe biochemical thyroid status, as assessed by TSH, FT4 and FT3 concentration, in the period between cessation of ATD therapy and the end of the trial in each patient. Specifically we will plot the time taken for TSH to normalise in individual patients and determine the proportion of time that TSH, FT4 and FT3 concentrations are within the normal reference range in the period between ATD stopping (end of year 1) and trial end (end of year 2). 5). The frequency and nature of adverse events. ;Timepoint(s) of evaluation of this end point: 2 years after treatment with Rituximab | — |
Countries
United Kingdom
Contacts
Public ContactAnn Marie Hynes
Newcastle University Clinical Trial Unit
Outcome results
None listed