Chronic Focal EncephalitisPhase 1NCT00259805
A Pilot Study of the Use of Rituximab in the Treatment of Chronic Focal Encephalitis
A Phase 1 study testing Rituximab in people with Chronic Focal Encephalitis and Rasmussen's Encephalitis, run by California Pacific Medical Center Research Institute at 1 site in United States.
Trial summary
The purpose of this study is to assess the safety, tolerability and effectiveness of rituximab in the treatment of chronic focal encephalitis. Read more about this study
- Who is it for?
- Ages 5 to 25 years
- Conditions the study is for
- Chronic Focal Encephalitis, Rasmussen's Encephalitis
- What is being tested?
- Rituximab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2005to Dec 2008
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 5 to 25 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Diagnosis of chronic focal encephalitis
- IgG \& IgM levels within normal limits
- Adequate renal function
- Stable anticonvulsant drug regimen
Who cannot join
- 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
Show all 11Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
California Pacific Medical Center
San Francisco, California, 94115
About this study
The purpose of this study is to assess the safety, tolerability and effectiveness of rituximab in the treatment of chronic focal encephalitis.
Read the 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.
- Being tested
- Rituximab
- Keywords
- encephalitis, epilepsy, Rasmussens, rituximab, autoimmune
- Medical subject headings
- Encephalitis, Epilepsy
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RituximabDrug
375 mg/m2 given as an IV infusion once weekly for four doses
| Study group | Role | What they receive |
|---|---|---|
| IV Infusion | Experimental | Not described Receives: Drug: Rituximab |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 12 months
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
Measured: 12 months
Secondary outcomes (1)
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.
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Dec 2005 (estimated)
- Study startJan 2005
- Primary completionDec 2008
- Study completionDec 2008
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (8)Papers the sponsor has linked to this study.
- Other trials for Chronic Focal EncephalitisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Lead sponsor
- California Pacific Medical Center Research Institute
- Sponsor type
- University, hospital or other
- Collaborators
- Genentech, Inc.
- Responsible party
- Principal investigator, Kenneth D. Laxer, M.D., California Pacific Medical Center Research Institute
- Investigators
- Kenneth D Laxer, M.D., Principal investigator, California Pacific Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00259805
- Sponsor's protocol ID
- CPMC-IRB25.102
- Other IDs
- Genentech CFE-001
- Status last verified
- Mar 2008
- First submitted
- 29 Nov 2005
- Last updated
- 22 Mar 2013
- Results posted
- No
- Data monitoring committee
- No
Publications
Baranzini SE, Laxer K, Bollen A, Oksenberg JR. Gene expression analysis reveals altered brain transcription of glutamate receptors and inflammatory genes in a patient with chronic focal (Rasmussen's) encephalitis. J Neuroimmunol. 2002 Jul;128(1-2):9-15. doi: 10.1016/s0165-5728(02)00109-1.
PubMed 12098505Prayson RA, Frater JL. Rasmussen encephalitis: a clinicopathologic and immunohistochemical study of seven patients. Am J Clin Pathol. 2002 May;117(5):776-82. doi: 10.1309/AD8R-560C-4V11-C5E2.
PubMed 12090428Baranzini SE, Laxer K, Saketkhoo R, Elkins MK, Parent JM, Mantegazza R, Oksenberg JR. Analysis of antibody gene rearrangement, usage, and specificity in chronic focal encephalitis. Neurology. 2002 Mar 12;58(5):709-16. doi: 10.1212/wnl.58.5.709.
PubMed 11889232Whitney KD, Andrews PI, McNamara JO. Immunoglobulin G and complement immunoreactivity in the cerebral cortex of patients with Rasmussen's encephalitis. Neurology. 1999 Sep 11;53(4):699-708. doi: 10.1212/wnl.53.4.699.
PubMed 10489029Prayson RA, Bingaman W, Frater JL, Wyllie E. Histopathologic findings in 37 cases of functional hemispherectomy. Ann Diagn Pathol. 1999 Aug;3(4):205-12. doi: 10.1016/s1092-9134(99)80052-5.
PubMed 10459046Li Y, Uccelli A, Laxer KD, Jeong MC, Vinters HV, Tourtellotte WW, Hauser SL, Oksenberg JR. Local-clonal expansion of infiltrating T lymphocytes in chronic encephalitis of Rasmussen. J Immunol. 1997 Feb 1;158(3):1428-37.
PubMed 9013988Hart YM, Cortez M, Andermann F, Hwang P, Fish DR, Dulac O, Silver K, Fejerman N, Cross H, Sherwin A, et al. Medical treatment of Rasmussen's syndrome (chronic encephalitis and epilepsy): effect of high-dose steroids or immunoglobulins in 19 patients. Neurology. 1994 Jun;44(6):1030-6. doi: 10.1212/wnl.44.6.1030.
PubMed 8208394Rasmussen T. Further observations on the syndrome of chronic encephalitis and epilepsy. Appl Neurophysiol. 1978;41(1-4):1-12. doi: 10.1159/000102395.
PubMed 103497
Study at a glance
From the registry record, last updated by the sponsor on 22 Mar 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pilot Study of the Use of Rituximab in the Treatment of Chronic Focal Encephalitis
- ClinicalTrials.gov ID
- NCT00259805
- Acronym / sponsor ID
- CPMC-IRB25.102
- Keywords
- encephalitis, epilepsy, Rasmussens, rituximab, autoimmune
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 10 participants (actual)
- Lead sponsor
- California Pacific Medical Center Research InstituteUniversity, hospital or other
- Collaborators
- Genentech, Inc.
- Study start
- Jan 2005
- Primary completion
- Dec 2008 (actual)
- Study completion
- Dec 2008 (actual)
- First posted
- 1 Dec 2005 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to assess the safety, tolerability and effectiveness of rituximab in the treatment of chronic focal encephalitis.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| IV Infusion | Experimental | Drug: Rituximab |
Who may qualify
- Ages
- 5 to 25 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (4 listed)
- Diagnosis of chronic focal encephalitis
- IgG \& IgM levels within normal limits
- Adequate renal function
- Stable anticonvulsant drug regimen
Key exclusion criteria (11 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Rituximab375 mg/m2 given as an IV infusion once weekly for four doses | Drug | IV Infusion |
Primary outcome
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
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
1 secondary outcome
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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Mar 2013.
- Background: PubMed 12098505Baranzini SE, Laxer K, Bollen A, Oksenberg JR. Gene expression analysis reveals altered brain transcription of glutamate receptors and inflammatory genes in a patient with chronic focal (Rasmussen's) encephalitis. J Neuroimmunol. 2002 Jul;128(1-2):9-15. doi: 10.1016/s0165-5728(02)00109-1.
- Background: PubMed 12090428Prayson RA, Frater JL. Rasmussen encephalitis: a clinicopathologic and immunohistochemical study of seven patients. Am J Clin Pathol. 2002 May;117(5):776-82. doi: 10.1309/AD8R-560C-4V11-C5E2.
- Background: PubMed 11889232Baranzini SE, Laxer K, Saketkhoo R, Elkins MK, Parent JM, Mantegazza R, Oksenberg JR. Analysis of antibody gene rearrangement, usage, and specificity in chronic focal encephalitis. Neurology. 2002 Mar 12;58(5):709-16. doi: 10.1212/wnl.58.5.709.
- Background: PubMed 10489029Whitney KD, Andrews PI, McNamara JO. Immunoglobulin G and complement immunoreactivity in the cerebral cortex of patients with Rasmussen's encephalitis. Neurology. 1999 Sep 11;53(4):699-708. doi: 10.1212/wnl.53.4.699.
- Background: PubMed 10459046Prayson RA, Bingaman W, Frater JL, Wyllie E. Histopathologic findings in 37 cases of functional hemispherectomy. Ann Diagn Pathol. 1999 Aug;3(4):205-12. doi: 10.1016/s1092-9134(99)80052-5.
- Background: PubMed 9013988Li Y, Uccelli A, Laxer KD, Jeong MC, Vinters HV, Tourtellotte WW, Hauser SL, Oksenberg JR. Local-clonal expansion of infiltrating T lymphocytes in chronic encephalitis of Rasmussen. J Immunol. 1997 Feb 1;158(3):1428-37.
- Background: PubMed 8208394Hart YM, Cortez M, Andermann F, Hwang P, Fish DR, Dulac O, Silver K, Fejerman N, Cross H, Sherwin A, et al. Medical treatment of Rasmussen's syndrome (chronic encephalitis and epilepsy): effect of high-dose steroids or immunoglobulins in 19 patients. Neurology. 1994 Jun;44(6):1030-6. doi: 10.1212/wnl.44.6.1030.
- Background: PubMed 103497Rasmussen T. Further observations on the syndrome of chronic encephalitis and epilepsy. Appl Neurophysiol. 1978;41(1-4):1-12. doi: 10.1159/000102395.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Kenneth D Laxer, M.D. principal investigator
California Pacific Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Rituximab in people with Chronic Focal Encephalitis and Rasmussen's Encephalitis, run by California Pacific Medical Center Research Institute at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Mar 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00259805, which also lists 8 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Mar 2013.