BeatMG: Phase II Trial of Rituximab In Myasthenia Gravis

NCT ID: NCT02110706

Last Updated: 2020-03-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 52 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-05-31
• Study Completion Date: 2018-05-31

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.

Conditions

Myasthenia Gravis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Placebo

The placebo group will receive a vehicle control infusion

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

The placebo group will receive a vehicle control infusion

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

Group Type: EXPERIMENTAL

Rituximab

Intervention Type: DRUG

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

Interventions

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

Intervention Type: DRUG

Placebo

The placebo group will receive a vehicle control infusion

Intervention Type: DRUG

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.

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).

• Minimum Eligible Age: 21 Years
• Maximum Eligible Age: 90 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Neurological Disorders and Stroke (NINDS)

NIH

Sponsor Role: collaborator

Yale University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Richard J Nowak, MD, MS

Role: PRINCIPAL_INVESTIGATOR

Yale University

Locations

University of Alabama at Birmingham

Birmingham, Alabama, United States

University of California - Davis

Davis, California, United States

University of California - Los Angeles

Los Angeles, California, United States

University of Colorado - Denver

Denver, Colorado, United States

Yale School of Medicine, Department of Neurology

New Haven, Connecticut, United States

University of Miami School of Medicine

Miami, Florida, United States

Emory University

Atlanta, Georgia, United States

Northwestern University

Evanston, Illinois, United States

University of Kansas Medical Center

Kansas City, Kansas, United States

Brigham & Women's Hospital

Boston, Massachusetts, United States

Washington University

St Louis, Missouri, United States

SUNY Downstate Medical Center

Brooklyn, New York, United States

SUNY Buffalo

Buffalo, New York, United States

Columbia University Medical Center

New York, New York, United States

Weill Cornell Medical Center

New York, New York, United States

University of Rochester

Rochester, New York, United States

SUNY Stony Brook

Stony Brook, New York, United States

Montefiore Medical Center

The Bronx, New York, United States

University of Cincinnati

Cincinnati, Ohio, United States

Ohio State University

Columbus, Ohio, United States

Oregon Health and Science University

Portland, Oregon, United States

University of Pittsburgh

Pittsburgh, Pennsylvania, United States

University of Texas Southwestern Medical Center

Dallas, Texas, United States

University of Utah

Salt Lake City, Utah, United States

University of Virginia

Charlottesville, Virginia, United States

Swedish Medical Center

Seattle, Washington, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 34857535 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 32098874 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 28801338 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

http://www.neuronext.org/

NeuroNEXT Network

http://medicine.yale.edu/neurology/index.aspx

Yale School of Medicine, Department of Neurology

http://www.nih.gov/

National Institutes of Health

Other Identifiers

1U01NS084495-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

U01NS077179-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

U01NS077352

Identifier Type: NIH

Identifier Source: secondary_id

View Link

1401013253-0

Identifier Type: -

Identifier Source: org_study_id