Ignite Creation Date:
2024-05-05 @ 11:51 AM
Last Modification Date:
2024-10-26 @ 9:14 AM
Study NCT ID:
NCT00150111
Status:
COMPLETED
Last Update Posted:
2006-10-06
First Post:
2005-09-06
Brief Title:
Rituximab in the Treatment of Graves Disease
Sponsor:
Odense University Hospital
Organization:
Odense University Hospital
Study Overview
Official Title:
B Cell Depletion With the Anti-CD20 Monoclonal Antibody Rituximab in the Treatment of Graves Disease
Status:
COMPLETED
Status Verified Date:
2006-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Aim
In a phase II pilot study encompassing 20 patients with Graves disease to evaluate the effect of rituximab
1 Biochemically as assessed by markers of disease activity free T4 free T3 TSH TSH-receptor antibodies anti-TPO
In a phase II pilot study encompassing 20 patients with Graves disease to evaluate the effect of rituximab
1 Biochemically as assessed by markers of disease activity free T4 free T3 TSH TSH-receptor antibodies anti-TPO
Detailed Description:
Background
Rituximab is a chimeric murinehuman anti-CD20 monoclonal antibody which was originally introduced in the clinic years ago for the treatment of malignant lymphomas The antibody is an IgG1 kappa immunoglobulin containing murine light-and heavy chain variable region sequences and human constant region sequences The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes Possible mechanisms of cell lysis include complement-dependent cytotoxicity antibody-dependent cellular cytotoxicity and induction of apoptosis
The mechanisms behind the favourable response of rituximab in autoimmune cytopenias are unsettled A depletion of peripheral blood B cells occurs after just one antibody infusion Accordingly it has been proposed that opsonized CD20 B cells inhibit and saturate macrophage Fc-receptor function and thereby clearance of IgG-coated blood cells by reticuloendothelial cells Suppression of auto reactive B-cell clones may be another potential mechanism
Most recently several studies have shown that rituximab- also is very effective in the treatment of various autoimmune cytopenias and autoimmune diseases - idiopathic thrombocytopenic purpura ITP warm and cold autoimmune haemolytic anemias autoimmune neutropenia pure red cell aplasia Wegeners granulomatosis systemic lupus erythematosus membranous glomerulonephritis and rheumatoid arthritis - including disorders which have been considered to be primarily diseases elicited by aberrant T-cell responses eg rheumatoid arthritis However recently the importance of the B-cell in the pathogenesis of these autoimmune disorders have been debated and emphasized
Graves disease is an autoimmune disease in which both B- and T-cells are activated and participate in its pathogenesis However B-cell activation with the production of IgG - thyroid-stimulating antibodies binding to and activating the thyrotropin receptor on thyroid cells is a prerequisite for the development of Graves hyperthyroidism The thyroid-stimulating antibodies cause thyroid hypersecretion hypertrophy and hyperplasia of the thyroid follicles and ultimately diffuse goiter together with clinical hyperthyroidism In addition to thyroid-stimulating antibodies against thyroglobulin and thyroid peroxidase are also produced in Graves disease The pathogenesis of the other clinical features of disease - the ophthalmopathy and the localized dermopathy or myxedema - is far less elucidated It has been proposed that the ophthalmopathy develops consequent to an autoimmune response to the thyrotropin receptor which is also expressed by a preadipocyte subpopulation of orbital fibroblasts The treatment of Graves disease includes antithyroid drugs radioactive iodine and surgery All three treatment modalities are associated with adverse effects or side-effects
The most serious complication of antithyroid drugs is agranulocytosis and less frequently acute hepatic necrosis cholestatic hepatitis and vasculitis As to treatment with radioactive iodine this therapy may worsen ophthalmopathy In addition the treatment is followed by hypothyroidism in a large proportion of the patients
Based upon the above mentioned observations of a very effective response in many patients with otherwise refractory autoimmune disorders and the pathogenetic concept of Graves disease as a disorder elicited by auto antibodies stimulating the thyrotropin receptor on thyroid cells hyperthyroidism and goiter and similar antigens in the orbit ophthalmopathy the hypothesis is that B-cell depletion with rituximab may be a very efficacious therapy reducing or abolishing the production of the auto antibodies which are responsible for Graves disease
Aim of the study
In a phase II pilot study encompassing 20 patients with Graves disease to evaluate the effect of rituximab
1 Biochemically as assessed by markers of disease activity free T4 free T3 TSH TSH-receptor antibodies anti-TPO
Study design
Material and methods 20 patients with recent onset untreated Graves disease start antithyroid treatment methimazole When euthyroidism is reached - defined by normal thyroid parameters free T4 free T3 and TSH - the patients are randomised to - rituximab treatment
Afterwards the 2 patient groups are followed for 1 year
10 euthyroid patients treated 4 weeks with rituximab when antithyroid treatment is discontinued
10 euthyroid patients who do not receive rituximab antithyroid treatment being discontinued after 4 weeks
Effect parameters
Differences in relapse remission rate at 3 6 9 and 12 months follow up time to relapse as assessed by
Biochemistry free T4 free T3 TSH TSH-receptor antibodies anti-TPO
Treatment
Rituximab in a dose of 375 mgm² administered by iv Infusion once a week for 4 weeks
Premedication with paracetamol 1g po or tavestin 2 mg iv is given 30-60 min before each infusion
Rituximab is a chimeric murinehuman anti-CD20 monoclonal antibody which was originally introduced in the clinic years ago for the treatment of malignant lymphomas The antibody is an IgG1 kappa immunoglobulin containing murine light-and heavy chain variable region sequences and human constant region sequences The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes Possible mechanisms of cell lysis include complement-dependent cytotoxicity antibody-dependent cellular cytotoxicity and induction of apoptosis
The mechanisms behind the favourable response of rituximab in autoimmune cytopenias are unsettled A depletion of peripheral blood B cells occurs after just one antibody infusion Accordingly it has been proposed that opsonized CD20 B cells inhibit and saturate macrophage Fc-receptor function and thereby clearance of IgG-coated blood cells by reticuloendothelial cells Suppression of auto reactive B-cell clones may be another potential mechanism
Most recently several studies have shown that rituximab- also is very effective in the treatment of various autoimmune cytopenias and autoimmune diseases - idiopathic thrombocytopenic purpura ITP warm and cold autoimmune haemolytic anemias autoimmune neutropenia pure red cell aplasia Wegeners granulomatosis systemic lupus erythematosus membranous glomerulonephritis and rheumatoid arthritis - including disorders which have been considered to be primarily diseases elicited by aberrant T-cell responses eg rheumatoid arthritis However recently the importance of the B-cell in the pathogenesis of these autoimmune disorders have been debated and emphasized
Graves disease is an autoimmune disease in which both B- and T-cells are activated and participate in its pathogenesis However B-cell activation with the production of IgG - thyroid-stimulating antibodies binding to and activating the thyrotropin receptor on thyroid cells is a prerequisite for the development of Graves hyperthyroidism The thyroid-stimulating antibodies cause thyroid hypersecretion hypertrophy and hyperplasia of the thyroid follicles and ultimately diffuse goiter together with clinical hyperthyroidism In addition to thyroid-stimulating antibodies against thyroglobulin and thyroid peroxidase are also produced in Graves disease The pathogenesis of the other clinical features of disease - the ophthalmopathy and the localized dermopathy or myxedema - is far less elucidated It has been proposed that the ophthalmopathy develops consequent to an autoimmune response to the thyrotropin receptor which is also expressed by a preadipocyte subpopulation of orbital fibroblasts The treatment of Graves disease includes antithyroid drugs radioactive iodine and surgery All three treatment modalities are associated with adverse effects or side-effects
The most serious complication of antithyroid drugs is agranulocytosis and less frequently acute hepatic necrosis cholestatic hepatitis and vasculitis As to treatment with radioactive iodine this therapy may worsen ophthalmopathy In addition the treatment is followed by hypothyroidism in a large proportion of the patients
Based upon the above mentioned observations of a very effective response in many patients with otherwise refractory autoimmune disorders and the pathogenetic concept of Graves disease as a disorder elicited by auto antibodies stimulating the thyrotropin receptor on thyroid cells hyperthyroidism and goiter and similar antigens in the orbit ophthalmopathy the hypothesis is that B-cell depletion with rituximab may be a very efficacious therapy reducing or abolishing the production of the auto antibodies which are responsible for Graves disease
Aim of the study
In a phase II pilot study encompassing 20 patients with Graves disease to evaluate the effect of rituximab
1 Biochemically as assessed by markers of disease activity free T4 free T3 TSH TSH-receptor antibodies anti-TPO
Study design
Material and methods 20 patients with recent onset untreated Graves disease start antithyroid treatment methimazole When euthyroidism is reached - defined by normal thyroid parameters free T4 free T3 and TSH - the patients are randomised to - rituximab treatment
Afterwards the 2 patient groups are followed for 1 year
10 euthyroid patients treated 4 weeks with rituximab when antithyroid treatment is discontinued
10 euthyroid patients who do not receive rituximab antithyroid treatment being discontinued after 4 weeks
Effect parameters
Differences in relapse remission rate at 3 6 9 and 12 months follow up time to relapse as assessed by
Biochemistry free T4 free T3 TSH TSH-receptor antibodies anti-TPO
Treatment
Rituximab in a dose of 375 mgm² administered by iv Infusion once a week for 4 weeks
Premedication with paracetamol 1g po or tavestin 2 mg iv is given 30-60 min before each infusion
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None