Clinical trial NCT00294658: Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy
Official title: A Multi-Center, Single-Blind, Randomized Study Comparing Thymectomy to No Thymectomy in Non-Thymomatous Myasthenia Gravis (MG) Patients Receiving Prednisone
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Myasthenia Gravis
Keywords: myasthenia gravis
thymectomy
prednisone
corticosteroid
extended transsternal thymectomy
ETTX
MG
thymus
thymoma
Lead sponsor: University of Alabama at Birmingham
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2006-02-22
Enrollment: 126
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Time-weighted Average Quantitative Myasthenia Gravis Weakness Score Over 3 Years
timeFrame: baseline, month 3, 4, 6 and every 3 months through 36 months
measure: Time-weighted Average Alternate-day Prednisone Dose (mg) Measured Over 3 Years
timeFrame: baseline, month 1 , 2 , 3, 4, 6 and every 3 months through 36 months
Secondary outcomes:
measure: Subgroup Analyses of Time-weighted Average Quantitative Myasthenia Gravis Score by Prednisone Use at Enrollment
timeFrame: baseline, month 3, 4, 6 and every 3 months through 36 months
measure: Subgroup Analyses of Time-weighted Average Quantitative Myasthenia Gravis Score by Sex
timeFrame: baseline, month 3, 4, 6 and every 3 months through 36 months
measure: Subgroup Analyses of Time-weighted Average Quantitative Myasthenia Gravis Score by Age at Disease Onset
timeFrame: baseline, month 3, 4, 6 and every 3 months through 36 months
measure: Subgroup Analyses of Time-weighted Average Alternate-day Prednisone Dose (mg) by Prednisone Use at Enrollment
timeFrame: baseline, month 3, 4, 6 and every 3 months through 36 months
measure: Subgroup Analyses of Time-weighted Average Alternate-day Prednisone Dose (mg) by Sex
timeFrame: baseline, month 3, 4, 6 and every 3 months through 36 months
measure: Subgroup Analyses of Time-weighted Average Average Alternate-day Prednisone Dose (mg) by Age at Disease Onset
timeFrame: baseline, month 3, 4, 6 and every 3 months through 36 months
measure: Number of Serious Adverse Events
timeFrame: baseline to 3 years
measure: Number of Patients With at Least One Serious Adverse Events
timeFrame: baseline to 3 years
measure: Classification of Serious Adverse Events
timeFrame: baseline to 3 years
measure: Hospitalization for Exacerbation of Myasthenia Gravis
timeFrame: baseline to 2 years and baseline to 3 years
measure: Cumulative Number of Hospital Days
timeFrame: baseline to 3 years
measure: Reason for Hospitalization According to Medical Dictionary for Regulatory Activities Term
timeFrame: baseline to 3 years
measure: Time-weighted Average Prescribed Alternate Day Prednisone Dose (mg)
timeFrame: baseline-day 20, month 1,2, 3, 4, 6 and every 3 months through 36 months
measure: Penalized Time-weighted Average Alternative Day Prednisone Dose (mg; Method 1: Penalized Using Maximum Dose Before Azathioprine)
timeFrame: baseline, month 3, 4, 6 and every 3 months through 36 months
measure: Penalized Time-weighted Average Alternative Day Prednisone Dose (mg; Method 2: Penalized Using Dose at Time of Starting Azathioprine)
timeFrame: baseline, month 1 , 2 , 3, 4, 6 and every 3 months through 36 months
measure: Time-Weighted Average MG Activity of Daily Living (MG-ADL)
timeFrame: baseline, month 4, 6 and every 3 months through 36 months
measure: Time-Weighted Average MG Activity of Daily Living (MG-ADL) at Month 12, 24, and 36
timeFrame: Month 12, 24, and 36
measure: Azathioprine Use
timeFrame: baseline to 3 years
measure: Plasma Exchange Use
timeFrame: baseline to 3 years
measure: Intravenous Immunoglobulin Use
timeFrame: baseline to 3 years
measure: Minimal Manifestation (MM) Status at Month 12, 24 and 36
timeFrame: Month 12, 24 and 36
measure: Cumulative Days in Hospital for Myasthenia Gravis Exacerbation
timeFrame: baseline to 2 years
measure: Cumulative Days in Hospital for Myasthenia Gravis Exacerbation
timeFrame: baseline to 3 years
measure: Short Form-36 Standardized Physical Component
timeFrame: Month 0, Month 12, Month 24 and Month 36
measure: Short Form-36 Standardized Mental Component
timeFrame: Month 0, Month 12, Month 24 and Month 36
measure: Treatment Associated Complications (TAC)
timeFrame: Month 0, 1, 2, 3, 4 then every 3 months through Month 36
measure: Treatment Associated Symptoms (TAS)
timeFrame: Month 0, 1, 2, 3, 4 then every 3 months through Month 36
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham, Department of Neurology, Sparks Center, Suite 350, 1720 7th Avenue South
state: Alabama
city: Birmingham
country: United States
facility: Data Coordination Center: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Barrow Neurological Institute, Saint Joseph's Hospital and Medical Center, 350 W Thomas Rd
state: Arizona
city: Los Angeles
country: United States
facility: University of Southern California, Doheny Institute, 1450 San Pablo St
state: California
city: Orange
country: United States
facility: University of California Irvine, 101 The City Drive S, Bldg. 22 C, Route 13
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center, Castro St & Duboce Ave
state: California
city: Jacksonville
country: United States
facility: University of Florida Jacksonville, Tower I, 8th Floor, 580 W. 8th ST.
state: Florida
city: Miami
country: United States
facility: University of Miami, 1120 NW 14th Street, Suite 1300
state: Florida
city: Atlanta
country: United States
facility: Emory University, 201 Dowman Dr
state: Georgia
city: Augusta
country: United States
facility: Augusta University, 1120 15th St
state: Georgia
city: Indianapolis
country: United States
facility: Indiana University, Dept of Neurology, Regenstrief Health Center, 6th floor, 1050 Walnut St, Indiana University Medical Center
state: Indiana
city: Kansas City
country: United States
facility: The University of Kansas Medical Center, 3901 Rainbow Blvd.
state: Kansas
city: Boston
country: United States
facility: Brigham and Women's Hospital, 75 Francis Street, 5th Floor Tower
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State University School of Medicine, 4201 St Antoine, 8D UHC
state: Michigan
city: Royal Oak
country: United States
facility: William Beaumont Hospital, 3601 W. Thirteen Mile Road, Royal Oak
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota, Department of Neurology, MMC 295, 420 Delaware St. S.E.,
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic Rochester, 200 First St. SW
state: Minnesota
city: St. Louis
country: United States
facility: St. Louis University, One North Grand St. Louis
state: Missouri
city: New Brunswick
country: United States
facility: Robert Wood Johnson University,
state: New Jersey
city: New York
country: United States
facility: Mount Sinai Hospital,1 Gustave L. Levy Pl
state: New York
city: Rochester
country: United States
facility: University of Rochester, 601 Elmwood Ave
state: New York
city: Durham
country: United States
facility: Duke University, 200 Trent Dr
state: North Carolina
city: Cleveland
country: United States
facility: Case Western Reserve University, University Hospitals of Cleveland, 1100 Euclid Avenue
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Wexmer Medical Center, Rm 461 Means Hall, The Ohio State University Medical Center,1654 Upham Dr.
state: Ohio
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center, 5232 Harry Hines Blvd,
state: Texas
city: Galveston
country: United States
facility: University of Texas Medical Branch, 301 University Blvd
state: Texas
city: Houston
country: United States
facility: Nerve and Muscle Center of Texas, 6624 Fannin St # 1670
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center, Mail code 7883, 7703 Floyd Curl Drive
state: Texas
city: Burlington
country: United States
facility: University of Vermont College of Medicine, Given Bldg C225, 89 Beaumont Avenue
state: Vermont
city: Charlottesville
country: United States
facility: University of Virginia, 1215 Lee St
state: Virginia
city: Seattle
country: United States
facility: University of Washington, 1410 NE Campus Pkwy
state: Washington
city: Morgantown
country: United States
facility: West Virginia University, Dept of Neurology, WVU Eye Institute, Neurology Suite, 1 Stadium Drive,
state: West Virginia
city: Milwaukee
country: United States
facility: Medical College of Wisconsin, 8701 Watertown Plank Road
state: Wisconsin
city: Buenos Aires
country: Argentina
facility: University of Buenis, Centro de Asistencia Docencia e Investigacion en Miastenia (CADIMI) Av. Forest 1146 - Ciudad Autonoma de Buenos Aires
city: Sydney
country: Australia
facility: University of Sydney, Royal Prince Alfred Hospital and The University of Sydney
city: Victoria
country: Australia
facility: University of Melbourne, Melbourne, The Royal Melbourne Hospital, Dept of Neurology, Royal Melbourne Hospital
city: Brasilia
country: Brazil
facility: Hospital de Base do Distrito Federal
city: Curitiba
country: Brazil
facility: Universidade Federal do Parana
city: Rio De Janeiro
country: Brazil
facility: Federal University of Rio De Janeiro
city: Calgary
country: Canada
facility: University of Calgary, Heritage Medical Research Clinic Room 1132 3330 Hospital Dr NW
state: Alberta
city: Vancouver
country: Canada
facility: University of British Columbia
state: British Columbia
city: Ottawa
country: Canada
facility: University of Ottawa, The Ottawa Hospital General Campus, Division of Neurology, 501 Smyth Rd. Box 601
state: Ontario
city: Montreal
country: Canada
facility: McGill University Health Center
state: Quebec
city: Santiago
country: Chile
facility: Hospital Del Salvador, Departamento de Ciencias Neurológicas, Universidad de Chile, Salvador 95 Of 416, Providencia
city: Mannheim
country: Germany
facility: University of Heidelberg, Seminarstraße 2
state: Baden-Württemberg
city: Regensburg
country: Germany
facility: University of Regensburg, Dept. of Neurology, Universitätsstr. 84, D
state: Bavaria
city: Düsseldorf
country: Germany
facility: University of Düsseldorf
state: North Rhine-Westphalia
city: Mainz
country: Germany
facility: Johannes-Gutenberg University, Klinikum der Johannes Gutenberg-Universität, Klinik und Poliklinik für Neurologie, Langenbeckstr
state: Rhineland-Palatinate
city: Münster
country: Germany
facility: University of Münster, Schlossplatz 2
city: Tübingen
country: Germany
facility: University of Tübingen
city: Milan
country: Italy
facility: National Neurological Institute "Carlo Besta", Myopathology and Immunology Unit, Dept of Neurology IV, Natl. Neurolog Inst. "C. Besta", Via Celoria, 11,
city: Rome
country: Italy
facility: University of Rome "Sapienza"
city: Rome
country: Italy
facility: Catholic University, Universita Cattolica del Sacro Cuore, Largo Agostino Gemelli 8, e
city: Torino
country: Italy
facility: University of Torino
city: Kanazawa
country: Japan
facility: Kanazawa University, Department of Neurology, Kanazawa University Hospital, 13-1 Takaramachi
state: Ishikawa
city: Nagasaki
country: Japan
facility: Nagasaki University, First Department of Internal Medicine,Graduate School of Biomedical Sciences,1-7-1,Sakamoto
state: Kyushu
city: Mexico
country: Mexico
facility: Instituto Nacional de la Nutrición
city: Leiden
country: Netherlands
facility: Leiden University
city: Warsaw
country: Poland
facility: Medical University of Warsaw
state: Województwo
city: Warsaw
country: Poland
facility: Institute of Tuberculosis and Lung Disease
state: Województwo
city: Porto
country: Portugal
facility: Porto University, Serviço de Neurologia,Hospital Geral de Santo António, Largo Prof Abel Salazar
city: Cape Town
country: South Africa
facility: University of Cape Town, Division of Neurology E8-74, Groote Schuur Hospital,Observatory
city: Barcelona
country: Spain
facility: H. Sant Pau, Universitat Autònoma de Barcelona, Neurology Department, Hospital Sta Creu i Sant Pau, C/Mas Casanovas no 90 4o pis 4o modul.
city: New Taipei
country: Taiwan
facility: Fu-Jen Catholic University, No. 510, Zhongzheng Rd., Xinzhuang Dist
city: Bangkok
country: Thailand
facility: Ramathibodi Hospital, Mahidol University
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital, Glasgow
city: Liverpool
country: United Kingdom
facility: Walton Centre for Neurology and Neurosurgery, Liverpool Heart and Chest Hospital, Liverpool. The Walton Centre for Neurology and Neurosurgery, Lower Lane, Fazakerley
city: Manchester
country: United Kingdom
facility: University of Manchester, Oxford Road
city: Oxford
country: United Kingdom
facility: University of Oxford, Dept of Clinical Neurology, University of Oxford, Radcliffe Infirmary
city: Sheffield
country: United Kingdom
facility: University of Sheffield, Western Bank
Study officials:
affiliation: University of Alabama at Birmingham School of Public Health, Department of Biostatistics
name: Gary Cutter, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Buffalo, Jacobs School of Medicine and Biomedical Sciences
name: Gil Wolfe, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: George Washington University School of Medicine and Health Sciences
name: Henry Kaminski, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.