A Pilot Trial of Rituxan in Refractory Myasthenia Gravis

January 15, 2013 updated by: Dr. Rup Tandan, M.D., F.R.C.P., University of Vermont

Phase 1-2 Pilot Study of Rituximab (Rituxan) in Refractory Myasthenia Gravis.

Myasthenia gravis is a disease that happens because the immune system attacks the nervous system. The damage is caused by antibodies produced by B lymphocytes. These antibodies damage a special part of the muscle that helps transmit impulses from nerves to muscles to allow muscles to work properly. This damage results in symptoms of myasthenia gravis. Participants are being asked to participate in this research study because their myasthenia gravis has either failed to respond to treatments commonly used in the disease, or they have had bad side-effects from such treatments.

This is a research study of a drug called Rituximab. Rituximab, also called Rituxan, is a mouse antibody that has been changed to make it similar to a human antibody. Antibodies are proteins that can protect the body from foreign invaders, such as bacteria and viruses, by binding to substances called antigens. Rituxan works by binding to a protein, called the CD20 protein. Rituxan helps to destroy white blood cells that produce antibodies in the body, called B-lymphocytes. It is a treatment given through a vein in the participant's arm over a period of approximately 4-6 hours. It has been approved by the Food and Drug Administration (FDA) for use in patients with a form of cancer of the lymph glands called Non-Hodgkin's Lymphoma (NHL). Rituximab is not approved for their myasthenia gravis.

Treatment with Rituximab is being tried in this research study because Rituximab decreases B lymphocytes. There is preliminary evidence that Rituximab helps some patients with chronic and otherwise difficult to treat myasthenia gravis.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Myasthenia gravis (MG) is an immune-mediated disorder of the neuromuscular junction diagnosed on the basis of clinical, electrophysiological and serological features. Cyclosporine as a disease-modifying therapy has been effective in a controlled study; corticosteroids, immunosuppressive agents such as azathioprine and cyclophosphamide, plasmapheresis and intravenous human immune globulin have shown benefit in uncontrolled trials. There are several drawbacks to currently used medical treatments, including serious and debilitating side-effects, prohibitive costs, and the need for continuous or periodical treatment. Almost 20-25% of patients with MG are unresponsive to commonly used therapies, resulting in significant burden and economic loss. Rituximab is a chimeric anti-CD20 monoclonal antibody which produces a substantial reduction in circulating plasma cells (CD19+) and B cells (CD20+) and provides targeted therapy for B-cell lymphomas. Recently, rituximab has been found to be effective in several antibody-mediated autoimmune processes, including immune thrombocytopenia, autoimmune hemolytic anemia, and IgM-related polyneuropathies. There is preliminary evidence in the literature that treatment of MG patients with rituximab is likely to be of benefit. These observations would strongly suggest that rituximab might benefit refractory MG and needs further study.

Study Type

Interventional

Enrollment (Anticipated)

10

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • New York
      • Syracuse, New York, United States, 13210
        • State University of New York
    • Vermont
      • Burlington, Vermont, United States, 05405
        • University of Vermont Department of Neurology

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

Criteria for patient selection will be based upon the recent recommendations for clinical research standards by the Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America (Jaretzki et al, 2000).

Patients will be included in the trial based upon fulfilling all the criteria given below, except that they will be required to fulfill criterion 3 OR 4:

  1. Patients must have a diagnosis of "Definite" MG (Seybold, 1999) as based on clinical, electrophysiological and serological criteria (Appendix 1)
  2. Patients must have disease predominantly affecting bulbar or respiratory muscles of moderate or severe degree (Osserman grades 2B, 3 without crisis, or 4 without crisis) (Osserman and Genkins, 1971 and Appendix 2) as listed in Appendix 3, and a Quantitative MG score of <25 (Appendix 7)
  3. Patients must have disease refractory to treatment for at least 12 months with prednisone at a dose of 15mg/day and/or immunosuppressive drugs (azathioprine or cyclophosphamide at a dose of 100mg/day or cyclosporine at a dose to produce trough levels of >50), with or without thymectomy and plasmapheresis/IVIG alone or in combination with above drugs at intervals of no more than once every 3 weeks, OR
  4. Patients must have experienced intolerance or unacceptable side-effects following treatment with corticosteroids, immunosuppressive drugs (azathioprine, cyclophosphamide or cyclosporine), plasmapheresis or IVIG
  5. Patients must be between 18 years and 80 years old

  6. Patients must have adequate organ function / laboratory parameters as measured by the following criteria (values should be obtained within 2 weeks prior to enrollment):

    • Documented CD20 + cells
    • Absolute neutrophil count: >2000/mm3
    • Platelets: >100,000/mm3
    • Hemoglobin: >10 gm/dL
    • Adequate renal function as indicated by normal BUN and creatinine levels
    • Adequate liver function, as indicated by AST and ALT <2x Upper Limit of normal.
    • Normal serum electrolytes
  7. Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for one year after completion of treatment
  8. Written informed consent.

Exclusion Criteria:

Patients will be excluded from the trial based on the following criteria:

  1. Myasthenic crisis with a forced vital capacity (FVC) of <30% predicted, irrespective of need for respiratory support, or severe bulbar involvement (Appendix 3)
  2. Patients requiring maintenance plasmapheresis or IVIG infusions at intervals of less than once every three weeks
  3. Patients requiring respiratory support with invasive or non-invasive ventilation
  4. Severe, uncontrolled or untreated concomitant cardiac (New York Heart Classification III or IV disease), hepatic, pulmonary, renal, hematologic or psychiatric disease
  5. Toxicity grade 2 or more prior to treatment with rituximab in patients who failed prior treatments
  6. Patients unwilling to attend for follow-up visits according to the study design

  7. Patients will be excluded based on the following criteria:

    • History of HIV disease
    • Active Hepatitis B infection
    • Pregnancy (a serum pregnancy test will be performed for all women of childbearing potential immediately before treatment)
    • Active infection
  8. Pregnant or breastfeeding women may not participate due to the lack of information on effects of rituximab on the fetus and developing child
  9. Concomitant malignancies or previous malignancies within the last 5 years, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix.
  10. No prior monoclonal antibody therapy.
  11. History of significant psychiatric disease that will interfere with the consenting procedure, research visits, treatment protocol or evaluation of patients in the study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
To examine the effects of rituximab on disease activity in MG patients with refractory disease.
Time Frame: Patients will be followed for one year
Patients will be followed for one year

Secondary Outcome Measures

Outcome Measure
Time Frame
To determine the safety and tolerability of rituximab in MG patients with refractory disease.
Time Frame: Patients will be followed for one year
Patients will be followed for one year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Vermont

Collaborators

Genentech, Inc.

Investigators

  • Principal Investigator: Rup Tandan, MD, FRCP, University of Vermont Department of Neurology

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

April 1, 2004

Primary Completion (Actual)

March 1, 2009

Study Completion (Actual)

March 1, 2009

Study Registration Dates

First Submitted

January 14, 2008

First Submitted That Met QC Criteria

February 8, 2008

First Posted (Estimate)

February 21, 2008

Study Record Updates

Last Update Posted (Estimate)

January 16, 2013

Last Update Submitted That Met QC Criteria

January 15, 2013

Last Verified

January 1, 2013

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RituxanMGPilot
  • BB-IND# 11403
  • Genentech #U2444S
  • UVM CHRMS #04-086

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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