Rituximab to Treat Stiff Person Syndrome
Condition: Stiff Person Syndrome
MeSH terms: Stiff-Person Syndrome; Syndrome
Study type: Interventional
Phase: Phase 2

Summary: 
      This study will test whether rituximab (RITUXAN (Trademark)) can relieve symptoms of stiff
      person syndrome (SPS), a progressive disease that causes stiffness of the muscles and muscle
      spasms induced by unexpected noises, touches, or stressful events. People with SPS may have
      certain proteins in their blood called anti-GAD antibodies that may cause some of the
      symptoms of the disease. Rituximab, a drug approved to treat lymphomas, targets certain white
      blood cells that produce antibodies. This study will see if rituximab can also be effective
      in patients with SPS who have high anti-GAD antibodies.

      Patients between 25 and 80 years of age with SPS may be eligible for this study. Candidates
      are screened with a medical history, physical examination, and blood tests. Participants
      undergo the following tests and procedures:

        -  Rituximab or placebo treatment: Patients are randomly assigned to receive two infusions
           by vein of either rituximab or placebo (a look-alike solution with no active ingredient)
           2 weeks apart. The infusions last from 3 to 4 hours, but may take as long as 16 hours if
           the rate must be slowed for any reason. Patients are followed monthly for up to 6 months
           and then every 2 months for up to 1 year after treatment.

        -  Medical history and interview, physical and neurological examinations: Patients are
           questioned about their vaccination history, medical, surgical, and psychiatric history,
           exposure to environmental toxins or viruses, and family and social history, including
           habits and employment.

        -  Blood drawing: Blood samples are collected before the two infusions and at all follow-up
           visits.

        -  Apheresis: For this procedure, which is used to collect white blood cells, blood is
           collected through a needle in an arm vein, similar to donating blood. The blood flows
           from the vein through a catheter (plastic tube) into a machine that separates it into
           its components by centrifugation (spinning). The white cells are removed and the rest of
           the blood (red cells, plasma and platelets) is returned to the body through a second
           needle in the other arm. The procedure takes about 60 to 90 minutes.

        -  Lumbar puncture (spinal tap): Lumbar puncture is done to sample a small amount of
           cerebrospinal fluid (CSF, the fluid that bathes the brain and spinal cord), for
           analysis. For this procedure, the patient is given a local anesthetic and a needle is
           inserted into the space between the bones in the lower back where the CSF circulates
           below the spinal cord. A small amount of fluid is withdrawn through the needle.
    

Detailed description: 
      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-four 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.
    

Intervention name(s): Rituximab; rituximab or placebo
Intervention type(s): Drug; Drug
Intervention description(s): A fixed dose of Rituximab or placebo 1GM on Day 1 and 1GM on day 15 (+/- 2 days)
Other intervention name(s): Rituxan
Intervention MeSH terms: Rituximab
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: Double
Primary purpose: Treatment
Keywords: RITUXAN; GABA; B Cells; Humanized Monoclonal Antibodies; GAD; Stiff Person Syndrome; SPS