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MGTX

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

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Year of Publication: 2016

Authors: G.I. Wolfe, H.J. Kaminski, I.B. Aban, ..., for the MGTX Study Group

Journal: New England Journal of Medicine

Citation: N Engl J Med 2016;375:511-22. DOI: 10.1056/NEJMoa1602489

Link: https://clinicaltrials.gov/ct2/show/NCT00294658

Clinical Question

Is extended transsternal thymectomy combined with a standardized prednisone protocol superior to prednisone alone for improving myasthenic weakness, reducing prednisone requirements, and enhancing quality of life over 3 years in patients with non-thymomatous generalized myasthenia gravis?

Bottom Line

Thymectomy significantly improved clinical outcomes over 3 years, with lower QMG scores (difference 2.85 points), 41% lower prednisone requirements, reduced need for azathioprine (17% vs 48%), and fewer hospitalizations for exacerbations (9% vs 37%). This landmark trial provides the first randomized evidence supporting thymectomy in non-thymomatous myasthenia gravis.

Major Points

  • Time-weighted average QMG score was significantly lower in thymectomy group (6.15 vs 8.99; difference 2.85; p<0.001)
  • Alternate-day prednisone requirement was 41% lower with thymectomy (32 mg vs 54 mg; p<0.001)
  • Only 17% of thymectomy patients required azathioprine vs 48% in prednisone-only group (p<0.001)
  • Hospitalizations for MG exacerbations: 9% thymectomy vs 37% prednisone-only (p<0.001)
  • 67% of thymectomy patients achieved minimal manifestation status at 36 months vs 47% (p=0.03)
  • Thymectomy group had fewer treatment-associated symptoms (p<0.001) and lower distress levels (p=0.003)
  • No significant difference in treatment-associated complications between groups (p=0.73)
  • First randomized, controlled trial to definitively establish benefit of thymectomy in non-thymomatous MG

Design

Study Type: Multicenter, international, randomized, single-blind (rater-blinded), controlled trial

Randomization: 1

Blinding: Single-blind (rater-blinded); participants wore high-collared obscuring shirts to conceal surgical incisions; separate blinded evaluators for efficacy assessments; unblinded neurologist managed clinical care until month 4

Enrollment Period: September 2006 to November 2012

Follow-up Duration: 36 months (3 years)

Centers: 36

Countries: United States, United Kingdom, Germany, Argentina, Canada, Chile, South Africa, Italy, Thailand, Australia, Brazil, Japan, Poland, Mexico, Netherlands

Sample Size: 126

Analysis: Intention-to-treat; two-stage primary analysis with 99.5% CI for QMG score difference followed by two-sided t-test for prednisone dose at α=0.05; time-weighted averages computed using trapezoidal method; multiple imputation methods for missing data

Inclusion Criteria

  • Age 18-65 years (initially 18-60, expanded in October 2008)
  • Generalized non-thymomatous myasthenia gravis
  • Disease duration <5 years (initially <3 years, expanded in October 2008)
  • Serum acetylcholine-receptor antibody level >1.00 nmol/L (or 0.50-0.99 nmol/L with confirmatory testing)
  • MGFA clinical classification II-IV
  • Taking appropriate anticholinesterase therapy with or without oral glucocorticoids

Exclusion Criteria

  • Thymoma on CT or MRI of chest
  • Previous thymectomy
  • Immunotherapy other than prednisone
  • Pregnancy or lactation
  • Unwillingness to avoid pregnancy
  • Contraindications to glucocorticoids
  • Substantial medical illness precluding participation

Arms

FieldThymectomy + PrednisoneControl
InterventionExtended transsternal thymectomy via median sternotomy with en bloc resection of all mediastinal thymic tissue, performed within 30 days of randomization, plus standardized alternate-day prednisone protocol starting at 10 mg and increasing to maximum 100 mg or 1.5 mg/kg alternate-day; prednisone tapered after achieving minimal manifestation status and QMG <14Standardized alternate-day prednisone protocol starting at 10 mg, increased in 10 mg steps to maximum 100 mg alternate-day or 1.5 mg/kg (up to 120 mg if needed); tapered by 10 mg every 2 weeks after achieving minimal manifestation status and QMG <14; azathioprine permitted after 12 months if minimal manifestation status not achieved
Duration36 months follow-up36 months follow-up

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Dual primary outcome: (1) Time-weighted average Quantitative Myasthenia Gravis (QMG) score over 3 years; (2) Time-weighted average required alternate-day prednisone dose over 3 yearsPrimary
Time-weighted average MG-ADL score over 3 yearsSecondary3.412.240.008
Azathioprine useSecondary48%17%<0.001
Minimal manifestation status at month 36Secondary47%67%0.03
Hospitalization for MG exacerbationSecondary37%9%<0.001
Treatment-associated complications (survey)SecondaryNo differenceNo difference0.73
Treatment-associated symptoms (number of patients with symptoms)SecondaryHigherLower<0.001
Distress level related to symptomsSecondaryHigherLower0.003
Cumulative hospital daysSecondary19.2 ± 24.58.4 ± 8.60.09
Any serious adverse eventAdverse55% (33/60 patients; 93 events)38% (25/66 patients; 48 events)0.05
Life-threatening eventAdverse12% (7/60)2% (1/66)0.03
Disability or incapacityAdverse3% (2/60)12% (8/66)0.10
DeathAdverse2% (1/60)0%0.48
Complication due to thymectomyAdverseNA2% (1/66)
Hospitalization (any cause)Adverse52% (31/60)23% (15/66)<0.001
Hospitalization for MG exacerbationAdverse37% (22/60)9% (6/66)<0.001
Nervous system disorder hospitalizationAdverse37% (22/60)12% (8/66)0.001
Infection/infestation hospitalizationAdverse12% (7/60)6% (4/66)0.35

Subgroup Analysis

Three prespecified subgroups analyzed: (1) Previous vs no previous glucocorticoid use: Among glucocorticoid-naive patients, significant difference in prednisone dose but not QMG; among those with prior exposure, both outcomes favored thymectomy. (2) Sex: Women showed significant between-group differences in both outcomes; men showed significant difference in prednisone dose only. (3) Age at disease onset (<40 vs ≥40 years): Both subgroups showed significant benefit for thymectomy on both outcomes. Tests for interaction were not significant in any subgroup analysis.

Criticisms

  • Single-blind (rater-blinded) design without sham surgery control; not feasible to subject controls to sham sternotomy
  • Pill counts may not precisely measure actual prednisone intake despite diary confirmation
  • Extended transsternal thymectomy may not represent less-invasive approaches now commonly used
  • Concern that minimally invasive techniques may leave ectopic thymic tissue affecting long-term outcomes
  • 8 patients in thymectomy group declined surgery; 8 in prednisone group crossed over to thymectomy
  • Prednisone doses at 36 months higher than routine clinical practice due to protocol requirements
  • Unable to conclude about differential benefits in subgroups due to non-significant interaction tests
  • Small numbers limit interpretation in glucocorticoid-naive and male subgroups
  • Did not test less-invasive thymectomy approaches with similar effectiveness and better cosmesis
  • Restrictive eligibility criteria (disease duration <5 years, age 18-65) limit generalizability

Funding

National Institute of Neurological Disorders and Stroke (grant U01 NS042685), Muscular Dystrophy Association, Myasthenia Gravis Foundation of America

Based on: MGTX (New England Journal of Medicine, 2016)

Authors: G.I. Wolfe, H.J. Kaminski, I.B. Aban, ..., for the MGTX Study Group

Citation: N Engl J Med 2016;375:511-22. DOI: 10.1056/NEJMoa1602489

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