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Efficacy of Methotrexate in Myasthenia Gravis

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ClinicalTrials.gov Identifier: NCT00814138
Recruitment Status : Completed
First Posted : December 24, 2008
Results First Posted : December 23, 2015
Last Update Posted : May 26, 2016
Information provided by (Responsible Party):
Richard Barohn, MD, University of Kansas Medical Center

Brief Summary:

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

Condition or disease Intervention/treatment Phase
Myasthenia Gravis Drug: Methotrexate Other: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Phase II Trial of Methotrexate in Myasthenia Gravis
Study Start Date : April 2009
Actual Primary Completion Date : January 2014
Actual Study Completion Date : January 2014

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Active Comparator: 1
Drug: Methotrexate
10 mg weekly for 2 weeks and then increase to 15mg for 2 weeks and then 20mg weekly until the end of the study

Placebo Comparator: 2
Other: Placebo

Primary Outcome Measures :
  1. Total Prednisone Dose Area Under the Curve [ Time Frame: 9 months ]
    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.

Secondary Outcome Measures :
  1. Average Prednisone Daily Dose (mg/Day) [ Time Frame: Total length of time daily dose information was collected, i.e. 9 months. ]
    Participants were asked to fill out the amount of prednisone they took every day on a paper diary.

  2. Quantitative Myasthenia Gravis (QMG) Score [ Time Frame: Change from Baseline to Month 12 ]
    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.

  3. Manual Muscle Testing 12 Month Change [ Time Frame: Change from Baseline to Month 12 ]
    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).

  4. MGQOL 12 Month Change [ Time Frame: Change from Baseline to Month 12 ]
    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).

  5. MG-ADL 12 Month Change [ Time Frame: Change from Baseline to Month 12 ]
    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)

  6. MG Composite Change Over 12 Months [ Time Frame: Change from Baseline to Month 12 ]
    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.

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00814138

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United States, Arizona
Phoenix Neurological Associates
Phoenix, Arizona, United States, 85018
United States, California
University of California, San Francisco
Fresno, California, United States, 93701
University of California-Irvine
Irvine, California, United States, 92697
Forbes Norris MDA/ALS Research Center
San Francisco, California, United States, 94115
United States, Florida
University of Florida, Health Science Center Jacksonville
Jacksonville, Florida, United States, 32209
United States, Iowa
University of Iowa Hospitals and Clinics
Iowa City, Iowa, United States, 52242
United States, Kansas
University of Kansas Medical Center
Kansas City, Kansas, United States, 66160
United States, Massachusetts
Massachusetts General Hospitals
Boston, Massachusetts, United States, 02114
United States, North Carolina
University of North Carolina
Chapel Hill, North Carolina, United States, 27599
United States, Ohio
Ohio State University
Columbus, Ohio, United States, 43210
United States, Pennsylvania
Penn State College of Medicine, The Milton S. Hershey Medical Center
Hershey, Pennsylvania, United States, 17033
United States, Texas
University of Texas Southwestern Medical Center
Dallas, Texas, United States, 75390
The Nerve and Muscle Center of Texas
Houston, Texas, United States, 77030
University Health Sciences Center, San Antonio
San Antonio, Texas, United States, 78229
United States, Virginia
University of Virginia
Charlottesville, Virginia, United States, 22908
Canada, Ontario
University of Toronto
Toronto, Ontario, Canada, M5G 2C4
Sponsors and Collaborators
University of Kansas Medical Center
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Principal Investigator: Richard Barohn, MD University of Kansas Medical Center
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Responsible Party: Richard Barohn, MD, Gertrude and Dewey Zeigler Professor of Neurology, Chairman Deptartment of Neurology, University of Kansas Medical Center
ClinicalTrials.gov Identifier: NCT00814138    
Other Study ID Numbers: 11552
FDA OOPD 003538 ( Other Grant/Funding Number: RO1FD003538 )
First Posted: December 24, 2008    Key Record Dates
Results First Posted: December 23, 2015
Last Update Posted: May 26, 2016
Last Verified: April 2016
Keywords provided by Richard Barohn, MD, University of Kansas Medical Center:
myasthenia gravis
Additional relevant MeSH terms:
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Myasthenia Gravis
Muscle Weakness
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Pathologic Processes
Paraneoplastic Syndromes, Nervous System
Nervous System Neoplasms
Neoplasms by Site
Paraneoplastic Syndromes
Autoimmune Diseases of the Nervous System
Neurodegenerative Diseases
Neuromuscular Junction Diseases
Neuromuscular Diseases
Autoimmune Diseases
Immune System Diseases
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors