Disease-Modifying Treatments for Myasthenia Gravis (PROMISE-MG)

• ClinicalTrials.gov Identifier: NCT03490539
• Recruitment Status: Completed
• First Posted: April 6, 2018
• Last Update Posted: February 3, 2021
• Sponsor: Duke University
• Collaborators: Beth Israel Deaconess Medical Center; Patient-Centered Outcomes Research Institute
• Information provided by (Responsible Party): Duke University

Study Description

Brief Summary:

This study is designed to address the evidence gaps in a real-world setting and help patients with MG choose treatments that are best suited to them. It is a prospective, multicenter observational cohort study of comparative effectiveness of MG treatments, with a patient-centered primary outcome measure, to guide clinicians, patients and payers regarding the choice of treatment options for this chronic and serious disease.

Primary: To compare the effectiveness of azathioprine (AZT) and mycophenolate mofetil (MMF).

Secondary: To compare the outcomes in patients receiving an adequate dose and duration of AZT or MMF over the 2-3 year study period, vs. patients not receiving adequate doses and duration of these agents

Condition or disease	Intervention/treatment
Neurological Disorder; Autoimmune Diseases	Drug: Mycophenolate Mofetil; Drug: Azathioprine

Detailed Description:

Design & procedures - This is an observational study in the real world clinical setting to evaluate immunosuppressive treatment (IS) of myasthenia gravis (MG). Patients with acquired autoimmune MG ≥ 18 years of age who are not on IS agents, and have not been on corticosteroids for at least 30 days will be enrolled at 20 sites in the US and Canada. These patients will be treated according to the physician's judgment and patient preferences as in routine clinical practice. Patients will be followed prospectively, with the frequency of clinical visits and laboratory monitoring determined by the treating physician, which may differ among patients. Standard outcome measures measuring efficacy and adverse effects that are used in clinical practice will be collected, with emphasis on patient reported outcomes. Informed consent will be obtained using an approved consent form. Patient identifiable / clinical information from the medical record, including the study outcome measures will be uploaded to a centralized REDCap database. The investigators plan to recruit 220 patients, adjusting for a 10% drop out rate, with a final sample of 200 patients for analysis.

Study Design

• Study Type: Observational [Patient Registry]
• Actual Enrollment: 167 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Target Follow-Up Duration: 3 Years
• Official Title: Prospective Multicenter Observational Cohort Study of Comparative Effectiveness of Disease-modifying Treatments for Myasthenia Gravis
• Actual Study Start Date: May 7, 2018
• Actual Primary Completion Date: January 31, 2021
• Actual Study Completion Date: January 31, 2021

Groups and Cohorts

Group/Cohort	Intervention/treatment
azathioprine (AZT); Patients with MG who are receiving azathioprine as part of routine clinical care	Drug: Azathioprine; oral tablet; Other Name: Imuran
mycophenolate mofetil (MMF); Patients with MG who are receiving mycophenolate mofetil as part of routine clinical care	Drug: Mycophenolate Mofetil; oral tablets; Other Name: Cellcept

Outcome Measures

Primary Outcome Measures :

1. Change in Patient-Reported Myasthenia Gravis Quality of Life, 15, revised ( MG-QOL15r) [ Time Frame: Baseline, 24-36 months ]
   Measures MG symptoms, physical, social and emotional functioning related to MG, with 15 items, 3 response option, 0-2 for each item, Total score range 0-30, higher scores indicating worse function
2. Change in composite outcome of clinical improvement and adverse effects [ Time Frame: Baseline, 24-36 months ]

   measured by a composite of clinical improvement and adverse effects of treatments. Clinical improvement: achievement of MGFA Post-Intervention Status (PIS) Minimal Manifestation Status (MM) or better, defined below.

   Adverse effects end point: no more than Grade 1 CTCAE (Common Terminology Criteria for Adverse Events) medication side-effects, defined below.

   MGFA PIS- MM: the patient has no symptoms or functional limitations from MG but has some weakness on examination of some muscles

   CTCAE: list of adverse event (AE) terms commonly encountered in oncology but is useful to monitor the side effects of any intervention Each AE term is defined and graded on a 1 to 5 scale indicating the severity of the AE, 1 representing the mildest side effect and 5 representing death Grade 1 CTCAE side-effects: "asymptomatic or only mild symptoms; intervention not indicated"

Secondary Outcome Measures :

1. Change in Myasthenia gravis composite (MGC) scores [ Time Frame: Baseline, 24-36 months ]

   10 item scale of patient-reported functions and clinician-reported examination findings.

   Scores range from 0-50 (0- normal and 50- most severe)

2. Change in Myasthenia Gravis Activities of Daily Living Scale (MG-ADL) [ Time Frame: Baseline, 24-36 months ]
   Patient-reported 8- item questionnaire evaluating commonly reported symptoms in MG on a 4 response scale from 0-3 (0 - normal, 3- highest disability) Range 0-24, higher score is worse
3. Change in Myasthenia Gravis Manual Muscle Test scores (MG-MMT) [ Time Frame: Baseline, 24-36 months ]
   Clinician-assessed scale of 18 muscle functions commonly affected by MG, each graded from 0 (normal) to 4 (paralyzed/unable to perform), Range 0-120, higher score reflects worse function
4. Change in Visual Analogue Scale (VAS) for Disease Severity [ Time Frame: Baseline, 24-36 months ]
   Patient perception of disease severity measured in millimeters on a 100 mm line. Higher number indicates more severe disease
5. Change in Visual Analogue Scale (VAS) for Treatment Side effects [ Time Frame: Baseline, 24-36 months ]
   patient perception of side effects of treatment measured in millimeters on a 100 mm line. Higher number indicates worse side effects
6. Change in number of hospitalizations for MG [ Time Frame: Baseline, 24-36 months ]
   counts of hospitalizations for MG- higher count is worse

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

MG patients with autoimmune MG

Criteria

Inclusion Criteria:

Participants eligible for inclusion in this study must fulfill all of the following criteria:

1. Age ≥ 18 years of age

2. Acquired autoimmune MG, with weakness and confirmed by one or more of the following:

   1. Elevated AChR or MuSK antibodies
   2. Unequivocal response to cholinesterase inhibitors
   3. Abnormal RNS or increased jitter (without nerve or muscle disease sufficient to produce a decrement or increased jitter)
3. Patients seen initially at the participating center after January 1, 2017.
4. Patients on pyridostigmine at the first evaluation at the participating center ("baseline visit") may be included if pyridostigmine was started ≤3 months before the baseline visit.
5. Patients who received corticosteroids >90 days prior to baseline visit for a non-MG indication may be included. (Patients who have received corticosteroids for a non-MG indication between 31 and 90 days before baseline visit will be evaluated by the primary investigators on a case by case basis to determine if the extent and dose of corticosteroid could have impacted the course of MG or symptoms of MG.)

Exclusion Criteria:

Patients fulfilling any of the following criteria are not eligible for inclusion in this study. No additional exclusions may be applied by the investigator, in order to ensure that the study population will be representative of all eligible participants.

1. Patients with non-autoimmune MG (congenital myasthenic syndromes, drug-induced MG)
2. Patients on immunosuppressive agents at the baseline visit.
3. Patients who have previously received steroids for the treatment of MG.
4. Patients with steroid use for a non-MG indication < 30 days prior to the baseline visit.
5. Patients with previous thymectomy, IVIg or plasma exchange, or treatment with a non-steroidal immunosuppressive agent (azathioprine, mycophenolate mofetil cyclosporine, methotrexate, cyclophosphamide, tacrolimus, rituximab, or any investigational immunosuppressive agent). Patients who have outcomes measured within 24 hours after initiation of IVIg or PLEX are acceptable.

Contacts and Locations

Locations

United States, California

Stanford University

Palo Alto, California, United States, 84303

United States, Florida

Unversity of Miami

Miami, Florida, United States, 33136

United States, Illinois

Rush University Medical Center

Chicago, Illinois, United States, 60612

United States, Louisiana

Ochsner Clinic Foundation

New Orleans, Louisiana, United States, 70121

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

Brigham and Women's Hospital

Boston, Massachusetts, United States, 02115

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States, 02215

St. Elizabeth's Medical Center

Brighton, Massachusetts, United States, 02135

United States, New York

University at Buffalo, SUNY

Buffalo, New York, United States, 14202

University of Rochester Medical Center

Rochester, New York, United States, 14642

United States, North Carolina

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, United States, 27599

Duke University

Durham, North Carolina, United States, 27710

United States, Ohio

Cleveland Clinic

Cleveland, Ohio, United States, 44195

United States, Pennsylvania

University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

University of Pittsburgh

Pittsburgh, Pennsylvania, United States, 15213

United States, South Carolina

Medical University of South Carolina

Charleston, South Carolina, United States, 29425

United States, Vermont

University of Vermont - Larner College of Medicine

Burlington, Vermont, United States, 05401

Canada, Alberta

University of Alberta Hospital, Faculty of Medicine

Edmonton, Alberta, Canada, T6G2G3

Canada, Ontario

London Health Sciences Centre

London, Ontario, Canada, N6A5A5

Sponsors and Collaborators

Duke University

Beth Israel Deaconess Medical Center

Patient-Centered Outcomes Research Institute

Investigators

• Principal Investigator: Jeffery Guptill, MD; Duke University
• Principal Investigator: Donald Sanders, MD; Duke University
• Principal Investigator: Pushpa Narayanaswami, MD; Beth Israel Deaconess Medical Center

More Information

Additional Information:

U.S. Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 

Publications:

Deenen JC, Horlings CG, Verschuuren JJ, Verbeek AL, van Engelen BG. The Epidemiology of Neuromuscular Disorders: A Comprehensive Overview of the Literature. J Neuromuscul Dis. 2015;2(1):73-85.

Sanders DB, Wolfe GI, Narayanaswami P. Author response: International consensus guidance for management of myasthenia gravis: Executive summary. Neurology. 2017 Jan 31;88(5):505-506. doi: 10.1212/WNL.0000000000003570. No abstract available.

Burns TM, Sadjadi R, Utsugisawa K, Gwathmey KG, Joshi A, Jones S, Bril V, Barnett C, Guptill JT, Sanders DB, Hobson-Webb L, Juel VC, Massey J, Gable KL, Silvestri NJ, Wolfe G, Cutter G, Nagane Y, Murai H, Masuda M, Farrugia ME, Carmichael C, Birnbaum S, Hogrel JY, Nafissi S, Fatehi F, Ou C, Liu W, Conaway M. International clinimetric evaluation of the MG-QOL15, resulting in slight revision and subsequent validation of the MG-QOL15r. Muscle Nerve. 2016 Dec;54(6):1015-1022. doi: 10.1002/mus.25198. Epub 2016 Nov 7.

Mullins LL, Carpentier MY, Paul RH, Sanders DB; Muscle Study Group. Disease-specific measure of quality of life for myasthenia gravis. Muscle Nerve. 2008 Aug;38(2):947-56. doi: 10.1002/mus.21016.

Burns TM, Grouse CK, Wolfe GI, Conaway MR, Sanders DB; MG Composite and MG-OL15 Study Group. The MG-QOL15 for following the health-related quality of life of patients with myasthenia gravis. Muscle Nerve. 2011 Jan;43(1):14-8. doi: 10.1002/mus.21883.

Jaretzki A 3rd, Barohn RJ, Ernstoff RM, Kaminski HJ, Keesey JC, Penn AS, Sanders DB. Myasthenia gravis: recommendations for clinical research standards. Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Neurology. 2000 Jul 12;55(1):16-23. doi: 10.1212/wnl.55.1.16. No abstract available.

Burns TM, Conaway M, Sanders DB; MG Composite and MG-QOL15 Study Group. The MG Composite: A valid and reliable outcome measure for myasthenia gravis. Neurology. 2010 May 4;74(18):1434-40. doi: 10.1212/WNL.0b013e3181dc1b1e.

Sadjadi R, Conaway M, Cutter G, Sanders DB, Burns TM; MG Composite MG-QOL15 Study Group. Psychometric evaluation of the myasthenia gravis composite using Rasch analysis. Muscle Nerve. 2012 Jun;45(6):820-5. doi: 10.1002/mus.23260.

Burns TM, Conaway MR, Cutter GR, Sanders DB; Muscle Study Group. Construction of an efficient evaluative instrument for myasthenia gravis: the MG composite. Muscle Nerve. 2008 Dec;38(6):1553-62. doi: 10.1002/mus.21185.

Wolfe GI, Herbelin L, Nations SP, Foster B, Bryan WW, Barohn RJ. Myasthenia gravis activities of daily living profile. Neurology. 1999 Apr 22;52(7):1487-9. doi: 10.1212/wnl.52.7.1487.

Sanders DB, Tucker-Lipscomb B, Massey JM. A simple manual muscle test for myasthenia gravis: validation and comparison with the QMG score. Ann N Y Acad Sci. 2003 Sep;998:440-4. doi: 10.1196/annals.1254.057. No abstract available.

Gilhus NE, Verschuuren JJ. Myasthenia gravis: subgroup classification and therapeutic strategies. Lancet Neurol. 2015 Oct;14(10):1023-36. doi: 10.1016/S1474-4422(15)00145-3.

Bang H, Robins JM. Doubly robust estimation in missing data and causal inference models. Biometrics. 2005 Dec;61(4):962-73. doi: 10.1111/j.1541-0420.2005.00377.x.

Li F, Morgan KL, Zaslavsky AM. Balancing Covariates via Propensity Score Weighting. Journal of the American Statistical Association 2016;(In press).

Crump RK. Dealing with limited overlap in estimation of average treatment effects. Biometrika 2009;96(1):187-199.

Meriggioli MN, Sanders DB. Disorders of Neuromuscular Transmission. In: Bradley WG, Daroff RB, Fenichel GM, Jankovic J, Mazziotta JC, editors. Neurology in Clinical Practice. 6 ed. Philadelphia: Elsevier/Saunders; 2012. p 2046-2065.

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT03490539
• Other Study ID Numbers: Pro00087883
• First Posted: April 6, 2018
• Last Update Posted: February 3, 2021
• Last Verified: February 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Duke University:

observational; comparative effectiveness; myasthenia gravis

Additional relevant MeSH terms:

Myasthenia Gravis; Nervous System Diseases; Autoimmune Diseases; Immune System Diseases; Paraneoplastic Syndromes, Nervous System; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Paraneoplastic Syndromes; Autoimmune Diseases of the Nervous System; Neurodegenerative Diseases; Neuromuscular Junction Diseases; Neuromuscular Diseases; Mycophenolic Acid; Azathioprine; Antibiotics, Antineoplastic; Antineoplastic Agents; Antibiotics, Antitubercular; Antitubercular Agents; Anti-Bacterial Agents; Anti-Infective Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Antimetabolites, Antineoplastic; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents