BeatMG: Phase II Trial of Rituximab In Myasthenia Gravis

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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B Cell Targeted Treatment In Myasthenia Gravis (BeatMG): A Phase II Trial of Rituximab In Myasthenia Gravis

Conditions
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Myasthenia Gravis

Intervention / Treatment
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* Drug: Rituximab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects 21 to 90 years old 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. Elevated AChR antibody titer Subject's signs and symptoms should not be better explained by another disease process. Subjects must be on a stable standard immunosuppressive regimen: 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. 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). Subjects must be willing to complete the study and return for follow-up visits. 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. Able and willing to give written informed consent and comply with the requirements of the study protocol. 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. 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: A history of chronic degenerative, psychiatric, or neurologic disorder other than MG that can produce weakness or fatigue. Other major chronic or debilitating illnesses within six months prior to study entry. Female subjects who are premenopausal and are: pregnant on the basis of a serum pregnancy test, breast-feeding, or 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). Altered levels of consciousness, dementia, or abnormal mental status. Thymectomy in the previous six months. 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 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. Subjects who have received IVIg or PLEX treatment within the last 4 weeks (28 days) prior to the baseline visit. Unstable dose or a stable dose of > 480 mg/day of pyridostigmine in 2 weeks prior to screening visit. Daily use of non-steroidal anti-inflammatory drugs (NSAIDs). History of renal or hepatic insufficiency or elevated liver enzymes (AST or ALT >2.5 x Upper Limit of Normal). History of bone marrow hypoplasia, leucopenia, thrombocytopenia, significant anemia, clinical or laboratory evidence of immunodeficiency syndromes. Forced Vital Capacity (FVC) <50% of percent predicted. General Safety & Laboratory Exclusion Criteria ANC < 1.5 x 103 cells/microliter Hemoglobin: < 8.0 gm/dL Platelets: < 100,000/mm Positive Hepatitis B or C serology (Hep B surface antigen and Hep C antibody) History of positive HIV (HIV conducted during screening if applicable) Treatment with any investigational agent within 4 weeks of screening or 5 half-lives of the investigational drug (whichever is longer) Receipt of a live vaccine within 4 weeks prior to randomization Previous treatment with rituximab (MabThera® / Rituxan®) Previous treatment with natalizumab (Tysabri®) History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies History of recurrent significant infection or history of recurrent bacterial infections 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 Unstable steroid dose in the past 4 weeks (28 days) Lack of peripheral venous access History of drug, alcohol, or chemical abuse within 6 months prior to screening 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. History of psychiatric disorder that would interfere with normal participation in this protocol Significant cardiac or pulmonary disease (including obstructive pulmonary disease) 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 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. Prednisone dose of more than 100 mg/day (or 200 mg over a two day period).

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>The placebo group will receive a vehicle control infusion | Drug: Placebo<br>* The placebo group will receive a vehicle control infusion<br>|
| Experimental: Rituximab<br>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 | Drug: Rituximab<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Steroid Sparing Effect | Percent of subjects that achieve a ≥ 75% reduction in mean daily prednisone dose in the 4 weeks prior to week 52 and have clinical improvement or no significant worsening of symptoms (≤ 2 point increase in MGC score) as compared to 4-week period prior to randomization and initiation of treatment. | 4 weeks prior baseline and 4 weeks prior to week 52 | 
| Safety:Percentage of Study Participants With Treatment-related Adverse Experiences | Evaluate treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs) | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Myasthenia Gravis Composite (MGC) Scores From Baseline to Week 52 | Evaluate whether there is a trend towards clinical benefit at end of 52 week treatment period, as measured by mean change in the MGC score, an MG-specific clinical outcomes scale used as endpoint in prior MG clinical trials. The Myasthenia Gravis Composite (MGC) scale consists of test items from the MG-ADL (Myasthenia Gravis Activities of Daily Living) scale and the QMG (Quantitative Myasthenia Gravis Scale) that measure symptoms and signs of MG, with weighted response options. The minimum score is 0, and the maximum score is 50. Higher scores correlate with clinical worsening of the disease. | baseline and 52 weeks | 
| Change in Quantitative Myasthenia Gravis(QMG) Scores From Baseline to Week 52 | Evaluate whether there is a trend towards clinical benefit at end of 52 week treatment period, as measured by the mean change in the QMG score - a specific clinical outcome scale used as endpoint in prior MG clinical trials. The Quantitative Myasthenia Gravis Score (QMG) is a commonly used objective outcome measure in myasthenia gravis (MG) comprising 13 items, each with a possible score from 0 to 3, and a maximum possible of 39 points, where a higher score indicates more severe disease. | baseline and 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myasthenia Gravis, Rituximab, SNOMED code 31839002