Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy

Study Overview
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Brief Summary
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The purpose of this trial is to determine if thymectomy combined with prednisone therapy is more beneficial in treating non-thymomatous myasthenia gravis than prednisone therapy alone.

Detailed Description
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Myasthenia gravis (MG) is an autoimmune disease involving the thymus in which 85 percent of patients have antibodies to muscle acetylcholine receptors (AchR-Ab) that interfere with neuromuscular transmission. MG frequently causes severe disability that can be life-threatening. Thymectomy-a surgical procedure that removes thymus gland tissue from the chest cavity-has been an established therapy for non-thymomatous MG, or MG without thymoma, for more than 60 years (based on retrospective, non-randomized studies). Corticosteroids are now being used increasingly either as the sole treatment or in combination with thymectomy. Both therapies have associated adverse effects and indications for their use based on randomized trial data are lacking. The purpose of this 5-year trial is to determine if the surgical procedure, extended transsternal thymectomy (ETTX), combined with prednisone therapy is more beneficial in treating individuals with non-thymomatous MG than prednisone therapy alone. More specifically, this study will determine 1) if ETTX combined with prednisone results in a greater improvement in myasthenic weakness, compared to prednisone alone; 2) if ETTX combined with prednisone results in a lower total dose of prednisone, thus decreasing the likelihood of concurrent and long-term toxic effects, compared to prednisone alone; and 3) if ETTX combined with prednisone enhances quality of life by reducing adverse events and symptoms associated with the therapies, compared to prednisone alone. Learning that thymectomy results in a meaningful reduction of prednisone dosage or even full withdrawal or reduces side effects related to prednisone would support using the two treatments-thymectomy and prednisone-together. However, if no meaningful reduction of prednisone dosage or side effects is shown, the results would mean that using the two treatments together offers no advantages over prednisone treatment alone. After an initial screening, study participants will be randomized either to undergo the surgical procedure ETTX and receive prednisone treatment, or to receive prednisone treatment alone without surgery. Participants will be followed for at least 3 years.

Official Title
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A Multi-Center, Single-Blind, Randomized Study Comparing Thymectomy to No Thymectomy in Non-Thymomatous Myasthenia Gravis (MG) Patients Receiving Prednisone

Conditions
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Myasthenia Gravis

Intervention / Treatment
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* Procedure: thymectomy plus prednisone
* Drug: prednisone alone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female MG patients age greater than 18 and less than 65 years Onset of generalized MG within the last 5 years Positive serum anti-acetylcholine receptor binding antibodies (muscle acetylcholine receptors, AchRAb =/> 1.00 nmol/L. AchRAb levels of 0.50-0.99 nmol/L will be acceptable if there is another confirmatory test for MG, including single-fiber electromyography (EMG), repetitive nerve stimulation, or unequivocal edrophonium testing.) MGFA class II-IV at entry, using the MG Foundation of America (MGFA) classification, while receiving optimal anti-cholinesterase treatment with or without oral prednisone Exclusion Criteria: Ocular MG without generalized weakness (MGFA Class I) or minimal weakness that would not require the use of corticosteroids Myasthenic weakness requiring intubation (MGFA Class IV) in the prior month Immunosuppressive therapy other than corticosteroids in the preceding year Medically unfit for thymectomy Chest CT evidence of thymoma. Pregnancy or lactation; contraindications to the use of corticosteroids, unless postmenopausal or surgically sterile. Women considering becoming pregnant during the period of the study are to be excluded. A serious concurrent medical, neurological or psychiatric condition that would interfere with thymectomy or subsequent clinical assessments Current alternate day dose of prednisone > than 1.5 mg/kg or 100 mg or the equivalent daily doses (> 0.75 mg/kg or 50 mg). Participation in another experimental clinical trial History of alcohol or drug abuse within the 2 years prior to randomization.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Thymectomy plus prednisone<br>Procedure: Extended Transsternal Thymectomy plus prednisone treatment | Procedure: thymectomy plus prednisone<br>* The thymectomy will be performed as soon as possible after randomization.<br>* Other names: Extended transsternal thymectomy plus prednisone;|
| Placebo Comparator: Prednisone alone<br>Drug: prednisone alone protocol | Drug: prednisone alone<br>* Prednisone regimen will be every other day, starting at 10mg. The dose will increase by 10mg every 2 days to a target dose.<br>* Other names: prednisolone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-weighted Average Quantitative Myasthenia Gravis Weakness Score Over 3 Years | Myasthenia Gravis (QMG) test. QMG total scores range from 0 to 39 for a given visit, with higher scores indicating more severe disease. The time weighted average is a calculation that provides an integrated measure of the outcome over the time of followup. The denominator that was used to compute the time-weighted average for the Quantitative Myasthenia Gravis (QMG) score and the prednisone dose was the number of days from randomization to the last visit. Computations used the trapezoidal method where in the QMG score is multiplied by the number of days at this level from one visit to the next and added up over the entire followup experience and divided by the total number of days from randomization. | baseline, month 3, 4, 6 and every 3 months through 36 months | 
| Time-weighted Average Alternate-day Prednisone Dose (mg) Measured Over 3 Years | Participants reported alternate-day prednisone dose (mg) intake from baseline through withdrawn or completed 3 years follow up. The prednisone dosages had been weighted over the days of reporting period. | baseline, month 1 , 2 , 3, 4, 6 and every 3 months through 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Subgroup Analyses of Time-weighted Average Quantitative Myasthenia Gravis Score by Prednisone Use at Enrollment | Myasthenia Gravis (QMG) test. QMG total scores range from 0 to 39 for a given visit, with higher scores indicating more severe disease. | baseline, month 3, 4, 6 and every 3 months through 36 months | 
| Subgroup Analyses of Time-weighted Average Quantitative Myasthenia Gravis Score by Sex | Myasthenia Gravis (QMG) test. QMG total scores range from 0 to 39 for a given visit, with higher scores indicating more severe disease. | baseline, month 3, 4, 6 and every 3 months through 36 months | 
| Subgroup Analyses of Time-weighted Average Quantitative Myasthenia Gravis Score by Age at Disease Onset | Myasthenia Gravis (QMG) test. QMG total scores range from 0 to 39 for a given visit, with higher scores indicating more severe disease. | baseline, month 3, 4, 6 and every 3 months through 36 months | 
| Subgroup Analyses of Time-weighted Average Alternate-day Prednisone Dose (mg) by Prednisone Use at Enrollment | Participants reported alternate-day prednisone dose (mg) intake from baseline through withdrawn or completed 3 years follow up. The prednisone dosages had been weighted over the days of reporting period. | baseline, month 3, 4, 6 and every 3 months through 36 months | 
| Subgroup Analyses of Time-weighted Average Alternate-day Prednisone Dose (mg) by Sex | Participants reported alternate-day prednisone dose (mg) intake from baseline through withdrawn or completed 3 years follow up. The prednisone dosages had been weighted over the days of reporting period. | baseline, month 3, 4, 6 and every 3 months through 36 months | 
| Subgroup Analyses of Time-weighted Average Average Alternate-day Prednisone Dose (mg) by Age at Disease Onset | Participants reported alternate-day prednisone dose (mg) intake from baseline through withdrawn or completed 3 years follow up. The prednisone dosages had been weighted over the days of reporting period. | baseline, month 3, 4, 6 and every 3 months through 36 months | 
| Number of Serious Adverse Events | Number of participant who experienced at least one serious adverse events over 3 years: Thymectomy plus prednisone n=25 (out of 66); Prednisone alone n=33 (out of 60) | baseline to 3 years | 
| Number of Patients With at Least One Serious Adverse Events | Number of participant who experienced at least one serious adverse events over 3 years: Thymectomy plus prednisone n=25 (out of 66); Prednisone alone n=33 (out of 60) | baseline to 3 years | 
| Classification of Serious Adverse Events |  | baseline to 3 years | 
| Hospitalization for Exacerbation of Myasthenia Gravis |  | baseline to 2 years and baseline to 3 years | 
| Cumulative Number of Hospital Days | Number who had hospitalization: Thymectomy plus prednisone n=15 (out of 66); Prednisone alone n=31 (out of 60) | baseline to 3 years | 
| Reason for Hospitalization According to Medical Dictionary for Regulatory Activities Term | Number who had hospitalization: Thymectomy plus prednisone n=15 (out of 66); Prednisone alone n=31 (out of 60) | baseline to 3 years | 
| Time-weighted Average Prescribed Alternate Day Prednisone Dose (mg) | Physicians reported prescribed alternate-day prednisone dose (mg) intake from baseline through withdrawn or completed 3 years follow up. The prescribed prednisone dosages had been weighted over the days of reporting period. | baseline-day 20, month 1,2, 3, 4, 6 and every 3 months through 36 months | 
| Penalized Time-weighted Average Alternative Day Prednisone Dose (mg; Method 1: Penalized Using Maximum Dose Before Azathioprine) | For each participant who took azathioprine, we penalized them by taking the maximum dose of prednisone before azathioprine was added. We then applied the same method to compute the time-weighted alternative day prednisone dose from baseline, month 3, 4, 6 and every 3 months through 36 months. | baseline, month 3, 4, 6 and every 3 months through 36 months | 
| Penalized Time-weighted Average Alternative Day Prednisone Dose (mg; Method 2: Penalized Using Dose at Time of Starting Azathioprine) | For each participant who took azathioprine, we penalized them by taking the prednisone dose at the time azathioprine commenced. We then applied the same method to compute the time-weighted alternative day prednisone dose from baseline, month 3, 4, 6 and every 3 months through 36 months. | baseline, month 1 , 2 , 3, 4, 6 and every 3 months through 36 months | 
| Time-Weighted Average MG Activity of Daily Living (MG-ADL) | MG Activity of Daily Living total scores range from 0 to 24, with the lower scores indicating better daily living quality of life. | baseline, month 4, 6 and every 3 months through 36 months | 
| Time-Weighted Average MG Activity of Daily Living (MG-ADL) at Month 12, 24, and 36 | MG Activity of Daily Living total scores range from 0 to 24 by visit, with the lower scores indicating better daily living quality of life. | Month 12, 24, and 36 | 
| Azathioprine Use |  | baseline to 3 years | 
| Plasma Exchange Use |  | baseline to 3 years | 
| Intravenous Immunoglobulin Use |  | baseline to 3 years | 
| Minimal Manifestation (MM) Status at Month 12, 24 and 36 | Number of participants who were in minimal manifestation status at month 12, 24 and 36. | Month 12, 24 and 36 | 
| Cumulative Days in Hospital for Myasthenia Gravis Exacerbation | Number of patients with MG exacerbation: Thymectomy plus prednisone=6 (out of 66); Prednisone alone=17 (out of 60) | baseline to 2 years | 
| Cumulative Days in Hospital for Myasthenia Gravis Exacerbation | Number of patients with MG exacerbation: Thymectomy plus prednisone=6 (out of 66); Prednisone alone=22 (out of 60) | baseline to 3 years | 
| Short Form-36 Standardized Physical Component | Range from 0 to 100, the higher the physical component value, the better the mental health. | Month 0, Month 12, Month 24 and Month 36 | 
| Short Form-36 Standardized Mental Component | Range from 0 to 100, the higher the mental component value, the better the mental health. | Month 0, Month 12, Month 24 and Month 36 | 
| Treatment Associated Complications (TAC) | Treatment associated complications measured complications occurred by myasthenia gravis patients. Report number of participant with at least one complications by each visit. | Month 0, 1, 2, 3, 4 then every 3 months through Month 36 | 
| Treatment Associated Symptoms (TAS) | Treatment associated symptoms measured myasthenia gravis symptoms such as back pain and/or bruises. Report number of participant with at least one treatment associated symptoms by each visit. | Month 0, 1, 2, 3, 4 then every 3 months through Month 36 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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myasthenia gravis, thymectomy, prednisone, corticosteroid, extended transsternal thymectomy, ETTX, MG, thymus, thymoma