A Study Evaluating the Safety and Efficacy of Rituximab in Patients With Myasthenia Gravis

Study Overview
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Brief Summary
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A randomized, double-blind, placebo-controlled multicenter study evaluating the safety and efficacy of Rituximab (Mabthera®) in patients with new onset generalized myasthenia gravis (MG).

Detailed Description
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Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction caused by auto-antibodies. MG is characterized by weakness in skeletal muscles and occurs in all ages, but mostly among young adult women and in people of both sexes over the age of 60 years. The disease has a wide variation in severity, where in milder cases only symptom-relieving choline esterase blockers may be sufficient. In many cases, however, immunomodulatory drugs are required. Traditionally MG has been treated with high doses of corticosteroids over longer time periods, which causes significant risks of side effects. Therefore, since several decades, oral immunosuppressive drugs have been used in order to reduce the need for steroids. This group includes azathioprine, cyclosporine and mycophenolate. However, none of these drugs has been approved for use in MG and the effect is usually delayed. There is thus a great need to develop newer treatment algorithms for MG, for example including more effective biological drugs. Several small observational studies have shown that rituximab, an anti-CD20 monoclonal antibody that eliminate B cells, can have good effects in treatment refractory MG. The aim of the present study is to study the effect of rituximab compared to placebo in the treatment of new onset MG of moderate to severe symptomatology.

Official Title
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A Randomized, Double-blind, Placebo-controlled Multicenter Study Evaluating the Safety and Efficacy of Rituximab (Mabthera®) in Patients With New Onset Generalized Myasthenia Gravis (MG)

Conditions
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Generalized Myasthenia Gravis

Intervention / Treatment
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* Drug: Rituximab
* Drug: Sodium Chloride solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with oculobulbar, bulbar or generalized MG ≥ 18 years of age and with onset of generalized symptoms or neurophysiological detection of generalized disease not more than 12 months ago. The diagnosis of MG should be determined with the following: Clinical neurological status with motor symptoms consistent with MG and at least two of the following: a positive serologic test for anti-acetylcholine receptor antibody (AChR) and/or b. typical MG findings on neurophysiological testing of neuromuscular transmission with single fiber electromyography (SFEMG) and / or repetitive nerve stimulation (RNS), and / or c. Positive anti-choline esterase-test, e.g. edrophoniumchloride or improvement of MG symptoms with oral cholinesterase inhibitors as judged by the treating physician. MGFA Class II to IV at screening. Quantitative MG score ≥ 6 at screening Women of childbearing potential must have a negative pregnancy test. Patients must have provided written informed consent. Patients must be able and willing to comply with all study procedures. Exclusion Criteria: Weakness only affecting ocular or periocular muscles (MGFA Class I). MG crisis at screening (MGFA Class V) Thymectomy already carried out. In order to avoid difficulties to evaluate the effect of the study drug, thymectomy, where it is indicated, should be scheduled to the follow-up period, ie after the first 24 weeks. Strong suspicion of thymoma, where thymectomy as judged by the treating physician should be done within 24 weeks. Active malignancy, if not adequately treated Pregnancy or breast-feeding. Ongoing acute or chronic viral or systemic bacterial infections including HIV, latent hepatitis B, which is clinically significant, according to the study doctor's opinion and not treated with appropriate antibiotic / antiviral drugs. Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease Previous use of immunosuppressive drugs, including rituximab, except prednisolone at a dose of up to 40mg daily for less than 3 months. This does not apply to treatment with immunosuppressive drugs / corticosteroids (except rituximab) for other indications than MG, provided at least 12 months have passed since treatment was terminated. Suspected hypersensitivity to the study drug Participation in another trial of study drug within 30 days prior to screening. Any medical condition which, according to the study physician's opinion, may interfere with the patient's participation in the study, poses additional risks for the patient, or that complicate the assessment of patients. Vaccination within 4 weeks before inclusion.

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab<br>A single infusion at a dose of 500 mg of Mabthera/Rituximab. | Drug: Rituximab<br>* A single infusion at a dose of 500 mg Mabthera/Rituximab.<br>* Other names: Mabthera;|
| Sham Comparator: Sodium Chloride solution<br>A single infusion with sodium chloride solution. | Drug: Sodium Chloride solution<br>* A single infusion of Placebo/Sham.<br>* Other names: Sodium Chloride;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with quantitative MG ascore (QMG) score ≤ 4 and a daily Prednisolon dose of ≤ 10mg at 16 weeks after administration of study drug/placebo. | QMG is measured under standardized conditions with at least 12 hours since last intake of choline esterase inhibitors | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| QMG score at 24 weeks after administration of study drug/placebo. | QMG is measured under standardized conditions with at least 12 hours since last intake of choline esterase inhibitors | 24 weeks | 
| MG-activities of daily living (ADL) score at 16 weeks after administration of study drug/placebo | MG-ADL is a patient-reported outcome measured under standardized conditions with at least 12 hours since last intake of choline esterase inhibitors | 16 weeks | 
| MG-quality of life (QoL) score at 16 weeks after administration of study drug/placebo | MG-QoL is a patient-reported outcome measured under standardized conditions with at least 12 hours since last intake of choline esterase inhibitors | 16 weeks |