Efficacy of Methotrexate in Myasthenia Gravis

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

Study Description

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

Study Design

• 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

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: 1; Methotrexate	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; Placebo	Other: Placebo; Weekly

Outcome Measures

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.

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

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

Investigators

• Principal Investigator: Richard Barohn, MD; University of Kansas Medical Center

More Information

• 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
• 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:

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; Neoplasms; Paraneoplastic Syndromes; Autoimmune Diseases of the Nervous System; Neurodegenerative Diseases; Neuromuscular Junction Diseases; Neuromuscular Diseases; Autoimmune Diseases; Immune System Diseases; Methotrexate; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Reproductive Control Agents; Physiological Effects of Drugs; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Dermatologic Agents; Enzyme Inhibitors