Efficacy of Methotrexate in Myasthenia Gravis

Phase II Trial of Methotrexate in Myasthenia Gravis

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00814138

Enrollment

Registered

2008-12-24

Start date

2009-04-30

Completion date

2014-01-31

Last updated

2016-05-26

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Myasthenia Gravis

Keywords

myasthenia gravis

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

Interventions

DRUGMethotrexate

10 mg weekly for 2 weeks and then increase to 15mg for 2 weeks and then 20mg weekly until the end of the study

OTHERPlacebo

Weekly

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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.

Design outcomes

Primary

Measure	Time frame	Description
Total Prednisone Dose Area Under the Curve	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

Measure	Time frame	Description
Quantitative Myasthenia Gravis (QMG) Score	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.
Manual Muscle Testing 12 Month Change	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).
Average Prednisone Daily Dose (mg/Day)	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.
MG-ADL 12 Month Change	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)
MG Composite Change Over 12 Months	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.
MGQOL 12 Month Change	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).

Countries

Canada, United States

Participant flow

Participants by arm

Arm	Count
Methotrexate 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	25
Placebo Placebo: 10 mg weekly for 2 weeks and then increase to 15mg for 2 weeks and then 20mg weekly until the end of the study	25
Total	50

Baseline characteristics

Characteristic	Methotrexate	Placebo	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	12 Participants	15 Participants	27 Participants
Age, Categorical Between 18 and 65 years	13 Participants	10 Participants	23 Participants
Age, Continuous	66.5 years	68.6 years	67.6 years
Region of Enrollment Canada	3 participants	4 participants	7 participants
Region of Enrollment United States	22 participants	21 participants	43 participants
Sex: Female, Male Female	6 Participants	9 Participants	15 Participants
Sex: Female, Male Male	19 Participants	16 Participants	35 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	23 / 25	23 / 25
serious Total, serious adverse events	2 / 25	1 / 25

Outcome results

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.

Time frame: 9 months

Population: Myasthenia Gravis patients aged 18 and older that were acetylcholine antibody positive with a myasthenia gravis foundation score of Grade II, III or IV.

Arm	Measure	Value (NUMBER)
Methotrexate	Total Prednisone Dose Area Under the Curve	2996.6 mg*Months
Placebo	Total Prednisone Dose Area Under the Curve	3484.7 mg*Months

Comparison: If a study participant terminated, their last results were pulled forward.p-value: 0.2695% CI: [-2443.4, 1467.3]Wilcoxon (Mann-Whitney)

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.

Time frame: Total length of time daily dose information was collected, i.e. 9 months.

Arm	Measure	Value (MEAN)
Methotrexate	Average Prednisone Daily Dose (mg/Day)	12.8 mg/day
Placebo	Average Prednisone Daily Dose (mg/Day)	14.6 mg/day

Comparison: If a study participant terminated, their last results were pulled forward.p-value: 0.2695% CI: [-9.7, 5.8]Wilcoxon (Mann-Whitney)

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).