A Pilot Trial of Rituxan in Refractory Myasthenia Gravis

U.S. FDA Resources

Estimated Enrollment:	10
Study Start Date:	April 2004
Study Completion Date:	March 2009
Primary Completion Date:	March 2009 (Final data collection date for primary outcome measure)

Detailed Description:

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.

University of Vermont

Genentech

Rituxan Rituximab Myasthenia Gravis MG

Myasthenia Gravis Muscle Weakness Autoimmune Diseases of the Nervous System Nervous System Diseases Neuromuscular Junction Diseases Neuromuscular Diseases Autoimmune Diseases Immune System Diseases Muscular Diseases Musculoskeletal Diseases Neuromuscular Manifestations

Neurologic Manifestations Pathologic Processes Signs and Symptoms Rituximab Immunologic Factors Physiological Effects of Drugs Pharmacologic Actions Antirheumatic Agents Therapeutic Uses Antineoplastic Agents