BeatMG: Phase II Trial of Rituximab In Myasthenia Gravis

Myasthenia Gravis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02110706
• Other study ID #: 1401013253-0
• Secondary ID: 1U01NS084495-01A
• Status: Completed
• Phase: Phase 2
• Start date: May 2014
• Est. completion date: May 2018

Study information

• Verified date: March 2020
• Source: Yale University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 52
• Est. completion date: May 2018
• Est. primary completion date: July 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years to 90 Years

Eligibility

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).

Related Conditions & MeSH terms

• Muscle Weakness
• Myasthenia Gravis

Intervention

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
• Placebo
The placebo group will receive a vehicle control infusion

Locations

Country	Name	City	State
United States	Emory University	Atlanta	Georgia
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Brigham & Women's Hospital	Boston	Massachusetts
United States	Montefiore Medical Center	Bronx	New York
United States	SUNY Downstate Medical Center	Brooklyn	New York
United States	SUNY Buffalo	Buffalo	New York
United States	University of Virginia	Charlottesville	Virginia
United States	University of Cincinnati	Cincinnati	Ohio
United States	Ohio State University	Columbus	Ohio
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	University of California - Davis	Davis	California
United States	University of Colorado - Denver	Denver	Colorado
United States	Northwestern University	Evanston	Illinois
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	University of California - Los Angeles	Los Angeles	California
United States	University of Miami School of Medicine	Miami	Florida
United States	Yale School of Medicine, Department of Neurology	New Haven	Connecticut
United States	Columbia University Medical Center	New York	New York
United States	Weill Cornell Medical Center	New York	New York
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	University of Rochester	Rochester	New York
United States	Washington University	Saint Louis	Missouri
United States	University of Utah	Salt Lake City	Utah
United States	Swedish Medical Center	Seattle	Washington
United States	SUNY Stony Brook	Stony Brook	New York

Sponsors (2)

Lead Sponsor	Collaborator
Yale University	National Institute of Neurological Disorders and Stroke (NINDS)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Safety:Percentage of Study Participants With Treatment-related Adverse Experiences	Evaluate treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)	52 weeks
Secondary	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
Secondary	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

External Links

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