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

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.

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 (AchR Ab =/> 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 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.