Efficacy of Methotrexate in Myasthenia Gravis

Study Overview
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Brief Summary
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Myasthenia gravis is a rare neuromuscular disorder characterized by weakness and fatigability of ocular, bulbar, and extremity musculature. The specific aim of this study is to determine if oral methotrexate is an effective therapy for myasthenia gravis (MG) patients who are prednisone dependent. Patients will be randomized to receive either methotrexate or placebo and those who are entered onto this trial will have symptoms and signs of the disease while on prednisone therapy. The hypothesis is that adding methotrexate therapy in these patients will improve the MG manifestations so that the prednisone dose can be reduced and clinical measures of MG severity will improve. Funding Source - FDA OOPD

Official Title
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Phase II Trial of Methotrexate in Myasthenia Gravis

Conditions
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Myasthenia Gravis

Intervention / Treatment
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* Drug: Methotrexate
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have MGFA MG grades 2, 3, or 4 generalized myasthenia gravis, according to the MGFA classification system Elevated acetylcholine receptor antibody (AChR-Ab) titer. Patient's signs and symptoms should not be better explained by another disease process. Prednisone dose of at least 10 mg/day (or the equivalent in alternate days) and the subject must be on a stable dose of prednisone for 30 days prior to the screening visit. 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 patients who are premenopausal and are: (a) pregnant on the basis of a serum pregnancy test, (b) breast-feeding, or (c) not using an effective method of double barrier (1 hormonal plus 1 barrier method or 2 simultaneous barrier methods) 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. Evidence of thymoma on chest CT or MRI. Such a finding could require immediate thymectomy and would preclude entry into the study. Thymectomy in the previous three months. Patients who have been medicated with azathioprine, cyclosporine, cyclophosphamide, mycophenolate mofetil, IVIg, or other immunosuppressive drugs within the last 60 days. Chest X-ray with evidence of tumor, infection, or interstitial lung disease. Clinical history of chronic or recurrent infections. Daily use of non-steroidal anti-inflammatory drugs (NSAIDs). History of renal or hepatic insufficiency or liver enzymes greater than the 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 predicted. MG Grade 1 (ocular only) or 5 (crisis, requiring ventilator). Prior use of methotrexate for any condition.

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>Methotrexate | Drug: Methotrexate<br>* 10 mg weekly for 2 weeks and then increase to 15mg for 2 weeks and then 20mg weekly until the end of the study<br>|
| Placebo Comparator: 2<br>Placebo | Other: Placebo<br>* Weekly<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Prednisone Dose Area Under the Curve | The primary outcome measure was the nine-month prednisone area under the dose-time curve (AUDTC, months 4-12). The AUDTC was chosen because it accounted for changes in the prednisone dose that could occur frequently during a month. | 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Prednisone Daily Dose (mg/Day) | Participants were asked to fill out the amount of prednisone they took every day on a paper diary. | Total length of time daily dose information was collected, i.e. 9 months. | 
| Quantitative Myasthenia Gravis (QMG) Score | The QMG is a 13 item ordinal scale which measures ocular, bulbar, extremity fatigue and strength, along with respiratory function. The scale is from 0 - 3 for each item, with 0 meaning normal and 3 is severe. Total score can range from 0 to 39. | Change from Baseline to Month 12 | 
| Manual Muscle Testing 12 Month Change | This measurement was developed to measure the strength of muscle groups in the face, neck, arms and legs. Measurement is made by grading the amount of weakness. Participants are graded as having normal, mild (25%) weakness, moderate (50%) weakness or severe (75%) weakness and 4 = paralyzed/unable to do. Normal would receive a score of 0, mild would receive a score of 1, moderate would receive a score of 2, severe would receive a score of 3 and unable to perform would receive a score of 4. Range would be from 0 (no weakness) to 76 (complete paralysis). | Change from Baseline to Month 12 | 
| MGQOL 12 Month Change | This test is a 15 item patient-reported scale indicating how myasthenia gravis affects the quality of life. Each item is graded as how true each statement has been over the past 7 days. The scale is 0=Not at all, 1= a little bit, 2= somewhat, 3= quite a bit and 4= very much. The numbers are then added to produce a total score. The MGQOL score would range from 0 (no MG symptoms that affected their quality of life) to a score of 60 (MG symptoms affected they quality of life very much). | Change from Baseline to Month 12 | 
| MG-ADL 12 Month Change | The MG-ADL is an 8 item scale developed to assess myasthenia gravis symptoms. Score will range from 0 (normal - no MG symptoms) to 24 (severe MG symptoms) | Change from Baseline to Month 12 | 
| MG Composite Change Over 12 Months | This scale is composed of components of the QMG, MG-ADL and the MMT. These components have been shown to be the most responsive in previous clinical trials. Each item in the QMG, MG-ADL and the MMT was weighed (Rasch analysis performed) and then assigned a score. Score would range from 0 (no effects from the myasthenia gravis) to a score of 50. A participant with a score of 50 wwould be in the hospital on a ventilator. | Change from Baseline to Month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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myasthenia gravis