BeatMG: Phase II Trial of Rituximab In Myasthenia Gravis

Investigators plan on conducting a multicenter randomized, double-blind, placebo controlled
Phase II clinical trial utilizing a futility design. The study would include acetylcholine
receptor (AChR) antibody positive generalized MG subjects. This study also presents a unique
opportunity to study both drug and disease mechanisms because unlike many other autoimmune
diseases in which rituximab has been used, MG affords the investigation of antigen-specific
components that participate in the immunopathology of the disease, namely autoantibodies,
autoantibody-producing B cells, and antigen-specific T cells. This work will further our
understanding of MG immunopathology and it represents the first step toward gaining a more
complete understanding of the immune mechanisms underlying treatment of MG with rituximab
leading to new ways to treat the disease.

The specific aim of this study is to determine whether rituximab is a safe and effective
treatment for subjects with MG.

The SNOMED code for MG is 31839002.

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).