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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT00619671
Other study ID # RituxanMGPilot
Secondary ID BB-IND# 11403Gen
Status Completed
Phase Phase 1/Phase 2
First received January 14, 2008
Last updated January 15, 2013
Start date April 2004
Est. completion date March 2009

Study information

Verified date January 2013
Source University of Vermont
Contact n/a
Is FDA regulated No
Health authority United States: Food and Drug Administration
Study type Interventional

Clinical Trial 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.


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.


Recruitment information / eligibility

Status Completed
Enrollment 10
Est. completion date March 2009
Est. primary completion date March 2009
Accepts healthy volunteers No
Gender Both
Age group 18 Years to 80 Years
Eligibility 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.

Study Design

Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment


Related Conditions & MeSH terms


Intervention

Drug:
Rituximab (Rituxan)
Four weekly IV infusions of Rituxan with dosage individually calculated per subject.

Locations

Country Name City State
United States University of Vermont Department of Neurology Burlington Vermont
United States State University of New York Syracuse New York

Sponsors (2)

Lead Sponsor Collaborator
University of Vermont Genentech, Inc.

Country where clinical trial is conducted

United States, 

References & Publications (28)

AAEM Quality Assurance Committee. American Association of Electrodiagnostic Medicine. Practice parameter for repetitive nerve stimulation and single fiber EMG evaluation of adults with suspected myasthenia gravis or Lambert-Eaton myasthenic syndrome: summary statement. Muscle Nerve. 2001 Sep;24(9):1236-8. — View Citation

Aranda JM Jr, Scornik JC, Normann SJ, Lottenberg R, Schofield RS, Pauly DF, Miles M, Hill JA, Sleasman JW, Skoda-Smith S. Anti-CD20 monoclonal antibody (rituximab) therapy for acute cardiac humoral rejection: a case report. Transplantation. 2002 Mar 27;73(6):907-10. — View Citation

Barohn RJ, McIntire D, Herbelin L, Wolfe GI, Nations S, Bryan WW. Reliability testing of the quantitative myasthenia gravis score. Ann N Y Acad Sci. 1998 May 13;841:769-72. — View Citation

Besinger UA, Toyka KV, Hömberg M, Heininger K, Hohlfeld R, Fateh-Moghadam A. Myasthenia gravis: long-term correlation of binding and bungarotoxin blocking antibodies against acetylcholine receptors with changes in disease severity. Neurology. 1983 Oct;33(10):1316-21. — View Citation

Chemnitz J, Draube A, Scheid C, Staib P, Schulz A, Diehl V, Söhngen D. Successful treatment of severe thrombotic thrombocytopenic purpura with the monoclonal antibody rituximab. Am J Hematol. 2002 Oct;71(2):105-8. — View Citation

Chiu HC, Chen WH, Yeh JH. The six year experience of plasmapheresis in patients with myasthenia gravis. Ther Apher. 2000 Aug;4(4):291-5. — View Citation

Dallaire B, Leonard J, Varns C et al. IDEC-C2B8 (Rituximab): Biology and preclinical studies. J Mol Med 75:B230, 1997.

Davis TA, Grillo-López AJ, White CA, McLaughlin P, Czuczman MS, Link BK, Maloney DG, Weaver RL, Rosenberg J, Levy R. Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin's lymphoma: safety and efficacy of re-treatment. J Clin Oncol. 2000 Sep;18(17):3135-43. — View Citation

Gajra A, Vajpayee N, Grethlein SJ. Response of myasthenia gravis to rituximab in a patient with non-Hodgkin lymphoma. Am J Hematol. 2004 Oct;77(2):196-7. — View Citation

Grob D. Natural history of myasthenia gravis. In: Engel AG (ed). Myasthenia Gravis and Myasthenic Disorders. New York: Oxford University Press, 1999, pp 131-145.

Grollo-Lopez A, Varns C, Waldichuk C et al. IDEC-C2B8 chimeric anti-CD20 antibody: Safety and clinical activity in the treatment of patients with relapsed low-grade or follicular (IWF:A-D) non-Hodgkin's lymphoma (NHL). Br J Haematol 93:283, 1996.

Hilkevich O, Drory VE, Chapman J, Korczyn AD. The use of intravenous immunoglobulin as maintenance therapy in myasthenia gravis. Clin Neuropharmacol. 2001 May-Jun;24(3):173-6. — View Citation

Jaretzki A 3rd, Barohn RJ, Ernstoff RM, Kaminski HJ, Keesey JC, Penn AS, Sanders DB. Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Neurology. 2000 Jul 12;55(1):16-23. Review. — View Citation

Jenkins D, DiFrancesco L, Chaudhry A, Morris D, Glück S, Jones A, Woodman R, Brown CB, Russell J, Stewart DA. Successful treatment of post-transplant lymphoproliferative disorder in autologous blood stem cell transplant recipients. Bone Marrow Transplant. 2002 Sep;30(5):321-6. — View Citation

Leget GA, Czuczman MS. Use of rituximab, the new FDA-approved antibody. Curr Opin Oncol. 1998 Nov;10(6):548-51. Review. — View Citation

Levine TD, Pestronk A. IgM antibody-related polyneuropathies: B-cell depletion chemotherapy using Rituximab. Neurology. 1999 May 12;52(8):1701-4. — View Citation

Mantegazza R, Antozzi C, Peluchetti D, Sghirlanzoni A, Cornelio F. Azathioprine as a single drug or in combination with steroids in the treatment of myasthenia gravis. J Neurol. 1988 Nov;235(8):449-53. — View Citation

Oosterhuis HJ. The natural course of myasthenia gravis: a long term follow up study. J Neurol Neurosurg Psychiatry. 1989 Oct;52(10):1121-7. — View Citation

Osserman KE, Genkins G. Studies in myasthenia gravis: review of a twenty-year experience in over 1200 patients. Mt Sinai J Med. 1971 Nov-Dec;38(6):497-537. Review. — View Citation

Pascuzzi RM, Coslett HB, Johns TR. Long-term corticosteroid treatment of myasthenia gravis: report of 116 patients. Ann Neurol. 1984 Mar;15(3):291-8. — View Citation

Paul RH, Nash JM, Cohen RA, Gilchrist JM, Goldstein JM. Quality of life and well-being of patients with myasthenia gravis. Muscle Nerve. 2001 Apr;24(4):512-6. — View Citation

Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R, Newman RA, Hanna N, Anderson DR. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood. 1994 Jan 15;83(2):435-45. — View Citation

Seybold ME. Diagnosis of myasthenia gravis. In: Engel AG (ed). Myasthenia Gravis and Myasthenic Disorders. New York: Oxford University Press, 1999, pp 146-166.

Seybold ME. Treatment of myasthenia gravis. In: Engel AG (ed). Myasthenia Gravis and Myasthenic Disorders. New York: Oxford University Press, 1999a, pp 167-201.

Tindall RS, Phillips JT, Rollins JA, Wells L, Hall K. A clinical therapeutic trial of cyclosporine in myasthenia gravis. Ann N Y Acad Sci. 1993 Jun 21;681:539-51. — View Citation

Wolfe GI, Herbelin L, Nations SP, Foster B, Bryan WW, Barohn RJ. Myasthenia gravis activities of daily living profile. Neurology. 1999 Apr 22;52(7):1487-9. — View Citation

Zaja F, Russo D, Fuga G, Perella G, Baccarani M. Rituximab for myasthenia gravis developing after bone marrow transplant. Neurology. 2000 Oct 10;55(7):1062-3. — View Citation

Zecca M, De Stefano P, Nobili B, Locatelli F. Anti-CD20 monoclonal antibody for the treatment of severe, immune-mediated, pure red cell aplasia and hemolytic anemia. Blood. 2001 Jun 15;97(12):3995-7. — View Citation

* Note: There are 28 references in allClick here to view all references

Outcome

Type Measure Description Time frame Safety issue
Primary To examine the effects of rituximab on disease activity in MG patients with refractory disease. Patients will be followed for one year No
Secondary To determine the safety and tolerability of rituximab in MG patients with refractory disease. Patients will be followed for one year No
See also
  Status Clinical Trial Phase
Recruiting NCT05332587 - Efficacy and Safety of Low-dose Rituximab in the Treatment of Refractory Myasthenia Gravis Phase 3