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

This study has been completed.
Sponsor:
Collaborator:
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
Gary Cutter, PhD, University of Alabama at Birmingham
ClinicalTrials.gov Identifier:
NCT00294658
First received: February 21, 2006
Last updated: April 12, 2017
Last verified: April 2017
  Purpose
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.

Condition Intervention Phase
Myasthenia Gravis Procedure: thymectomy plus prednisone Drug: prednisone alone Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Multi-Center, Single-Blind, Randomized Study Comparing Thymectomy to No Thymectomy in Non-Thymomatous Myasthenia Gravis (MG) Patients Receiving Prednisone

Resource links provided by NLM:


Further study details as provided by Gary Cutter, PhD, University of Alabama at Birmingham:

Primary Outcome Measures:
  • Time-weighted Average Quantitative Myasthenia Gravis Weakness Score Over 3 Years [ Time Frame: baseline, month 3, 4, 6 and every 3 months through 36 months ]
    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-weighted Average Alternate-day Prednisone Dose (mg) Measured Over 3 Years [ Time Frame: baseline, month 1 , 2 , 3, 4, 6 and every 3 months through 36 months ]
    Participants reported alternate-day prednisone dose (mg) intake from baseline through withdrawn or completed 3 years follow up.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.


Secondary Outcome Measures:
  • Subgroup Analyses of Time-weighted Average Quantitative Myasthenia Gravis Score by Prednisone Use at Enrollment [ Time Frame: baseline, month 3, 4, 6 and every 3 months through 36 months ]
    Myasthenia Gravis (QMG) test. QMG total scores range from 0 to 39 for a given visit, with higher scores indicating more severe disease.

  • Subgroup Analyses of Time-weighted Average Quantitative Myasthenia Gravis Score by Sex [ Time Frame: baseline, month 3, 4, 6 and every 3 months through 36 months ]
    Myasthenia Gravis (QMG) test. QMG total scores range from 0 to 39 for a given visit, with higher scores indicating more severe disease.

  • Subgroup Analyses of Time-weighted Average Quantitative Myasthenia Gravis Score by Age at Disease Onset [ Time Frame: baseline, month 3, 4, 6 and every 3 months through 36 months ]
    Myasthenia Gravis (QMG) test. QMG total scores range from 0 to 39 for a given visit, with higher scores indicating more severe disease.

  • 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 ]
    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.

  • 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 ]
    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.

  • 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 ]
    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.

  • Number of Serious Adverse Events [ Time Frame: baseline to 3 years ]
    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)

  • Number of Patients With at Least One Serious Adverse Events [ Time Frame: baseline to 3 years ]
    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)

  • 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 [ Time Frame: baseline to 3 years ]
    Number who had hospitalization: Thymectomy plus prednisone n=15 (out of 66); Prednisone alone n=31 (out of 60)

  • Reason for Hospitalization According to Medical Dictionary for Regulatory Activities Term [ Time Frame: baseline to 3 years ]
    Number who had hospitalization: Thymectomy plus prednisone n=15 (out of 66); Prednisone alone n=31 (out of 60)

  • Time-weighted Average Prescribed Alternate Day Prednisone Dose (mg) [ Time Frame: baseline-day 20, month 1,2, 3, 4, 6 and every 3 months through 36 months ]
    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.

  • Penalized Time-weighted Average Alternative Day Prednisone Dose (mg; Method 1: Penalized Using Maximum Dose Before Azathioprine) [ Time Frame: baseline, month 3, 4, 6 and every 3 months through 36 months ]
    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.

  • Penalized Time-weighted Average Alternative Day Prednisone Dose (mg; Method 2: Penalized Using Dose at Time of Starting Azathioprine) [ Time Frame: baseline, month 1 , 2 , 3, 4, 6 and every 3 months through 36 months ]
    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-Weighted Average MG Activity of Daily Living (MG-ADL) [ Time Frame: baseline, month 4, 6 and every 3 months through 36 months ]
    MG Activity of Daily Living total scores range from 0 to 24, with the lower scores indicating better daily living quality of life.

  • Time-Weighted Average MG Activity of Daily Living (MG-ADL) at Month 12, 24, and 36 [ Time Frame: 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.

  • 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 [ Time Frame: Month 12, 24 and 36 ]
    Number of participants who were in minimal manifestation status at month 12, 24 and 36.

  • Cumulative Days in Hospital for Myasthenia Gravis Exacerbation [ Time Frame: baseline to 2 years ]
    Number of patients with MG exacerbation: Thymectomy plus prednisone=6 (out of 66); Prednisone alone=17 (out of 60)

  • Cumulative Days in Hospital for Myasthenia Gravis Exacerbation [ Time Frame: baseline to 3 years ]
    Number of patients with MG exacerbation: Thymectomy plus prednisone=6 (out of 66); Prednisone alone=22 (out of 60)

  • Short Form-36 Standardized Physical Component [ Time Frame: Month 0, Month 12, Month 24 and Month 36 ]
    Range from 0 to 100, the higher the physical component value, the better the mental health.

  • Short Form-36 Standardized Mental Component [ Time Frame: Month 0, Month 12, Month 24 and Month 36 ]
    Range from 0 to 100, the higher the mental component value, the better the mental health.

  • Treatment Associated Complications (TAC) [ Time Frame: Month 0, 1, 2, 3, 4 then every 3 months through Month 36 ]
    Treatment associated complications measured complications occurred by myasthenia gravis patients. Report number of participant with at least one complications by each visit.

  • Treatment Associated Symptoms (TAS) [ Time Frame: Month 0, 1, 2, 3, 4 then every 3 months through Month 36 ]
    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.


Enrollment: 126
Study Start Date: June 2006
Study Completion Date: December 2015
Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Thymectomy plus prednisone
Procedure: Extended Transsternal Thymectomy plus prednisone treatment
Procedure: thymectomy plus prednisone
The thymectomy will be performed as soon as possible after randomization.
Other Name: Extended transsternal thymectomy plus prednisone
Placebo Comparator: Prednisone alone
Drug: prednisone alone protocol
Drug: 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.
Other Name: prednisolone

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

Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00294658

  Show 70 Study Locations
Sponsors and Collaborators
University of Alabama at Birmingham
National Institute of Neurological Disorders and Stroke (NINDS)
Investigators
Principal Investigator: Gary Cutter, PhD University of Alabama at Birmingham School of Public Health, Department of Biostatistics
Principal Investigator: Gil Wolfe, MD University of Buffalo, Jacobs School of Medicine and Biomedical Sciences
Principal Investigator: Henry Kaminski, MD George Washington University School of Medicine and Health Sciences
  More Information

Publications:
Wolfe GI, Kaminski HJ, Aban IB, Minisman G, Kuo HC, Marx A, Ströbel 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. Erratum in: N Engl J Med. 2017 May 25;376(21):2097. [Dosage error in article text].

Responsible Party: Gary Cutter, PhD, Principle Investigator, University of Alabama at Birmingham
ClinicalTrials.gov Identifier: NCT00294658     History of Changes
Other Study ID Numbers: R01NS050733
1U01NS042685-01A2 ( U.S. NIH Grant/Contract )
CRC ( Other Identifier: NINDS )
Study First Received: February 21, 2006
Results First Received: September 19, 2016
Last Updated: April 12, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

Keywords provided by Gary Cutter, PhD, University of Alabama at Birmingham:
myasthenia gravis
thymectomy
prednisone
corticosteroid
extended transsternal thymectomy
ETTX
MG
thymus
thymoma

Additional relevant MeSH terms:
Muscle Weakness
Myasthenia Gravis
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Manifestations
Neurologic Manifestations
Nervous System Diseases
Pathologic Processes
Signs and Symptoms
Autoimmune Diseases of the Nervous System
Neuromuscular Junction Diseases
Neuromuscular Diseases
Autoimmune Diseases
Immune System Diseases
Prednisone
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents

ClinicalTrials.gov processed this record on September 19, 2017