Clinical trial NCT02110706: BeatMG: Phase II Trial of Rituximab In Myasthenia Gravis
Official title: B Cell Targeted Treatment In Myasthenia Gravis (BeatMG): A Phase II Trial of Rituximab In Myasthenia Gravis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Myasthenia Gravis
Keywords: Myasthenia Gravis
Rituximab
SNOMED code 31839002
Lead sponsor: Yale University
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2014-04-10
Enrollment: 52
Sex: ALL
Minimum age (years): 21
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The specific primary objective of this study is to determine whether rituximab is a safe and beneficial therapeutic for Myasthenia Gravis (MG) that warrants further study in a phase III efficacy trial.

Detailed description: Investigators plan on conducting a multicenter randomized, double-blind, placebo controlled Phase II clinical trial utilizing a futility design. The study would include acetylcholine receptor (AChR) antibody positive generalized MG subjects. This study also presents a unique opportunity to study both drug and disease mechanisms because unlike many other autoimmune diseases in which rituximab has been used, MG affords the investigation of antigen-specific components that participate in the immunopathology of the disease, namely autoantibodies, autoantibody-producing B cells, and antigen-specific T cells. This work will further our understanding of MG immunopathology and it represents the first step toward gaining a more complete understanding of the immune mechanisms underlying treatment of MG with rituximab leading to new ways to treat the disease.

The specific aim of this study is to determine whether rituximab is a safe and effective treatment for subjects with MG.

The SNOMED code for MG is 31839002.

Eligibility criteria: Inclusion Criteria:

1. Subjects 21 to 90 years old
2. Subjects must have generalized MG, defined as MGFA clinical classification grades 2 (mild), 3 (moderate), or 4 (severe, but not intubated) at the time of screening/randomization.
3. Elevated AChR antibody titer
4. Subject's signs and symptoms should not be better explained by another disease process.
5. Subjects must be on a stable standard immunosuppressive regimen:

   1. Prednisone only: Prednisone dose must be at least 15mg/day (or the equivalent on alternate days), and the dose of prednisone must have been stable for at least 4 weeks (28 days) prior to the baseline visit.
   2. Prednisone plus another immunosuppressive therapy (IST). Immunosuppressive therapies other than prednisone, specifically azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus or methotrexate, are permitted, but the dose must have been stable for at least 6 months prior to the baseline visit.

   (Note: The prednisone dose must be stable as defined in the prednisone only group. The IST dose must remain stable throughout the course of the study).
6. Subjects must be willing to complete the study and return for follow-up visits.
7. No history of thymoma, tumor, infection, or interstitial lung disease on chest CT, MRI, or chest x-ray. Note: Chest x-ray will be completed at screening to look of interstitial lung disease. A chest CT or MRI to evaluate for thymoma must be completed as part of prescreening.
8. Able and willing to give written informed consent and comply with the requirements of the study protocol.
9. Subjects must be able to give written informed consent before participating in this study. A copy of the signed consent must be kept in the subject's medical record.
10. Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for twelve months (1 year) after completion of treatment.

Exclusion Criteria:

1. A history of chronic degenerative, psychiatric, or neurologic disorder other than MG that can produce weakness or fatigue.
2. Other major chronic or debilitating illnesses within six months prior to study entry.
3. Female subjects who are premenopausal and are:

   1. pregnant on the basis of a serum pregnancy test,
   2. breast-feeding, or
   3. not using an effective method of double barrier (1 hormonal plus 1 barrier method or 2 simultaneous barrier methods) or birth control (birth control pills, male condom, female condom, intrauterine device, Norplant, tubal ligation, or other sterilization procedures).
4. Altered levels of consciousness, dementia, or abnormal mental status.
5. Thymectomy in the previous six months.
6. Subjects who have been medicated with immunosuppressive drugs not listed in inclusion #5 within the last 8 weeks (56 days) prior to the baseline visit
7. Subjects who have been medicated with an immunosuppressive agent such as azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus or methotrexate, that is withdrawn within 8 weeks (56 days) of the Baseline Visit.
8. Subjects who have received IVIg or PLEX treatment within the last 4 weeks (28 days) prior to the baseline visit.
9. Unstable dose or a stable dose of \> 480 mg/day of pyridostigmine in 2 weeks prior to screening visit.
10. Daily use of non-steroidal anti-inflammatory drugs (NSAIDs).
11. History of renal or hepatic insufficiency or elevated liver enzymes (AST or ALT \>2.5 x Upper Limit of Normal).
12. History of bone marrow hypoplasia, leucopenia, thrombocytopenia, significant anemia, clinical or laboratory evidence of immunodeficiency syndromes.
13. Forced Vital Capacity (FVC) \<50% of percent predicted.

    General Safety \& Laboratory Exclusion Criteria
14. ANC \< 1.5 x 103 cells/microliter
15. Hemoglobin: \< 8.0 gm/dL
16. Platelets: \< 100,000/mm
17. Positive Hepatitis B or C serology (Hep B surface antigen and Hep C antibody)
18. History of positive HIV (HIV conducted during screening if applicable)
19. Treatment with any investigational agent within 4 weeks of screening or 5 half-lives of the investigational drug (whichever is longer)
20. Receipt of a live vaccine within 4 weeks prior to randomization
21. Previous treatment with rituximab (MabThera® / Rituxan®)
22. Previous treatment with natalizumab (Tysabri®)
23. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies
24. History of recurrent significant infection or history of recurrent bacterial infections
25. Known active bacterial, viral fungal mycobacterial, or other infection (including tuberculosis or atypical mycobacterial disease, but excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening
26. Unstable steroid dose in the past 4 weeks (28 days)
27. Lack of peripheral venous access
28. History of drug, alcohol, or chemical abuse within 6 months prior to screening
29. Concomitant malignancies or previous malignancies, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or prostate.
30. History of psychiatric disorder that would interfere with normal participation in this protocol
31. Significant cardiac or pulmonary disease (including obstructive pulmonary disease)
32. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the subject at high risk from treatment complications
33. Subjects that do not record daily prednisone doses for at least 28 days before the Baseline Visit, or subjects whose prednisone dose varies by ≥6mg/day on average.
34. Prednisone dose of more than 100 mg/day (or 200 mg over a two day period).

Primary outcomes:
measure: Steroid Sparing Effect
timeFrame: 4 weeks prior baseline and 4 weeks prior to week 52
measure: Safety:Percentage of Study Participants With Treatment-related Adverse Experiences
timeFrame: 52 weeks
Secondary outcomes:
measure: Change in Myasthenia Gravis Composite (MGC) Scores From Baseline to Week 52
timeFrame: baseline and 52 weeks
measure: Change in Quantitative Myasthenia Gravis(QMG) Scores From Baseline to Week 52
timeFrame: baseline and 52 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Davis
country: United States
facility: University of California - Davis
state: California
city: Los Angeles
country: United States
facility: University of California - Los Angeles
state: California
city: Denver
country: United States
facility: University of Colorado - Denver
state: Colorado
city: New Haven
country: United States
facility: Yale School of Medicine, Department of Neurology
state: Connecticut
city: Miami
country: United States
facility: University of Miami School of Medicine
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Evanston
country: United States
facility: Northwestern University
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Boston
country: United States
facility: Brigham & Women's Hospital
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Brooklyn
country: United States
facility: SUNY Downstate Medical Center
state: New York
city: Buffalo
country: United States
facility: SUNY Buffalo
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical Center
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Stony Brook
country: United States
facility: SUNY Stony Brook
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Seattle
country: United States
facility: Swedish Medical Center
state: Washington
Study officials:
affiliation: Yale University
name: Richard J Nowak, MD, MS
role: PRINCIPAL_INVESTIGATOR
References:
citation: Nowak RJ, Coffey CS, Goldstein JM, Dimachkie MM, Benatar M, Kissel JT, Wolfe GI, Burns TM, Freimer ML, Nations S, Granit V, Smith AG, Richman DP, Ciafaloni E, Al-Lozi MT, Sams LA, Quan D, Ubogu E, Pearson B, Sharma A, Yankey JW, Uribe L, Shy M, Amato AA, Conwit R, O'Connor KC, Hafler DA, Cudkowicz ME, Barohn RJ; NeuroNEXT NN103 BeatMG Study Team. Phase 2 Trial of Rituximab in Acetylcholine Receptor Antibody-Positive Generalized Myasthenia Gravis: The BeatMG Study. Neurology. 2022 Jan 25;98(4):e376-e389. doi: 10.1212/WNL.0000000000013121.
citation: Di Stefano V, Lupica A, Rispoli MG, Di Muzio A, Brighina F, Rodolico C. Rituximab in AChR subtype of myasthenia gravis: systematic review. J Neurol Neurosurg Psychiatry. 2020 Apr;91(4):392-395. doi: 10.1136/jnnp-2019-322606. Epub 2020 Feb 25.
citation: Hehir MK, Hobson-Webb LD, Benatar M, Barnett C, Silvestri NJ, Howard JF Jr, Howard D, Visser A, Crum BA, Nowak R, Beekman R, Kumar A, Ruzhansky K, Chen IA, Pulley MT, LaBoy SM, Fellman MA, Greene SM, Pasnoor M, Burns TM. Rituximab as treatment for anti-MuSK myasthenia gravis: Multicenter blinded prospective review. Neurology. 2017 Sep 5;89(10):1069-1077. doi: 10.1212/WNL.0000000000004341. Epub 2017 Aug 11.