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

University of Alabama at Birmingham126 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

SINGLE

Enrollment

126

Conditions

Myasthenia Gravis

Interventions

thymectomy plus prednisonePROCEDURE

The thymectomy will be performed as soon as possible after randomization.

prednisone aloneDRUG

Prednisone regimen will be every other day, starting at 10mg. The dose will increase by 10mg every 2 days to a target dose.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

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.

Locations (70)

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: baseline, month 1 , 2 , 3, 4, 6 and every 3 months through 36 months

Secondary Outcomes

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.

Time frame: 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.

Time frame: baseline, month 3, 4, 6 and every 3 months through 36 months

Data from ClinicalTrials.gov

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University of Alabama at Birmingham, Department of Neurology, Sparks Center, Suite 350, 1720 7th Avenue South

Birmingham, Alabama, United States

Data Coordination Center: University of Alabama at Birmingham

Birmingham, Alabama, United States

Barrow Neurological Institute, Saint Joseph's Hospital and Medical Center, 350 W Thomas Rd

Phoenix, Arizona, United States

University of Southern California, Doheny Institute, 1450 San Pablo St

Los Angeles, California, United States

University of California Irvine, 101 The City Drive S, Bldg. 22 C, Route 13

Orange, California, United States

California Pacific Medical Center, Castro St & Duboce Ave

San Francisco, California, United States

University of Florida Jacksonville, Tower I, 8th Floor, 580 W. 8th ST.

Jacksonville, Florida, United States

University of Miami, 1120 NW 14th Street, Suite 1300

Miami, Florida, United States

Emory University, 201 Dowman Dr

Atlanta, Georgia, United States

Augusta University, 1120 15th St

Augusta, Georgia, United States

...and 60 more locations

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.

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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)

Time frame: 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)

Time frame: baseline to 3 years

Classification of Serious Adverse Events

Time frame: baseline to 3 years

Hospitalization for Exacerbation of Myasthenia Gravis

Time frame: 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)

Time frame: 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)

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Month 12, 24, and 36

Azathioprine Use

Time frame: baseline to 3 years

Plasma Exchange Use

Time frame: baseline to 3 years

Intravenous Immunoglobulin Use

Time frame: 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.

Time frame: 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)

Time frame: 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)

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Month 0, 1, 2, 3, 4 then every 3 months through Month 36