Rituximab in the Treatment of Graves' Disease
Primary Purpose
Graves´ Disease, Thyroid Associated Ophthalmopathy
Status
Completed
Phase
Phase 1
Locations
Denmark
Study Type
Interventional
Intervention
Methimazole
Rituximab
Immunization with various vaccines
Sponsored by
About this trial
This is an interventional treatment trial for Graves´ Disease focused on measuring Graves disease, thyroid, ophthalmopathy, autoimmunity, B lymphocyte depletion, rituximab, immunization
Eligibility Criteria
Inclusion Criteria: Graves´ disease Adequate anticonception in women. Exclusion Criteria: Performance status >2 Previous rituximab treatment Immunosuppressive treatment Serious concomitant disease Active infections Pregnancy / breast feeding.
Sites / Locations
- Department of Endocrinology, Odense University Hospital
- Department of Hematology, Odense University Hospital
Outcomes
Primary Outcome Measures
Time to relapse after cessation of treatment judged at 1, 3, 6, 9 and 12 months post cessation.
Secondary Outcome Measures
Safety
Changes in autoantibodies (monthly)
Immunological changes (monthly)
Response to vaccines (1 month post-immunization)
Full Information
NCT ID
NCT00150111
First Posted
September 6, 2005
Last Updated
October 5, 2006
Sponsor
Odense University Hospital
1. Study Identification
Unique Protocol Identification Number
NCT00150111
Brief Title
Rituximab in the Treatment of Graves' Disease
Official Title
B Cell Depletion With the Anti-CD20 Monoclonal Antibody Rituximab in the Treatment of Graves' Disease
Study Type
Interventional
2. Study Status
Record Verification Date
October 2006
Overall Recruitment Status
Completed
Study Start Date
June 2003 (undefined)
Primary Completion Date
undefined (undefined)
Study Completion Date
October 2006 (undefined)
3. Sponsor/Collaborators
Name of the Sponsor
Odense University Hospital
4. Oversight
5. Study Description
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)
Detailed Description
Background
Rituximab is a chimeric murine/human 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 mechanism(s) 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, Wegener's 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, e.g., 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 mg/m², administered by iv. Infusion once a week for 4 weeks.
Premedication with paracetamol 1g p.o. or tavestin 2 mg i.v. is given 30-60 min. before each infusion.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Graves´ Disease, Thyroid Associated Ophthalmopathy
Keywords
Graves disease, thyroid, ophthalmopathy, autoimmunity, B lymphocyte depletion, rituximab, immunization
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
20 (false)
8. Arms, Groups, and Interventions
Intervention Type
Drug
Intervention Name(s)
Methimazole
Intervention Type
Drug
Intervention Name(s)
Rituximab
Intervention Type
Biological
Intervention Name(s)
Immunization with various vaccines
Primary Outcome Measure Information:
Title
Time to relapse after cessation of treatment judged at 1, 3, 6, 9 and 12 months post cessation.
Secondary Outcome Measure Information:
Title
Safety
Title
Changes in autoantibodies (monthly)
Title
Immunological changes (monthly)
Title
Response to vaccines (1 month post-immunization)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Graves´ disease
Adequate anticonception in women.
Exclusion Criteria:
Performance status >2
Previous rituximab treatment
Immunosuppressive treatment
Serious concomitant disease
Active infections
Pregnancy / breast feeding.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Daniel El-Fassi, MD
Organizational Affiliation
Odense University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Endocrinology, Odense University Hospital
City
Odense
State/Province
Funen
ZIP/Postal Code
5000
Country
Denmark
Facility Name
Department of Hematology, Odense University Hospital
City
Odense
ZIP/Postal Code
5000
Country
Denmark
12. IPD Sharing Statement
Citations:
PubMed Identifier
16645007
Citation
El Fassi D, Nielsen CH, Hasselbalch HC, Hegedus L. The rationale for B lymphocyte depletion in Graves' disease. Monoclonal anti-CD20 antibody therapy as a novel treatment option. Eur J Endocrinol. 2006 May;154(5):623-32. doi: 10.1530/eje.1.02140.
Results Reference
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Learn more about this trial
Rituximab in the Treatment of Graves' Disease
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