Clinical trial NCT00619671: A Pilot Trial of Rituxan in Refractory Myasthenia Gravis
Official title: Phase 1-2 Pilot Study of Rituximab (Rituxan) in Refractory Myasthenia Gravis.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Refractory Myasthenia Gravis
Keywords: Rituxan
Rituximab
Myasthenia Gravis
MG
Lead sponsor: University of Vermont
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
First posted: 2008-02-21
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Myasthenia gravis is a disease that happens because the immune system attacks the nervous system. The damage is caused by antibodies produced by B lymphocytes. These antibodies damage a special part of the muscle that helps transmit impulses from nerves to muscles to allow muscles to work properly. This damage results in symptoms of myasthenia gravis. Participants are being asked to participate in this research study because their myasthenia gravis has either failed to respond to treatments commonly used in the disease, or they have had bad side-effects from such treatments.

This is a research study of a drug called Rituximab. Rituximab, also called Rituxan, is a mouse antibody that has been changed to make it similar to a human antibody. Antibodies are proteins that can protect the body from foreign invaders, such as bacteria and viruses, by binding to substances called antigens. Rituxan works by binding to a protein, called the CD20 protein. Rituxan helps to destroy white blood cells that produce antibodies in the body, called B-lymphocytes. It is a treatment given through a vein in the participant's arm over a period of approximately 4-6 hours. It has been approved by the Food and Drug Administration (FDA) for use in patients with a form of cancer of the lymph glands called Non-Hodgkin's Lymphoma (NHL). Rituximab is not approved for their myasthenia gravis.

Treatment with Rituximab is being tried in this research study because Rituximab decreases B lymphocytes. There is preliminary evidence that Rituximab helps some patients with chronic and otherwise difficult to treat myasthenia gravis.

Detailed description: Myasthenia gravis (MG) is an immune-mediated disorder of the neuromuscular junction diagnosed on the basis of clinical, electrophysiological and serological features. Cyclosporine as a disease-modifying therapy has been effective in a controlled study; corticosteroids, immunosuppressive agents such as azathioprine and cyclophosphamide, plasmapheresis and intravenous human immune globulin have shown benefit in uncontrolled trials. There are several drawbacks to currently used medical treatments, including serious and debilitating side-effects, prohibitive costs, and the need for continuous or periodical treatment. Almost 20-25% of patients with MG are unresponsive to commonly used therapies, resulting in significant burden and economic loss. Rituximab is a chimeric anti-CD20 monoclonal antibody which produces a substantial reduction in circulating plasma cells (CD19+) and B cells (CD20+) and provides targeted therapy for B-cell lymphomas. Recently, rituximab has been found to be effective in several antibody-mediated autoimmune processes, including immune thrombocytopenia, autoimmune hemolytic anemia, and IgM-related polyneuropathies. There is preliminary evidence in the literature that treatment of MG patients with rituximab is likely to be of benefit. These observations would strongly suggest that rituximab might benefit refractory MG and needs further study.

Eligibility criteria: Inclusion Criteria:

Criteria for patient selection will be based upon the recent recommendations for clinical research standards by the Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America (Jaretzki et al, 2000).

Patients will be included in the trial based upon fulfilling all the criteria given below, except that they will be required to fulfill criterion 3 OR 4:

1. Patients must have a diagnosis of "Definite" MG (Seybold, 1999) as based on clinical, electrophysiological and serological criteria (Appendix 1)
2. Patients must have disease predominantly affecting bulbar or respiratory muscles of moderate or severe degree (Osserman grades 2B, 3 without crisis, or 4 without crisis) (Osserman and Genkins, 1971 and Appendix 2) as listed in Appendix 3, and a Quantitative MG score of \<25 (Appendix 7)
3. Patients must have disease refractory to treatment for at least 12 months with prednisone at a dose of 15mg/day and/or immunosuppressive drugs (azathioprine or cyclophosphamide at a dose of 100mg/day or cyclosporine at a dose to produce trough levels of \>50), with or without thymectomy and plasmapheresis/IVIG alone or in combination with above drugs at intervals of no more than once every 3 weeks, OR
4. Patients must have experienced intolerance or unacceptable side-effects following treatment with corticosteroids, immunosuppressive drugs (azathioprine, cyclophosphamide or cyclosporine), plasmapheresis or IVIG
5. Patients must be between 18 years and 80 years old
6. Patients must have adequate organ function / laboratory parameters as measured by the following criteria (values should be obtained within 2 weeks prior to enrollment):

   * Documented CD20 + cells
   * Absolute neutrophil count: \>2000/mm3
   * Platelets: \>100,000/mm3
   * Hemoglobin: \>10 gm/dL
   * Adequate renal function as indicated by normal BUN and creatinine levels
   * Adequate liver function, as indicated by AST and ALT \<2x Upper Limit of normal.
   * Normal serum electrolytes
7. Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for one year after completion of treatment
8. Written informed consent.

Exclusion Criteria:

Patients will be excluded from the trial based on the following criteria:

1. Myasthenic crisis with a forced vital capacity (FVC) of \<30% predicted, irrespective of need for respiratory support, or severe bulbar involvement (Appendix 3)
2. Patients requiring maintenance plasmapheresis or IVIG infusions at intervals of less than once every three weeks
3. Patients requiring respiratory support with invasive or non-invasive ventilation
4. Severe, uncontrolled or untreated concomitant cardiac (New York Heart Classification III or IV disease), hepatic, pulmonary, renal, hematologic or psychiatric disease
5. Toxicity grade 2 or more prior to treatment with rituximab in patients who failed prior treatments
6. Patients unwilling to attend for follow-up visits according to the study design
7. Patients will be excluded based on the following criteria:

   * History of HIV disease
   * Active Hepatitis B infection
   * Pregnancy (a serum pregnancy test will be performed for all women of childbearing potential immediately before treatment)
   * Active infection
8. Pregnant or breastfeeding women may not participate due to the lack of information on effects of rituximab on the fetus and developing child
9. Concomitant malignancies or previous malignancies within the last 5 years, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix.
10. No prior monoclonal antibody therapy.
11. History of significant psychiatric disease that will interfere with the consenting procedure, research visits, treatment protocol or evaluation of patients in the study.

Primary outcomes:
measure: To examine the effects of rituximab on disease activity in MG patients with refractory disease.
timeFrame: Patients will be followed for one year
Secondary outcomes:
measure: To determine the safety and tolerability of rituximab in MG patients with refractory disease.
timeFrame: Patients will be followed for one year
Other outcomes:
Locations:
city: Syracuse
country: United States
facility: State University of New York
state: New York
city: Burlington
country: United States
facility: University of Vermont Department of Neurology
state: Vermont
Study officials:
affiliation: University of Vermont Department of Neurology
name: Rup Tandan, MD, FRCP
role: PRINCIPAL_INVESTIGATOR
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