BeatMG: Phase II Trial of Rituximab In Myasthenia Gravis

B Cell Targeted Treatment In Myasthenia Gravis (BeatMG): A Phase II Trial of Rituximab In Myasthenia Gravis

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.

Study Overview

• Status: Completed
• Conditions: Myasthenia Gravis
• Intervention / Treatment: Drug: Placebo; Drug: Rituximab

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.

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • California
    • Davis, California, United States, 95616
      • University of California - Davis
    • Los Angeles, California, United States, 90095
      • University of California - Los Angeles
  • Colorado
    • Denver, Colorado, United States, 80217
      • University of Colorado - Denver
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale School of Medicine, Department of Neurology
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami School of Medicine
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Illinois
    • Evanston, Illinois, United States, 60208
      • Northwestern University
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham & Women's Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63130
      • Washington University
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center
    • Brooklyn, New York, United States, 11203
      • SUNY Downstate Medical Center
    • Buffalo, New York, United States, 14260
      • SUNY Buffalo
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10065
      • Weill Cornell Medical Center
    • Rochester, New York, United States, 14627
      • University of Rochester
    • Stony Brook, New York, United States, 11790
      • SUNY Stony Brook
  • Ohio
    • Cincinnati, Ohio, United States, 45220
      • University of Cincinnati
    • Columbus, Ohio, United States, 43210
      • Ohio State University
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15260
      • University of Pittsburgh
  • Texas
    • Dallas, Texas, United States, 75235
      • University of Texas Southwestern Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • University of Utah
  • Virginia
    • Charlottesville, Virginia, United States, 22904
      • University of Virginia
  • Washington
    • Seattle, Washington, United States, 98107
      • Swedish Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; The placebo group will receive a vehicle control infusion	Drug: Placebo; The placebo group will receive a vehicle control infusion
Experimental: Rituximab; Intervention (rituximab): The treatment group will receive a total of two cycles of rituximab separated by 6 months. Each cycle is defined as one infusion (375mg/m2 IV) per week for four consecutive weeks	Drug: Rituximab; Intervention (rituximab): The treatment group will receive a total of two cycles of rituximab separated by 6 months. Each cycle is defined as one infusion (375mg/m2 IV) per week for four consecutive weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Steroid Sparing Effect	Percent of subjects that achieve a ≥ 75% reduction in mean daily prednisone dose in the 4 weeks prior to week 52 and have clinical improvement or no significant worsening of symptoms (≤ 2 point increase in MGC score) as compared to 4-week period prior to randomization and initiation of treatment.	4 weeks prior baseline and 4 weeks prior to week 52
Safety:Percentage of Study Participants With Treatment-related Adverse Experiences	Evaluate treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)	52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Myasthenia Gravis Composite (MGC) Scores From Baseline to Week 52	Evaluate whether there is a trend towards clinical benefit at end of 52 week treatment period, as measured by mean change in the MGC score, an MG-specific clinical outcomes scale used as endpoint in prior MG clinical trials. The Myasthenia Gravis Composite (MGC) scale consists of test items from the MG-ADL (Myasthenia Gravis Activities of Daily Living) scale and the QMG (Quantitative Myasthenia Gravis Scale) that measure symptoms and signs of MG, with weighted response options. The minimum score is 0, and the maximum score is 50. Higher scores correlate with clinical worsening of the disease.	baseline and 52 weeks
Change in Quantitative Myasthenia Gravis(QMG) Scores From Baseline to Week 52	Evaluate whether there is a trend towards clinical benefit at end of 52 week treatment period, as measured by the mean change in the QMG score - a specific clinical outcome scale used as endpoint in prior MG clinical trials. The Quantitative Myasthenia Gravis Score (QMG) is a commonly used objective outcome measure in myasthenia gravis (MG) comprising 13 items, each with a possible score from 0 to 3, and a maximum possible of 39 points, where a higher score indicates more severe disease.	baseline and 52 weeks

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Richard J Nowak, MD, MS, Yale University

Publications and helpful links

General Publications

• 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. 2021 Dec 2. pii: 10.1212/WNL.0000000000013121. doi: 10.1212/WNL.0000000000013121. [Epub ahead of print]
• 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.
• 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.

Helpful Links

• NeuroNEXT Network
• Yale School of Medicine, Department of Neurology
• National Institutes of Health

Study record dates

Study Major Dates

• Study Start: May 1, 2014
• Primary Completion (Actual): July 1, 2017
• Study Completion (Actual): May 1, 2018

Study Registration Dates

• First Submitted: April 7, 2014
• First Submitted That Met QC Criteria: April 7, 2014
• First Posted (Estimate): April 10, 2014

Study Record Updates

• Last Update Posted (Actual): March 6, 2020
• Last Update Submitted That Met QC Criteria: March 4, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Rituximab; Myasthenia Gravis; SNOMED code 31839002
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Neoplasms; Autoimmune Diseases of the Nervous System; Autoimmune Diseases; Neoplasms by Site; Neurologic Manifestations; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Neuromuscular Manifestations; Nervous System Neoplasms; Paraneoplastic Syndromes, Nervous System; Paraneoplastic Syndromes; Neuromuscular Junction Diseases; Muscle Weakness; Myasthenia Gravis; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: 1401013253-0; 1U01NS084495-01A1 (U.S. NIH Grant/Contract); U01NS077179-01 (U.S. NIH Grant/Contract); U01NS077352 (U.S. NIH Grant/Contract)