Overview

The primary objective of this phase III trial is to investigate if Rituximab can reduce patients' functional impairment caused by MG. The secondary objectives of this trial are to assess whether treatment with rituximab in patients with MG will:

• Allow faster and greater corticosteroid tapering
• Reduce the frequency of exacerbations
• Improve quality of life
• Offer an acceptable safety and tolerability profile.

Eligibility

Inclusion Criteria:

1. Positive serologic test for anti-AChR or anti-MuSK antibody titers as confirmed at screening (one retest allowed), and

At least one of the following:

        i)-History of abnormal neuromuscular transmission test results demonstrated by single-
        fiber electromyography or repetitive nerve stimulation; or ii)-History of positive
        anticholinesterase test (eg, edrophonium chloride test); or iii)-Patient demonstrated
        improvement in MG signs on oral cholinesterase inhibitors, as assessed by the treating
        physician; or iv)-Clinical syndrome consistent with a diagnosis of MG, and not otherwise
        explained by another condition. c. MGFA Clinical Classification Class II, III, or IV at the
        time of screening and randomization.
        d. MG-ADL score of 5 or greater at screening and at randomization with > 50% of this
        score attributed to non-ocular items. e. QMG score of 11 or greater at screening and at
        randomization. f. Willing and able to comply with the protocol, complete study assessments,
        and return for follow- up visits.
        g. Females of childbearing potential who are sexually active with a non-sterilized male
        partner must use at least one highly effective contraception method (Table 1) from the time
        of screening and for 12 months after the final dose of IP. Periodic abstinence, the rhythm
        method, and the withdrawal method are not acceptable methods of contraception. h. Females
        of childbearing potential are defined as those who are not surgically sterile (ie,
        bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or those who
        are not postmenopausal (defined as 12 months with no menses without an alternative medical
        cause).
        i. Non-sterilized males who are sexually active with a female partner of childbearing
        potential must use a condom from Day 1 for the duration of the study and for 3 months after
        the last dose of IP. Because male condom is not a highly effective contraception method, it
        is strongly recommended that female partners of a male study subject also use a highly
        effective method of contraception throughout this period.
        Exclusion Criteria:
          1. Any condition that, in the opinion of the Investigator, would place the patient at
             unacceptable risk of complications, interfere with evaluation of the IP, or confound
             the interpretation of patient safety or study results.
          2. Lactating or pregnant females, or females who intend to become pregnant anytime from
             signing the informed consent form (ICF) throughout the RCP plus 6 months following
             last dose of IP.
          3. History of drug or alcohol abuse within < 1 year prior to screening, or any condition
             associated with poor compliance as judged by the Investigator.
          4. Site staff and their family members.
          5. Currently committed to an institution by way of official or judicial order.
          6. Subjects diagnosed with congenital myasthenic syndromes.
          7. Known immunodeficiency disorder, including human immunodeficiency virus (HIV)
             infection.
          8. Thymectomy within ≤ 12 months prior to baseline (Day 1) visit or planned thymectomy
             during the duration of the RCP.
        10. Receipt of the following medications or treatments at any time prior to randomization:
          1. Alemtuzumab (Lemtrada®, Campath®)
          2. Total lymphoid irradiation
          3. Bone marrow transplant
          4. T-cell vaccination therapy
          5. Natalizumab (Tysabri®) 10. Receipt of ANY immunosuppressive treatment (excluding
             corticosteroids) at ANY time prior to randomization (such as Azathioprine,
             Mycophenolate mofetil or Mycophenolic acid, Cyclosporine (except eye drop), Tacrolimus
             (except topical), Methotrexate, Cyclophosphamide, Tocilizumab (Actemra®), Belimumab
             (Benlysta®), Eculizumab (Soliris®), rituximab (MabThera®, Rituxan®), ocrelizumab
             (Ocrevus®), ofatumumab (Arzerra®), obinutuzumab (Gazyva®), inebilizumab, or any
             experimental B-cell depleting agent) 11. Receipt within the 4 weeks prior to Day 1:
        a. Intravenous immunoglobulin (IVIg) b. Plasma exchange (PLEX) treatment 12. Current use
        of:
          1. Prednisone < 20 mg/day or < 40 mg over a 2-day period (or equivalent dose of other
             corticosteroids)
          2. Pyridostigmine > 480 mg/day or unstable dose in the 2 weeks prior to Day 1 13.
             Concurrent/previous enrollment in another clinical study involving an investigational
             treatment within 4 weeks or 5 half-lives of the investigational treatment, whichever
             is longer, prior to Day 1.
             14. Receipt of a live attenuated vaccine within 4 weeks prior to randomization.
             Administration of inactivated (killed) vaccines is acceptable. 15. History of severe
             allergic or anaphylactic reactions to biologic agents or known allergy to any
             component of the IP formulation. 16. History of recurrent significant infections (eg,
             requiring hospitalization or IV antibiotics).
             17. Within 2 weeks prior to the screening visit: clinically significant active
             infection requiring antimicrobial medication but allowing chronic nail infections. 18.
             Unresected thymoma (Note: subjects with a benign thymoma resected > 1 year prior to
             screening may enroll. Benign is defined as no known metastases and no extension into
             or beyond the capsule on pathological examination. Imaging to evaluate for thymoma
             must have been performed prior to randomization per standard of care). 19. History of
             cancer, except for the following:
        a. In situ carcinoma of the cervix treated with apparent success with curative therapy for
        > 12 months prior to screening b. Cutaneous basal cell or squamous cell carcinoma treated
        with apparent success with curative therapy for > 12 months prior to screening c. Prostate
        cancer treated with radical prostatectomy or radiation therapy with curative intent > 3
        years prior to screening and without known recurrence or current treatment d. Malignant
        thymoma (i.e. Masaoka stage ≥ IIa) resected > 5 years prior to screening with no evidence
        of active disease and no therapy received over the previous 5 years. Imaging to evaluate
        for thymoma must have been performed prior to randomization per standard of care 21.
        Spontaneous or induced abortion, still or live birth, or pregnancy ≤ 4 weeks prior to
        screening.
        22. Any of the following laboratory abnormalities at screening (one repeat test may be
        conducted to confirm results prior to randomization within the same screening period):
        a. Elevated liver enzymes (aspartate aminotransferase (AST) or alanine aminotransferase
        (ALT) > 2.5 × upper limit of normal (ULN)). b. Total bilirubin > 1.5 × ULN (unless due to
        Gilbert's syndrome) c. Estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m2 d.
        CD19+ B-cell count < 40 cells/μL e. Absolute neutrophil count (ANC) < 1.2 × 103 cells/μl f.
        Platelet count < 75,000/μL (or < 75 × 109/L) g. Hemoglobin < 8.0 g/dL h. Total
        immunoglobulin < 600 mg/dL 23. Positive test for chronic hepatitis B infection at
        screening, defined as either (1) positive hepatitis B surface antigen (HBsAg) or (2) a
        positive hepatitis B core antibody (anti-HBc) PLUS negative hepatitis B surface antibody
        (anti-HBs). Note: Subjects with a positive anti-HBs only, or a positive anti-HBc plus
        positive anti-HBs and negative HBsAg, are eligible to enroll. 24. Positive test for
        hepatitis C virus antibody. 25. Positive HIV test. 26. Blood transfusion within 4 weeks
        prior to screening or during the screening period.
        27. Inability to read. 28. History of active or latent tuberculosis (TB), or a positive
        QuantiFERON®-TB Gold test at screening, unless treatment for tuberculosis was completed per
        local guidelines. Subjects with latent TB or a positive QuantiFERON®-TB Gold test who are
        actively on anti-TB treatment can enroll if they have completed at least 1 month of anti-TB
        treatment and intend to complete the full course of anti-TB treatment. Subjects with an
        indeterminate QuantiFERON®-TB Gold test result can enroll if a repeat QuantiFERON®-TB Gold
        is negative or a tuberculin skin test is negative.