NN103: A Phase II Trial of Rituximab In Myasthenia Gravis

Rituximab in the Management of Myasthenia Gravis Objectives: The specific aim of this study is to determine if rituximab is a safe and effective treatment for patients with myasthenia gravis.The primary clinical endpoint will be the steroid sparing effect of rituximab.Our retrospective study showed that rituximab treatment had a measurable and significant effect on conventional immunosuppression, specifically demonstrating an unmistakable prednisone dose reduction. Importantly, steroid-reduction was recently demonstrated to be a practical outcome measure in a MG trial by an independent group. Also in 2012, the Task Force on MG Study Design of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America (MGFA) recommended steroid-sparing effect as a clinical outcome measure. Our primary outcome measure is the percent of patients achieving ≥ 75% mean daily prednisone dose reduction in the 4 weeks prior to week 52 and with clinical improvement or no worsening of symptoms (≤ 2 point change in MG Composite score). We plan a multicenter randomized, double-blind, placebo controlled clinical trial evaluating the safety and steroid-sparing effect of rituximab in MG. The study would enroll50 AChR antibody positive generalized MG patients. We expect to enroll 25 AChR+ patients in a treatment group along with a size matched control placebo group. Intervention (rituximab): Treatment group will receive a total of two cycles of rituximab separated by 6 months. Each cycle is defined as one infusion (375mg/m2IV) per week for four consecutive weeks. As such, cycle 1 will be administered weeks 1-4 and cycle 2 will be given weeks 24-28. The placebo group will receive a vehicle control infusion. Duration: We set a study period of 52 weeks based on the delayed benefits observed following rituximab treatment and in the setting of utilizing a two-cycle protocol. Sample Size and Population: Sample Size: 50 Population: Generalized AChR+ Myasthenia Gravis Randomization: 1:1 randomization. Inclusion Criteria: 1.Patients 18 and older. 2.Patients must have MGFA MG grades 2, 3, or 4 generalized myasthenia gravis, according to the MGFA classification system These grades correspond to mild (2), moderate (3), and severe (4). 3.Elevated AChR antibody titer at Mayo Medical Laboratory Rochester, MN 4.Patient’s signs and symptoms should not be better explained by another disease process. 5.Prednisone dose of at least 15 mg/day (or the equivalent in alternate days) and the subject must be on a stable dose of prednisone for 4 weeks prior to the screening visit. 6.Patients 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. 8.Patients must give written informed consent before participating in this study. 9.Patients can be on a stable dose of pyridostigmine(≤ 240 mg/day). 10.Able and willing to give written informed consent and comply with the requirements of the study protocol. 11.Patients must give written informed consent before participating in this study. A copy of the signed consent must be kept in the patient’s medical record. 12.Negative serum pregnancy test (for women of child bearing age). 13.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