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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
Sponsor:
Information provided by (Responsible Party):
Richard Barohn, MD, University of Kansas Medical Center

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Myasthenia Gravis
Interventions Drug: Methotrexate
Other: Placebo
Enrollment 50
Recruitment Details  
Pre-assignment Details  
Arm/Group Title 1 - Methotrexate (2.5 mg) Placebo
Hide Arm/Group Description 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: 10 mg weekly for 2 weeks and then increase to 15mg for 2 weeks and then 20mg weekly until the end of the study
Period Title: Overall Study
Started 25 25
Completed 24 18
Not Completed 1 7
Arm/Group Title Methotrexate Placebo Total
Hide Arm/Group Description 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: 10 mg weekly for 2 weeks and then increase to 15mg for 2 weeks and then 20mg weekly until the end of the study Total of all reporting groups
Overall Number of Baseline Participants 25 25 50
Hide Baseline Analysis Population Description
Eligible participatns were aged at least 18 years; had a diagnosis of generalized Myasthenia Gravis Foundation of America class II, III or IV; positive acetylcholine receptor antibodies; stable dose of greater than or equal to 10 mg/day of prednisone.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 25 participants 25 participants 50 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
13
  52.0%
10
  40.0%
23
  46.0%
>=65 years
12
  48.0%
15
  60.0%
27
  54.0%
Age, Continuous  
Mean (Full Range)
Unit of measure:  Years
Number Analyzed 25 participants 25 participants 50 participants
66.5
(28.5 to 83.9)
68.6
(26.6 to 87.2)
67.6
(26.6 to 87.2)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 25 participants 25 participants 50 participants
Female
6
  24.0%
9
  36.0%
15
  30.0%
Male
19
  76.0%
16
  64.0%
35
  70.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 25 participants 25 participants 50 participants
Canada 3 4 7
United States 22 21 43
1.Primary Outcome
Title Total Prednisone Dose Area Under the Curve
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Methotrexate Placebo
Hide Arm/Group Description:
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: 10 mg weekly for 2 weeks and then increase to 15mg for 2 weeks and then 20mg weekly until the end of the study
Overall Number of Participants Analyzed 25 25
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: mg*Months
2996.6
(1495.9 to 4497.3)
3484.7
(2151.8 to 4817.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Placebo
Comments If a study participant terminated, their last results were pulled forward.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.26
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -488.0
Confidence Interval (2-Sided) 95%
-2443.4 to 1467.3
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Average Prednisone Daily Dose (mg/Day)
Hide Description 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.
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Methotrexate Placebo
Hide Arm/Group Description:
Methotrexate: 10 mg/day for 2 weeks and then increase to 15mg/day for 2 weeks and then 20mg/day until the end of the study
Placebo: 10 mg/day for 2 weeks and then increase to 15mg/day for 2 weeks and then 20mg/day until the end of the study
Overall Number of Participants Analyzed 25 25
Mean (95% Confidence Interval)
Unit of Measure: mg/day
12.8
(9.1 to 16.5)
14.6
(11.5 to 17.8)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Placebo
Comments If a study participant terminated, their last results were pulled forward.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.26
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.9
Confidence Interval (2-Sided) 95%
-9.7 to 5.8
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Quantitative Myasthenia Gravis (QMG) Score
Hide Description 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.
Time Frame Change from Baseline to Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Methotrexate Placebo
Hide Arm/Group Description:
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: 10 mg weekly for 2 weeks and then increase to 15mg for 2 weeks and then 20mg weekly until the end of the study
Overall Number of Participants Analyzed 25 25
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-1.4
(-2.9 to 0.1)
0.3
(-1.8 to 2.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Placebo
Comments If a study participant terminated, their last results were pulled forward.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.29
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.7
Confidence Interval (2-Sided) 95%
-4.9 to 1.5
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Manual Muscle Testing 12 Month Change
Hide Description 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).
Time Frame Change from Baseline to Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Methotrexate Placebo
Hide Arm/Group Description:
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: 10 mg weekly for 2 weeks and then increase to 15mg for 2 weeks and then 20mg weekly until the end of the study
Overall Number of Participants Analyzed 25 25
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-5.5
(-7.4 to -3.8)
-3.3
(-6.6 to 0.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Placebo
Comments If a study participant terminated, their last results were pulled forward.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.28
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.2
Confidence Interval (2-Sided) 95%
-6.3 to 1.8
Estimation Comments [Not Specified]
5.Secondary Outcome
Title MGQOL 12 Month Change
Hide Description 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).
Time Frame Change from Baseline to Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Methotrexate Placebo
Hide Arm/Group Description:
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: 10 mg weekly for 2 weeks and then increase to 15mg for 2 weeks and then 20mg weekly until the end of the study
Overall Number of Participants Analyzed 25 25
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-4.6
(-9.1 to -0.1)
-3.7
(-8.4 to 1.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Placebo
Comments If a study participant terminated, their last results were pulled forward.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.82
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.9
Confidence Interval (2-Sided) 95%
-7.2 to 5.4
Estimation Comments [Not Specified]
6.Secondary Outcome
Title MG-ADL 12 Month Change
Time Frame Change from Baseline to Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Methotrexate Placebo
Hide Arm/Group Description:
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: 10 mg weekly for 2 weeks and then increase to 15mg for 2 weeks and then 20mg weekly until the end of the study
Overall Number of Participants Analyzed 25 25
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-1.2
(-2.3 to -0.5)
0.26
(-0.9 to 1.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Placebo
Comments If a study participant terminated, their last results were pulled forward.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.21
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.5
Confidence Interval (2-Sided) 95%
-3.7 to 0.8
Estimation Comments [Not Specified]
7.Secondary Outcome
Title MG Composite Change Over 12 Months
Hide Description 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.
Time Frame Change from Baseline to Month 12
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Methotrexate Placebo
Hide Arm/Group Description:
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: 10 mg weekly for 2 weeks and then increase to 15mg for 2 weeks and then 20mg weekly until the end of the study
Overall Number of Participants Analyzed 25 25
Mean (95% Confidence Interval)
Unit of Measure: units on a scale
-4.6
(-6.4 to -2.7)
-1.3
(-3.7 to 1.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Methotrexate, Placebo
Comments If a study participant terminated, their last results were pulled forward.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.09
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -3.3
Confidence Interval (2-Sided) 95%
-7.1 to 0.5
Estimation Comments [Not Specified]
Time Frame Adverse event data was collected over the 12 months the participants participated in the study.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Methotrexate Group - Adverse Events Placebo Group - Adverse Events
Hide Arm/Group Description Reported the number of adverse events in the group randomized to methotrexate. Reported the number of adverse events in the group randomized to placebo
All-Cause Mortality
Methotrexate Group - Adverse Events Placebo Group - Adverse Events
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Methotrexate Group - Adverse Events Placebo Group - Adverse Events
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   2/25 (8.00%)      1/25 (4.00%)    
Blood and lymphatic system disorders     
Thrombosis * 1 [1]  1/25 (4.00%)  1 1/25 (4.00%)  1
Gastrointestinal disorders     
Pancreatitis * 1 [2]  1/25 (4.00%)  1 0/25 (0.00%)  0
Nervous system disorders     
Stroke * 1 [3]  0/25 (0.00%)  0 1/25 (4.00%)  1
Respiratory, thoracic and mediastinal disorders     
Dyspnea * 1 [4]  0/25 (0.00%)  0 1/25 (4.00%)  1
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, CTCAE (3.0)
[1]
Subject was admitted to the hospital for possible thrombosis.
[2]
Subject admitted to hospital for Pancreatitis. Determined to not be study medication related.
[3]
Subject died after suffering a stroke at month 10. This was reviewed by the safety monitor and deemed not study medication related.
[4]
Participant admitted to the hospital for shortness of breath. This occurred between the screening visit and the baseline visit; therefore no medication had been dispensed at that time.
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Methotrexate Group - Adverse Events Placebo Group - Adverse Events
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   23/25 (92.00%)      23/25 (92.00%)    
Blood and lymphatic system disorders     
Edema/bruising * 1 [1]  6/25 (24.00%)  9 7/25 (28.00%)  11
Hematologic * 1  6/25 (24.00%)  13 5/25 (20.00%)  8
Endocrine disorders     
Allergic * 1  1/25 (4.00%)  1 0/25 (0.00%)  0
Eye disorders     
Ophthalomologic * 1 [2]  5/25 (20.00%)  5 4/25 (16.00%)  7
Gastrointestinal disorders     
Gastrointestinal * 1 [3]  15/25 (60.00%)  28 11/25 (44.00%)  16
General disorders     
Constitutional/other * 1 [4]  10/25 (40.00%)  24 8/25 (32.00%)  34
Hepatobiliary disorders     
Elevation of liver function tests * 1 [5]  3/25 (12.00%)  8 4/25 (16.00%)  12
Infections and infestations     
Infection * 1 [6]  13/25 (52.00%)  28 7/25 (28.00%)  17
Musculoskeletal and connective tissue disorders     
Pain * 1 [7]  13/25 (52.00%)  36 14/25 (56.00%)  29
Muscle weakness/fatigue * 1 [8]  10/25 (40.00%)  24 8/25 (32.00%)  34
Respiratory, thoracic and mediastinal disorders     
Pulmonary * 1 [9]  9/25 (36.00%)  13 7/25 (28.00%)  12
Skin and subcutaneous tissue disorders     
Dermatological * 1 [10]  3/25 (12.00%)  7 5/25 (20.00%)  10
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, CTCAE (3.0)
[1]
Described as swelling in ankles and legs, increased bruising in the arms.
[2]
Described as blurry vision
[3]
Most described as upset stomach, diarrhea, constipation
[4]
General fatigue
[5]
Elevated ALTs, ASTs or bilirubin was reported
[6]
Infections included sinus infections, upper respiratory infections
[7]
General Pain - not limited to a specific area
[8]
Worsening of the myasthenia gravis symptoms
[9]
Described as shortness of breath
[10]
Described as dry skin
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Richard J. Barohn, MD/ Chairman of Neurology
Organization: University of Kansas Medical Center
Phone: 913-588-6094
EMail: rbarohn@kumc.edu
Layout table for additonal information
Responsible Party: Richard Barohn, MD, University of Kansas Medical Center
ClinicalTrials.gov Identifier: NCT00814138     History of Changes
Other Study ID Numbers: 11552
FDA OOPD 003538 ( Other Grant/Funding Number: RO1FD003538 )
First Submitted: December 23, 2008
First Posted: December 24, 2008
Results First Submitted: July 23, 2015
Results First Posted: December 23, 2015
Last Update Posted: May 26, 2016