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

NCT ID: NCT00294658

Last Updated: 2017-05-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 126 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-06-30
• Study Completion Date: 2015-12-31

Brief Summary

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

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.

Conditions

Myasthenia Gravis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Thymectomy plus prednisone

Procedure: Extended Transsternal Thymectomy plus prednisone treatment

Group Type: ACTIVE_COMPARATOR

thymectomy plus prednisone

Intervention Type: PROCEDURE

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

Prednisone alone

Drug: prednisone alone protocol

Group Type: PLACEBO_COMPARATOR

prednisone alone

Intervention Type: DRUG

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

Interventions

thymectomy plus prednisone

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

Intervention Type: PROCEDURE

prednisone alone

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

Intervention Type: DRUG

Other Intervention Names

Extended transsternal thymectomy plus prednisone; prednisolone

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Neurological Disorders and Stroke (NINDS)

NIH

Sponsor Role: collaborator

University of Alabama at Birmingham

OTHER

Sponsor Role: lead

Responsible Party

Gary Cutter, PhD

Principle Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Gary Cutter, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Alabama at Birmingham School of Public Health, Department of Biostatistics

Gil Wolfe, MD

Role: PRINCIPAL_INVESTIGATOR

University of Buffalo, Jacobs School of Medicine and Biomedical Sciences

Henry Kaminski, MD

Role: PRINCIPAL_INVESTIGATOR

George Washington University School of Medicine and Health Sciences

Locations

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

Indiana University, Dept of Neurology, Regenstrief Health Center, 6th floor, 1050 Walnut St, Indiana University Medical Center

Indianapolis, Indiana, United States

The University of Kansas Medical Center, 3901 Rainbow Blvd.

Kansas City, Kansas, United States

Brigham and Women's Hospital, 75 Francis Street, 5th Floor Tower

Boston, Massachusetts, United States

Wayne State University School of Medicine, 4201 St Antoine, 8D UHC

Detroit, Michigan, United States

William Beaumont Hospital, 3601 W. Thirteen Mile Road, Royal Oak

Royal Oak, Michigan, United States

University of Minnesota, Department of Neurology, MMC 295, 420 Delaware St. S.E.,

Minneapolis, Minnesota, United States

Mayo Clinic Rochester, 200 First St. SW

Rochester, Minnesota, United States

St. Louis University, One North Grand St. Louis

St Louis, Missouri, United States

Robert Wood Johnson University,

New Brunswick, New Jersey, United States

Mount Sinai Hospital,1 Gustave L. Levy Pl

New York, New York, United States

University of Rochester, 601 Elmwood Ave

Rochester, New York, United States

Duke University, 200 Trent Dr

Durham, North Carolina, United States

Case Western Reserve University, University Hospitals of Cleveland, 1100 Euclid Avenue

Cleveland, Ohio, United States

The Ohio State University Wexmer Medical Center, Rm 461 Means Hall, The Ohio State University Medical Center,1654 Upham Dr.

Columbus, Ohio, United States

University of Texas Southwestern Medical Center, 5232 Harry Hines Blvd,

Dallas, Texas, United States

University of Texas Medical Branch, 301 University Blvd

Galveston, Texas, United States

Nerve and Muscle Center of Texas, 6624 Fannin St # 1670

Houston, Texas, United States

University of Texas Health Science Center, Mail code 7883, 7703 Floyd Curl Drive

San Antonio, Texas, United States

University of Vermont College of Medicine, Given Bldg C225, 89 Beaumont Avenue

Burlington, Vermont, United States

University of Virginia, 1215 Lee St

Charlottesville, Virginia, United States

University of Washington, 1410 NE Campus Pkwy

Seattle, Washington, United States

West Virginia University, Dept of Neurology, WVU Eye Institute, Neurology Suite, 1 Stadium Drive,

Morgantown, West Virginia, United States

Medical College of Wisconsin, 8701 Watertown Plank Road

Milwaukee, Wisconsin, United States

University of Buenis, Centro de Asistencia Docencia e Investigacion en Miastenia (CADIMI) Av. Forest 1146 - Ciudad Autonoma de Buenos Aires

Buenos Aires, , Argentina

University of Sydney, Royal Prince Alfred Hospital and The University of Sydney

Sydney, , Australia

University of Melbourne, Melbourne, The Royal Melbourne Hospital, Dept of Neurology, Royal Melbourne Hospital

Victoria, , Australia

Hospital de Base do Distrito Federal

Brasília, , Brazil

Universidade Federal do Parana

Curitiba, , Brazil

Federal University of Rio De Janeiro

Rio de Janeiro, , Brazil

University of Calgary, Heritage Medical Research Clinic Room 1132 3330 Hospital Dr NW

Calgary, Alberta, Canada

University of British Columbia

Vancouver, British Columbia, Canada

University of Ottawa, The Ottawa Hospital General Campus, Division of Neurology, 501 Smyth Rd. Box 601

Ottawa, Ontario, Canada

McGill University Health Center

Montreal, Quebec, Canada

Hospital Del Salvador, Departamento de Ciencias Neurológicas, Universidad de Chile, Salvador 95 Of 416, Providencia

Santiago, , Chile

University of Heidelberg, Seminarstraße 2

Mannheim, Baden-Wurttemberg, Germany

University of Regensburg, Dept. of Neurology, Universitätsstr. 84, D

Regensburg, Bavaria, Germany

University of Düsseldorf

Düsseldorf, North Rhine-Westphalia, Germany

Johannes-Gutenberg University, Klinikum der Johannes Gutenberg-Universität, Klinik und Poliklinik für Neurologie, Langenbeckstr

Mainz, Rhineland-Palatinate, Germany

University of Münster, Schlossplatz 2

Münster, , Germany

University of Tübingen

Tübingen, , Germany

National Neurological Institute "Carlo Besta", Myopathology and Immunology Unit, Dept of Neurology IV, Natl. Neurolog Inst. "C. Besta", Via Celoria, 11,

Milan, , Italy

University of Rome "Sapienza"

Rome, , Italy

Catholic University, Universita Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, e

Rome, , Italy

University of Torino

Torino, , Italy

Kanazawa University, Department of Neurology, Kanazawa University Hospital, 13-1 Takaramachi

Kanazawa, Ishikawa-ken, Japan

Nagasaki University, First Department of Internal Medicine,Graduate School of Biomedical Sciences,1-7-1,Sakamoto

Nagasaki, Kyushu, Japan

Instituto Nacional de la Nutrición

México, , Mexico

Leiden University

Leiden, , Netherlands

Medical University of Warsaw

Warsaw, Województwo, Poland

Institute of Tuberculosis and Lung Disease

Warsaw, Województwo, Poland

Porto University, Serviço de Neurologia,Hospital Geral de Santo António, Largo Prof Abel Salazar

Porto, , Portugal

University of Cape Town, Division of Neurology E8-74, Groote Schuur Hospital,Observatory

Cape Town, , South Africa

H. Sant Pau, Universitat Autònoma de Barcelona, Neurology Department, Hospital Sta Creu i Sant Pau, C/Mas Casanovas no 90 4o pis 4o modul.

Barcelona, , Spain

Fu-Jen Catholic University, No. 510, Zhongzheng Rd., Xinzhuang Dist

New Taipei City, , Taiwan

Ramathibodi Hospital, Mahidol University

Bangkok, , Thailand

Queen Elizabeth University Hospital, Glasgow

Glasgow, , United Kingdom

Walton Centre for Neurology and Neurosurgery, Liverpool Heart and Chest Hospital, Liverpool. The Walton Centre for Neurology and Neurosurgery, Lower Lane, Fazakerley

Liverpool, , United Kingdom

University of Manchester, Oxford Road

Manchester, , United Kingdom

University of Oxford, Dept of Clinical Neurology, University of Oxford, Radcliffe Infirmary

Oxford, , United Kingdom

University of Sheffield, Western Bank

Sheffield, , United Kingdom

Countries

United States; Argentina; Australia; Brazil; Canada; Chile; Germany; Italy; Japan; Mexico; Netherlands; Poland; Portugal; South Africa; Spain; Taiwan; Thailand; United Kingdom

References

Aban IB, Wolfe GI, Cutter GR, Kaminski HJ, Jaretzki A 3rd, Minisman G, Conwit R, Newsom-Davis J; Mgtx Advisory Committee. The MGTX experience: challenges in planning and executing an international, multicenter clinical trial. J Neuroimmunol. 2008 Sep 15;201-202:80-4. doi: 10.1016/j.jneuroim.2008.05.031.

Reference Type: RESULT

PMID: 18675464 (View on PubMed)

Newsom-Davis J, Cutter G, Wolfe GI, Kaminski HJ, Jaretzki A 3rd, Minisman G, Aban I, Conwit R. Status of the thymectomy trial for nonthymomatous myasthenia gravis patients receiving prednisone. Ann N Y Acad Sci. 2008;1132:344-7. doi: 10.1196/annals.1405.014.

Reference Type: RESULT

PMID: 18567886 (View on PubMed)

Minisman G, Bhanushali M, Conwit R, Wolfe GI, Aban I, Kaminski HJ, Cutter G. Implementing clinical trials on an international platform: challenges and perspectives. J Neurol Sci. 2012 Feb 15;313(1-2):1-6. doi: 10.1016/j.jns.2011.10.004. Epub 2011 Nov 1.

Reference Type: RESULT

PMID: 22047648 (View on PubMed)

Kaminski HJ, Kusner LL, Wolfe GI, Aban I, Minisman G, Conwit R, Cutter G. Biomarker development for myasthenia gravis. Ann N Y Acad Sci. 2012 Dec;1275(1):101-6. doi: 10.1111/j.1749-6632.2012.06787.x.

Reference Type: RESULT

PMID: 23278584 (View on PubMed)

Wolfe GI, Kaminski HJ, Aban IB, Minisman G, Kuo HC, Marx A, Strobel P, Mazia C, Oger J, Cea JG, Heckmann JM, Evoli A, Nix W, Ciafaloni E, Antonini G, Witoonpanich R, King JO, Beydoun SR, Chalk CH, Barboi AC, Amato AA, Shaibani AI, Katirji B, Lecky BR, Buckley C, Vincent A, Dias-Tosta E, Yoshikawa H, Waddington-Cruz M, Pulley MT, Rivner MH, Kostera-Pruszczyk A, Pascuzzi RM, Jackson CE, Garcia Ramos GS, Verschuuren JJ, Massey JM, Kissel JT, Werneck LC, Benatar M, Barohn RJ, Tandan R, Mozaffar T, Conwit R, Odenkirchen J, Sonett JR, Jaretzki A 3rd, Newsom-Davis J, Cutter GR; MGTX Study Group. Randomized Trial of Thymectomy in Myasthenia Gravis. N Engl J Med. 2016 Aug 11;375(6):511-22. doi: 10.1056/NEJMoa1602489.

Reference Type: RESULT

PMID: 27509100 (View on PubMed)

Lee I, Kuo HC, Aban IB, Cutter GR, McPherson T, Kaminski HJ, Sussman J, Strobel P, Oger J, Cea G, Heckmann JM, Evoli A, Nix W, Ciafaloni E, Antonini G, Witoonpanich R, King JO, Beydoun SR, Chalk CH, Barboi AC, Amato AA, Shaibani AI, Katirji B, Lecky BRF, Buckley C, Vincent A, Dias-Tosta E, Yoshikawa H, Waddington-Cruz M, Pulley MT, Rivner MH, Kostera-Pruszczyk A, Pascuzzi RM, Jackson CE, Verschuuren JJG, Massey JM, Kissel JT, Werneck LC, Benatar M, Barohn RJ, Tandan R, Mozaffar T, Conwit R, Minisman G, Sonett JR, Wolfe GI; MGTX study group. Minimal manifestation status and prednisone withdrawal in the MGTX trial. Neurology. 2020 Aug 11;95(6):e755-e766. doi: 10.1212/WNL.0000000000010031. Epub 2020 Jul 1.

Reference Type: DERIVED

PMID: 32611638 (View on PubMed)

Wolfe GI, Kaminski HJ, Aban IB, Minisman G, Kuo HC, Marx A, Strobel P, Mazia C, Oger J, Cea JG, Heckmann JM, Evoli A, Nix W, Ciafaloni E, Antonini G, Witoonpanich R, King JO, Beydoun SR, Chalk CH, Barboi AC, Amato AA, Shaibani AI, Katirji B, Lecky BRF, Buckley C, Vincent A, Dias-Tosta E, Yoshikawa H, Waddington-Cruz M, Pulley MT, Rivner MH, Kostera-Pruszczyk A, Pascuzzi RM, Jackson CE, Verschuuren JJGM, Massey JM, Kissel JT, Werneck LC, Benatar M, Barohn RJ, Tandan R, Mozaffar T, Silvestri NJ, Conwit R, Sonett JR, Jaretzki A 3rd, Newsom-Davis J, Cutter GR; MGTX Study Group. Long-term effect of thymectomy plus prednisone versus prednisone alone in patients with non-thymomatous myasthenia gravis: 2-year extension of the MGTX randomised trial. Lancet Neurol. 2019 Mar;18(3):259-268. doi: 10.1016/S1474-4422(18)30392-2. Epub 2019 Jan 25.

Reference Type: DERIVED

PMID: 30692052 (View on PubMed)

Other Identifiers

1U01NS042685-01A2

Identifier Type: NIH

Identifier Source: secondary_id

View Link

CRC

Identifier Type: OTHER

Identifier Source: secondary_id

R01NS050733

Identifier Type: -

Identifier Source: org_study_id