NIH Clinical Research Studies

Protocol Number: 04-N-0287

Active Accrual, Protocols Recruiting New Patients

Title:
Efficacy of Rituximab in Patients with Stiff Person Syndrome with Anti-GAD Antibodies: A Randomized Placebo-Controlled Trial
Number:
04-N-0287
Summary:
This study will examine the safety, tolerability, and efficacy of the humanized monoclonal antibody Rituximab to induce a clinical and serological remission in patients with Stiff Person Syndrome (SPS) associated with high anti-GAD antibodies. Rituximab is a monoclonal antibody specific for the common B cell antigen CD20. Its administration depletes pre-B and mature B lymphocytes without altering neutrophils or hematopoietic stem cells. In humans with indolent B cell lymphomas, Rituximab can be safely administered, is well tolerated, promotes selective B cell depletion and lowers the serum IgG and IgM levels. Preliminary experience in some non-malignant antibody-mediated disorders has shown that Rituximab was beneficial in improving the patients' symptoms and reducing antibody level.

SPS is an antibody-mediated autoimmune disease affecting GABA-ergic transmission resulting in incapacitating stiffness and spasms. The anti-GAD antibodies are also produced intrathecally and it is believed to be responsible for the reduction of GABA level in serum and CSF. Although removal or modulation of serum antibodies by plasmapheresis or IVIg results in clinical improvement, a number of patients do not respond or their response is modest and short-lived, and remain with significant disability. The need for more effective therapy prompted us to conduct the present study to examine in a randomized trial if Rituximab is effective in patients with GAD-antibody-positive SPS.

Twenty-two patients will be randomized, in a double blind fashion, to receive placebo or Rituximab given at a fixed dose of 1 GM on Day 1and 1 GM on day 15 (plus or minus 2 days). The primary outcome will be based on measurements of stiffness using the Distribution of Stiffness Index. Secondary outcomes will be measured by the Heightened-Sensitivity Scales. The serum and CSF anti-GAD antibody titers, including intrathecal GAD-specific IgG synthesis, will be monitored before and after treatment. Clearance of GAD-reactive T cells will be also examined in the serum and CSF using T cell clones established from PBL and CSF. It is anticipated that the study will: a) provide a new, immune-based and target-oriented therapy for patients with Stiff Person Syndrome and b) examine the pathogenetic role of anti-GAD antibodies in the cause of the disease.

Sponsoring Institute:
National Institute of Neurological Disorders and Stroke (NINDS)
Recruitment Detail
Type: Active Accrual Of New Subjects
Gender: Male & Female
Referral Letter Required: Yes
Population Exclusion(s): Children

Eligibility Criteria:
INCLUSION CRITERIA:

Stiff Person Syndrome with elevated anti-GAD antibody titers.

Between 25 to 80 years of age.

Willingness to stop IVIg therapy 6 weeks prior to Rituximab/Placebo treatment. [If receiving IVIg, patients will be allowed to receive the ongoing non-immunosuppressive drugs used to treat SPS including Diazepam, Neurontin or Baclofen. The dose of these drugs will remain stable throughout the study and unchanged for 6 weeks prior to enrollment.]

Willingness and legal ability to give and sign informed study consent.

Willingness to travel to NIH for scheduled protocol studies and treatment.

Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for six months after completion of treatment.

Adequate bone marrow, renal, and liver function: ANC greater than 1000/mm3, BUN/Cr in normal range for age.

Patients with Diabetes (Type II) will be allowed to participate because up to 40% of SPS patients have Diabetes.

Patients with a history of controlled epilepsy will be allowed to participate because up to 5% of SPS patients have mild epilepsy which is easily controlled.

EXCLUSION CRITERIA:

Immunosuppressive drug therapy at the time of or 6 months prior to enrollment. Specifically, candidates may not be taking prednisone, cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, anti-lymphocyte agents, cyclophosphamide, methotrexate, or other agents whose therapeutic effect is immunosuppressive.

Any medical or social condition that precludes follow-up visits.

Any active malignancy or any history of a hematogenous malignancy or lymphoma. Patients with primary, cutaneous basal cell or squamous cell cancers may be enrolled providing the lesions are treated prior to enrollment.

History of a coagulopathy or patients requiring anticoagulation.

Any history of cardiac insufficiency, major vascular disease, or symptomatic coronary artery disease. Patients with cardiomyopathy grade III or IV by the New York Heart Classification will be excluded from this study.

Systemic edema or pulmonary edema.

Chronic and severe symptomatic hypotension (SBP less than 100 mmHg).

Chronic liver disease or alcoholism.

Any condition, including active infections, that would likely increase the risk of protocol participation or confuse the understanding of the data.

Pregnancy. Serum pregnancy test will be performed and must be negative in all women of childbearing potential enrolled in the study.

History of active psychiatric disorder that may interfere with participation in the study.

LABORATORY EXCLUSION CRITERIA (AT SCREENING):

Hemoglobin: less than 7.0 gm/dL.

Platelets: less than 100,000/mm.

AST or ALT greater than 2.5 x Upper Limit of Normal unless related to primary disease.

Positive Hepatitis B or C serology (Hep Surface antigen and Hep C hepatitis C antibody).

Positive HIV.

Special Instructions: Currently Not Provided
Keywords:
RITUXAN
GABA
B Cells
Humanized Monoclonal Antibodies
GAD
Recruitment Keywords:
None
Conditions:
Stiff Person Syndrome
Investigational Drug(s):
Rituximab
Investigational Device(s):
None

Contacts:
Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:
Dalakas MC, Fujii M, Li M, McElroy B. The clinical spectrum of anti-GAD antibody-positive patients with stiff-person syndrome. Neurology. 2000 Nov 28;55(10):1531-5.

Dalakas MC, Li M, Fujii M, Jacobowitz DM. Stiff person syndrome: quantification, specificity, and intrathecal synthesis of GAD65 antibodies. Neurology. 2001 Sep 11;57(5):780-4.

Levy LM, Dalakas MC, Floeter MK. The stiff-person syndrome: an autoimmune disorder affecting neurotransmission of gamma-aminobutyric acid. Ann Intern Med. 1999 Oct 5;131(7):522-30. Review.

Active Accrual, Protocols Recruiting New Patients

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