Efficacy of Methotrexate in Myasthenia Gravis

Myasthenia Gravis Clinical Trial

Official title:

Phase II Trial of Methotrexate in Myasthenia Gravis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00814138
• Other study ID #: 11552
• Secondary ID: FDA OOPD 003538
• Status: Completed
• Phase: Phase 2
• First received: December 23, 2008
• Last updated: November 18, 2015
• Start date: April 2009
• Est. completion date: January 2014

Study information

• Verified date: November 2015
• Source: University of Kansas Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: January 2014
• Est. primary completion date: January 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Myasthenia Gravis

Intervention

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

Other:
• Placebo
Weekly

Locations

Country	Name	City	State
Canada	University of Toronto	Toronto	Ontario
United States	Massachusetts General Hospitals	Boston	Massachusetts
United States	University of North Carolina	Chapel Hill	North Carolina
United States	University of Virginia	Charlottesville	Virginia
United States	Ohio State University	Columbus	Ohio
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	University of California, San Francisco	Fresno	California
United States	Penn State College of Medicine, The Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	The Nerve and Muscle Center of Texas	Houston	Texas
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	University of California-Irvine	Irvine	California
United States	University of Florida, Health Science Center Jacksonville	Jacksonville	Florida
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	Phoenix Neurological Associates	Phoenix	Arizona
United States	University Health Sciences Center, San Antonio	San Antonio	Texas
United States	Forbes Norris MDA/ALS Research Center	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
University of Kansas Medical Center

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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.	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No