Disease-Modifying Treatments for Myasthenia Gravis

Autoimmune Diseases Clinical Trial

— PROMISE-MG  

Official title:

Prospective Multicenter Observational Cohort Study of Comparative Effectiveness of Disease-modifying Treatments for Myasthenia Gravis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03490539
• Other study ID #: Pro00087883
• Status: Completed
• Start date: May 7, 2018
• Est. completion date: January 31, 2021

Study information

• Verified date: February 2021
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 167
• Est. completion date: January 31, 2021
• Est. primary completion date: January 31, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Autoimmune Diseases
• Myasthenia Gravis
• Nervous System Diseases
• Neurological Disorder

Intervention

Drug:
• Mycophenolate Mofetil
oral tablets
• Azathioprine
oral tablet

Locations

Country	Name	City	State
Canada	University of Alberta Hospital, Faculty of Medicine	Edmonton	Alberta
Canada	London Health Sciences Centre	London	Ontario
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	St. Elizabeth's Medical Center	Brighton	Massachusetts
United States	University at Buffalo, SUNY	Buffalo	New York
United States	University of Vermont - Larner College of Medicine	Burlington	Vermont
United States	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Rush University Medical Center	Chicago	Illinois
United States	Cleveland Clinic	Cleveland	Ohio
United States	Duke University	Durham	North Carolina
United States	Unversity of Miami	Miami	Florida
United States	Ochsner Clinic Foundation	New Orleans	Louisiana
United States	Stanford University	Palo Alto	California
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	University of Rochester Medical Center	Rochester	New York

Sponsors (3)

Lead Sponsor	Collaborator
Duke University	Beth Israel Deaconess Medical Center, Patient-Centered Outcomes Research Institute

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (16)

Bang H, Robins JM. Doubly robust estimation in missing data and causal inference models. Biometrics. 2005 Dec;61(4):962-73. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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

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. — View Citation

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. Review. — View Citation

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. Review. — View Citation

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

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.

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Patient-Reported Myasthenia Gravis Quality of Life, 15, revised ( MG-QOL15r)	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	Baseline, 24-36 months
Primary	Change in composite outcome of clinical improvement and adverse effects	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"	Baseline, 24-36 months
Secondary	Change in Myasthenia gravis composite (MGC) scores	10 item scale of patient-reported functions and clinician-reported examination findings.; Scores range from 0-50 (0- normal and 50- most severe)	Baseline, 24-36 months
Secondary	Change in Myasthenia Gravis Activities of Daily Living Scale (MG-ADL)	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	Baseline, 24-36 months
Secondary	Change in Myasthenia Gravis Manual Muscle Test scores (MG-MMT)	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	Baseline, 24-36 months
Secondary	Change in Visual Analogue Scale (VAS) for Disease Severity	Patient perception of disease severity measured in millimeters on a 100 mm line. Higher number indicates more severe disease	Baseline, 24-36 months
Secondary	Change in Visual Analogue Scale (VAS) for Treatment Side effects	patient perception of side effects of treatment measured in millimeters on a 100 mm line. Higher number indicates worse side effects	Baseline, 24-36 months
Secondary	Change in number of hospitalizations for MG	counts of hospitalizations for MG- higher count is worse	Baseline, 24-36 months

External Links

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