A Pilot Study of the Use of Rituximab in the Treatment of Chronic Focal Encephalitis

This study has been completed.
Sponsor:
Collaborator:
Genentech
Information provided by (Responsible Party):
Kenneth D. Laxer, M.D., California Pacific Medical Center Research Institute
ClinicalTrials.gov Identifier:
NCT00259805
First received: November 29, 2005
Last updated: March 20, 2013
Last verified: March 2008
  Purpose

The purpose of this study is to assess the safety, tolerability and effectiveness of rituximab in the treatment of chronic focal encephalitis.


Condition Intervention Phase
Chronic Focal Encephalitis
Rasmussen's Encephalitis
Drug: Rituximab
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Pilot Study of the Use of Rituximab in the Treatment of Chronic Focal Encephalitis

Resource links provided by NLM:


Further study details as provided by California Pacific Medical Center Research Institute:

Primary Outcome Measures:
  • To assess the safety and tolerability of Rituximab in the treatment of CFE. Adverse and serious adverse events during the study period, reasonably or probably related to Rituximab, will be assessed at each study visit up to 12 months. [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  • The natural history of CFE is a progressive deterioration in cortical function; therefore, any evidence of stabilization or improvement in measures of motor function, cognition and/or seizure frequency will be evidence of efficacy and will be assessed at [ Time Frame: 12 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • The percentage of patients with a 50% reduction in seizure frequency (responder rate) at 6 months post treatment (as compared to the patient's baseline seizure frequency) will be determined. [ Time Frame: 12 months ] [ Designated as safety issue: No ]

Enrollment: 10
Study Start Date: January 2005
Study Completion Date: December 2008
Primary Completion Date: December 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: IV Infusion Drug: Rituximab
375 mg/m2 given as an IV infusion once weekly for four doses

Detailed Description:

Chronic Focal Encephalitis (Rasmussen's Encephalitis) is a condition characterized by a progressive hemiparesis, cognitive decline (including loss of language skills if the language dominant hemisphere is involved) and epileptic seizures that are typically refractory to medical treatment (Rasmussen). Attempts to control the seizures with anticonvulsants are ineffective and the only effective treatment to date is a hemispherectomy (surgical removal of half of the brain). Children with CFE who undergo cortical resections or hemispherectomies demonstrate an inflammatory histopathology consisting of perivascular lymphocytic cuffing, gliosis, neuronal loss, microglial nodules and later laminar necrosis and spongy degeneration

Rituximab is a genetically engineered, chimeric; murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant pre-B and mature B cells. It was approved by the FDA in 1997 for the treatment of relapsed or refractory low grade or follicular, CD20+, B-cell non-Hodgkin's lymphoma (NHL). Rituximab binds specifically to the CD20 antigen expressed on the surface of both normal and malignant pre-B and mature B cells. In vitro mechanism of action studies have demonstrated that the Fc portion of Rituximab binds human complement and can lead to cell lysis of the targeted cell through complement-dependent cytotoxicity. Additionally, it has been demonstrated that Rituximab has significant activity in assays of antibody dependent cellular cytotoxicity (Reff et al. 1994). More recently, Rituximab has been shown to induce apoptosis in vitro in DHL-4, a human B cell lymphoma line (Maloney et al. 1997). The relative extent to which these individual mechanisms account for the observed depletion of normal and malignant B cells in vivo is unknown.

While CFE represents only a very small percentage of patients with epilepsy, the devastating progressive nature of the disease with out any adequate treatments, relegates these children to the relentless loss of cognitive and motor skills, and continuing seizures. Recent evidence suggests this condition is immune mediated and includes the development of antibodies directed against various brain components including glutamate receptors (GluR3) (Rogers). Brain samples from patients with CFE have demonstrated immunoreactivity for IgG, C4 C8, and MAC (Andrews and Whitney) and involvement of both B and T-lymphocytes. Evidence supporting a role for clonally expanded B lymphocytes was found by Baranzini . By analyzing the T-cell receptor expression in brain lesions using PCR these investigators also demonstrated the local immune response in CFE included restricted T-cell populations probably expanding from a few precursor T-cells responding to discrete antigenic epitopes (Li). Following demonstration of antibodies directed against brain elements in CFE, a patient was treated with plasma exchange which produced a significant improvement in seizure frequency, cognition and hemiparesis, lending support to the hypothesis that circulating antibodies contribute to the disease pathogenesis. Subsequently attempts to modify this disease by immune modification (plasmaphoresis, steroids, gamma globulin) have demonstrated modest improvements but the improvements have been short-lived and have not affected the natural progression of this disease. This pilot study proposes to directly attack the cells (B-cells) thought to be instrumental in the development of this condition. Should this approach to treating CFE be successful it will have a major impact on these children's lives.

  Eligibility

Ages Eligible for Study:   5 Years to 25 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of chronic focal encephalitis
  • IgG & IgM levels within normal limits
  • Adequate renal function
  • Stable anticonvulsant drug regimen

Exclusion Criteria:

  • Evidence of significant ongoing medical condition or progressive neurologic condition (other than CFE)
  • Previous treatment with rituximab
  • History of significant recurrent infections, or ongoing active infection
  • Receipt of a live vaccine within 4 weeks prior to treatment
  • History of severe allergic reactions to humanized or murine monoclonal antibodies
  • History of drug, alcohol or chemical abuse within 6 months
  • Concomitant malignancies or previous malignancy
  • Use of steroids or immunoglobulins during the 4 weeks prior to treatment
  • Hemoglobin <8.5 gm/dL, Platelets < 100,00/mm, AST or ALT >2.5 ULN
  • Positive Hepatitis B or C serology
  • History of positive HIV
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00259805

Locations
United States, California
California Pacific Medical Center
San Francisco, California, United States, 94115
Sponsors and Collaborators
California Pacific Medical Center Research Institute
Genentech
Investigators
Principal Investigator: Kenneth D Laxer, M.D. California Pacific Medical Center
  More Information

Publications:

Responsible Party: Kenneth D. Laxer, M.D., Medical Doctor, California Pacific Medical Center Research Institute
ClinicalTrials.gov Identifier: NCT00259805     History of Changes
Other Study ID Numbers: CPMC-IRB25.102, Genentech CFE-001
Study First Received: November 29, 2005
Last Updated: March 20, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by California Pacific Medical Center Research Institute:
encephalitis
epilepsy
Rasmussens
rituximab
autoimmune

Additional relevant MeSH terms:
Encephalitis
Central Nervous System Viral Diseases
Virus Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Central Nervous System Infections
Rituximab
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents

ClinicalTrials.gov processed this record on September 16, 2014