BeatMG: Phase II Trial of Rituximab In Myasthenia Gravis
Condition: Myasthenia Gravis
MeSH terms: Myasthenia Gravis; Muscle Weakness
Intervention: Rituximab; Placebo
Intervention description: Intervention (rituximab): The treatment group will receive a total of two cycles of rituximab separated by 6 months. Each cycle is defined as one infusion (375mg/m2 IV) per week for four consecutive weeks; The placebo group will receive a vehicle control infusion
Intervention MeSH terms: Rituximab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 52.0
Sex: All
Minimum age: 21 Years
Maximum age: 90 Years
Healthy volunteers: No
Keywords: Myasthenia Gravis; Rituximab; SNOMED code 31839002

Summary:

      The specific primary objective of this study is to determine whether rituximab is a safe and
      beneficial therapeutic for Myasthenia Gravis (MG) that warrants further study in a phase III
      efficacy trial.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Subjects 21 to 90 years old

          2. Subjects must have generalized MG, defined as MGFA clinical classification grades 2
             (mild), 3 (moderate), or 4 (severe, but not intubated) at the time of
             screening/randomization.

          3. Elevated AChR antibody titer

          4. Subject's signs and symptoms should not be better explained by another disease
             process.

          5. Subjects must be on a stable standard immunosuppressive regimen:

               1. Prednisone only: Prednisone dose must be at least 15mg/day (or the equivalent on
                  alternate days), and the dose of prednisone must have been stable for at least 4
                  weeks (28 days) prior to the baseline visit.

               2. Prednisone plus another immunosuppressive therapy (IST). Immunosuppressive
                  therapies other than prednisone, specifically azathioprine, mycophenolate
                  mofetil, cyclosporine, tacrolimus or methotrexate, are permitted, but the dose
                  must have been stable for at least 6 months prior to the baseline visit.

             (Note: The prednisone dose must be stable as defined in the prednisone only group. The
             IST dose must remain stable throughout the course of the study).

          6. Subjects must be willing to complete the study and return for follow-up visits.

          7. No history of thymoma, tumor, infection, or interstitial lung disease on chest CT,
             MRI, or chest x-ray. Note: Chest x-ray will be completed at screening to look of
             interstitial lung disease. A chest CT or MRI to evaluate for thymoma must be completed
             as part of prescreening.

          8. Able and willing to give written informed consent and comply with the requirements of
             the study protocol.

          9. Subjects must be able to give written informed consent before participating in this
             study. A copy of the signed consent must be kept in the subject's medical record.

         10. Men and women of reproductive potential must agree to use an acceptable method of
             birth control during treatment and for twelve months (1 year) after completion of
             treatment.

        Exclusion Criteria:

          1. A history of chronic degenerative, psychiatric, or neurologic disorder other than MG
             that can produce weakness or fatigue.

          2. Other major chronic or debilitating illnesses within six months prior to study entry.

          3. Female subjects who are premenopausal and are:

               1. pregnant on the basis of a serum pregnancy test,

               2. breast-feeding, or

               3. not using an effective method of double barrier (1 hormonal plus 1 barrier method
                  or 2 simultaneous barrier methods) or birth control (birth control pills, male
                  condom, female condom, intrauterine device, Norplant, tubal ligation, or other
                  sterilization procedures).

          4. Altered levels of consciousness, dementia, or abnormal mental status.

          5. Thymectomy in the previous six months.

          6. Subjects who have been medicated with immunosuppressive drugs not listed in inclusion
             #5 within the last 8 weeks (56 days) prior to the baseline visit

          7. Subjects who have been medicated with an immunosuppressive agent such as azathioprine,
             mycophenolate mofetil, cyclosporine, tacrolimus or methotrexate, that is withdrawn
             within 8 weeks (56 days) of the Baseline Visit.

          8. Subjects who have received IVIg or PLEX treatment within the last 4 weeks (28 days)
             prior to the baseline visit.

          9. Unstable dose or a stable dose of > 480 mg/day of pyridostigmine in 2 weeks prior to
             screening visit.

         10. Daily use of non-steroidal anti-inflammatory drugs (NSAIDs).

         11. History of renal or hepatic insufficiency or elevated liver enzymes (AST or ALT >2.5 x
             Upper Limit of Normal).

         12. History of bone marrow hypoplasia, leucopenia, thrombocytopenia, significant anemia,
             clinical or laboratory evidence of immunodeficiency syndromes.

         13. Forced Vital Capacity (FVC) <50% of percent predicted.

             General Safety & Laboratory Exclusion Criteria

         14. ANC < 1.5 x 103 cells/microliter

         15. Hemoglobin: < 8.0 gm/dL

         16. Platelets: < 100,000/mm

         17. Positive Hepatitis B or C serology (Hep B surface antigen and Hep C antibody)

         18. History of positive HIV (HIV conducted during screening if applicable)

         19. Treatment with any investigational agent within 4 weeks of screening or 5 half-lives
             of the investigational drug (whichever is longer)

         20. Receipt of a live vaccine within 4 weeks prior to randomization

         21. Previous treatment with rituximab (MabThera® / Rituxan®)

         22. Previous treatment with natalizumab (Tysabri®)

         23. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal
             antibodies

         24. History of recurrent significant infection or history of recurrent bacterial
             infections

         25. Known active bacterial, viral fungal mycobacterial, or other infection (including
             tuberculosis or atypical mycobacterial disease, but excluding fungal infections of
             nail beds) or any major episode of infection requiring hospitalization or treatment
             with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks
             prior to screening

         26. Unstable steroid dose in the past 4 weeks (28 days)

         27. Lack of peripheral venous access

         28. History of drug, alcohol, or chemical abuse within 6 months prior to screening

         29. Concomitant malignancies or previous malignancies, with the exception of adequately
             treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the
             cervix or prostate.

         30. History of psychiatric disorder that would interfere with normal participation in this
             protocol

         31. Significant cardiac or pulmonary disease (including obstructive pulmonary disease)

         32. Any other disease, metabolic dysfunction, physical examination finding, or clinical
             laboratory finding giving reasonable suspicion of a disease or condition that
             contraindicates the use of an investigational drug or that may affect the
             interpretation of the results or render the subject at high risk from treatment
             complications

         33. Subjects that do not record daily prednisone doses for at least 28 days before the
             Baseline Visit, or subjects whose prednisone dose varies by ≥6mg/day on average.

         34. Prednisone dose of more than 100 mg/day (or 200 mg over a two day period).