- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02253264
A Phase 1 Trial of Intrathecal Rituximab for Progressive Multiple Sclerosis Patients
A Phase 1 Open-label Trial of Intrathecal Rituximab for Progressive Multiple Sclerosis Patients With Magnetic Resonance Imaging Evidence of Leptomeningeal Enhancement
Multiple sclerosis (MS) is a chronic inflammatory disorder affecting the central nervous system that is characterized pathologically by focal demyelinating lesions in the brain parenchyma. Meningeal inflammation in MS was first noted in 2004. Ectopic lymphoid follicles were described in the meninges of patients with secondary progressive MS (SPMS) and were thought to correlate with cortical lesions and atrophy (a surrogate marker for disability). Subsequently, inflammation in the meninges has been described in primary progressive MS (PPMS) as well as early relapsing MS.
The ectopic lymphoid follicles are composed of B-cells, T follicular helper cells and follicular dendritic cells. Rituximab is a monoclonal antibody against CD-20 (a B-cell marker) that is FDA approved for the treatment of various lymphomas. Intrathecal (IT) rituximab administration has been used in central nervous system (CNS) lymphoma to achieve greater cerebrospinal fluid (CSF) concentrations of rituximab. In MS, IT administration of rituximab could lead to higher CSF rituximab levels resulting in the disruption of meningeal ectopic lymphoid follicles, ultimately reducing cortical lesions and possibly disease progression.
The investigators hypothesize that IT rituximab therapy in patients with progressive forms of MS could disrupt ectopic lymphoid follicles in the meninges and thus slow progression of the disease, which is particularly important because there exist no FDA-approved therapies for progressive MS. The investigators hypothesize that using magnetic resonance imaging (MRI) to identify those with enhancing meningeal lesions will provide a biomarker to select patients who might be most likely to respond to IT rituximab and to use these lesions to monitor therapeutic response.
The primary aim of this study is to assess the safety of intrathecal administration of rituximab in patients with progressive MS. The secondary aims are to evaluate if IT rituximab leads to a decrease in the quantity of meningeal lesions on MRI or to changes in biomarkers of inflammatory activity or neuronal injury in the CSF.
Study Overview
Status
Intervention / Treatment
Detailed Description
Multiple sclerosis (MS) is a chronic inflammatory disorder affecting the central nervous system that is characterized pathologically by focal demyelinating lesions in the brain parenchyma. Meningeal inflammation in MS was first noted in 2004. Ectopic lymphoid follicles were described in the meninges of patients with secondary progressive MS (SPMS) and were thought to correlate with cortical lesions and atrophy (a surrogate marker for disability). Subsequently, inflammation in the meninges has been described in primary progressive MS (PPMS) as well as early relapsing MS.
The ectopic lymphoid follicles are composed of B-cells, T follicular helper cells and follicular dendritic cells. Rituximab is a monoclonal antibody against CD-20 (a B-cell marker) that is FDA approved for the treatment of various lymphomas. It has been shown to be effective when given intravenously in trials of Relapsing-Remitting Multiple Sclerosis (RRMS). However, the cerebrospinal fluid (CSF) penetrance of rituximab is minimal, such that CSF levels are < 1% of serum levels after the administration of intravenous (IV) rituximab. Indeed, IV rituximab failed to significantly slow disability in a clinical trial in progressive MS. Intrathecal (IT) rituximab administration has been used in CNS lymphoma to achieve greater CSF concentrations of rituximab. In MS, IT administration of rituximab could lead to higher CSF rituximab levels resulting in the disruption of meningeal ectopic lymphoid follicles, ultimately reducing cortical lesions and possibly disease progression.
A recently described finding is the presence of enhancing meningeal lesions on post-contrast FLAIR imaging in MS patients. These could possibly represent ectopic lymphoid follicles. This finding could serve as a biomarker to identify patients with ectopic meningeal lymphoid follicles who might be most likely to derive benefit from IT rituximab therapy.
The investigators hypothesize that IT rituximab therapy in patients with progressive forms of MS could disrupt ectopic lymphoid follicles in the meninges and thus slow progression of the disease, which is particularly important because there exist no FDA-approved therapies for progressive MS. The investigators hypothesize that using post-contrast FLAIR imaging to identify those with enhancing meningeal lesions will provide a biomarker to select patients who might be most likely to respond to IT rituximab and to use these lesions to monitor therapeutic response.
The primary aim of this study is to assess the safety of intrathecal administration of rituximab in patients with progressive MS. The secondary aims are to evaluate if IT rituximab leads to a decrease in the quantity of meningeal lesions on post-contrast FLAIR imaging or to changes in biomarkers of inflammatory activity or neuronal injury in the CSF.
Progressive MS currently has no FDA approved treatments. There is a great need for new therapeutic modalities for patients with progressive forms of MS. The identification of a novel treatment for progressive MS would have a beneficial impact on tens of thousands of patients with progressive MS.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
-
-
Maryland
-
Baltimore, Maryland, United States, 21287
- The Johns Hopkins Hospital
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Diagnosis of PPMS by revised McDonald criteria or SPMS by Lublin and Reingold criteria
- Age ≥ 18 years
- MRI Brain demonstrating evidence of leptomeningeal enhancement on contrast enhanced FLAIR images within the past 12 months, which is now part of the routine clinical MS MRI protocol at the Johns Hopkins Hospital.
- Patients may be on no MS treatment or should have been on the same treatment for at least 6 months and are not expected to switch therapy in the next 6 months
Exclusion Criteria:
- Severe intolerance of lumbar puncture in the past
- Treatment with a chemotherapeutic agent in the past year or chronic infectious disease
- Peripheral CD19 counts below lower limit of normal in patients previously treated with rituximab
- Calculated creatinine clearance ≥ 70 ml/min calculated using Cockroft-Gault equation
- Female patients of childbearing potential not willing to use contraception (intrauterine device (IUD), oral contraceptive pill (OCP) or double barrier method)
- Corticosteroid treatment within the past 30 days
- Known history of other neuroinflammatory or systemic autoimmune disease
- Known bleeding diathesis or ongoing anticoagulation (oral/ injectable)
- Receipt of live vaccination within 1 month prior to scheduled study drug dosing
- Hemoglobin < 10 mg/dL, or Platelet count < 100,000 /mm3 or white blood count (WBC) < 2,000 or > 15,000 /mm3
- Alanine transaminase (ALT) and/or aspartate aminotransferase (AST) > 2.5× the site laboratory upper limit of normal (ULN) or Total bilirubin > 2.5 ULN
- Positive for Hepatitis B surface antigen (HBsAg) or Positive for Hepatitis C antibody (HCV Ab)
- Moderate or severe acute illness with or without fever
- Current use (or use within the past 3 months) of natalizumab as MS therapy
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: NA
- Interventional Model: SINGLE_GROUP
- Masking: NONE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
EXPERIMENTAL: Intrathecal rituximab
25 mg of rituximab will be administered intrathecally by direct infusion over 10 minutes at two time points, two weeks apart.
|
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Number of serious adverse events over the course of the study at least possibly related to intrathecal rituximab therapy, as determined by the principal investigator.
Time Frame: 1 year
|
1 year
|
Collaborators and Investigators
Sponsor
Study record dates
Study Major Dates
Study Start
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Nervous System Diseases
- Immune System Diseases
- Demyelinating Autoimmune Diseases, CNS
- Autoimmune Diseases of the Nervous System
- Demyelinating Diseases
- Autoimmune Diseases
- Multiple Sclerosis
- Multiple Sclerosis, Chronic Progressive
- Sclerosis
- Physiological Effects of Drugs
- Antirheumatic Agents
- Antineoplastic Agents
- Immunologic Factors
- Antineoplastic Agents, Immunological
- Rituximab
Other Study ID Numbers
- IRB00027318
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
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.
Clinical Trials on Primary Progressive Multiple Sclerosis
-
University of MinnesotaMallinckrodtTerminatedPrimary Progressive Multiple Sclerosis | Secondary Progressive Multiple Sclerosis | Progressive Relapsing Multiple SclerosisUnited States
-
Rebecca SpainCompletedComparing Tolerability and Absorption of Racemic and R-lipoic Acid in Progressive Multiple SclerosisProgressive Multiple Sclerosis | Multiple Sclerosis | Primary Progressive Multiple Sclerosis | Secondary Progressive Multiple SclerosisUnited States
-
University of California, Los AngelesUnknownRelapsing-remitting Multiple Sclerosis | Secondary-progressive Multiple Sclerosis | Primary-progressive Multiple SclerosisUnited States
-
Brigham and Women's HospitalMassachusetts General HospitalRecruitingMultiple Sclerosis | Relapsing Multiple Sclerosis | Primary Progressive Multiple Sclerosis | Secondary Progressive Multiple SclerosisUnited States
-
Rigshospitalet, DenmarkUniversity of Copenhagen; Biogen; Copenhagen University Hospital, Hvidovre; Signifikans...CompletedPrimary Progressive Multiple Sclerosis | Secondary Progressive Multiple SclerosisDenmark
-
BiogenCompletedMultiple Sclerosis | Relapsing-Remitting Multiple Sclerosis | Secondary Progressive Multiple Sclerosis | Multiple Sclerosis, Primary Progressive | Multiple Sclerosis, Remittent ProgressiveJapan
-
University of California, Los AngelesRecruitingPrimary Progressive Multiple Sclerosis | Secondary Progressive Multiple SclerosisUnited States
-
University College DublinCompletedPrimary Progressive Multiple Sclerosis | Secondary Progressive Multiple SclerosisIreland
-
Innate ImmunotherapeuticsNational Multiple Sclerosis Society; Primorus Clinical TrialsCompletedPrimary Progressive Multiple Sclerosis | Secondary Progressive Multiple SclerosisNew Zealand
-
Queen Mary University of LondonTakeda Pharmaceuticals International, Inc.RecruitingRelapsing Remitting Multiple Sclerosis | Primary Progressive Multiple Sclerosis | Secondary Progressive Multiple SclerosisUnited Kingdom
Clinical Trials on Rituximab
-
Children's Oncology GroupNational Cancer Institute (NCI)Active, not recruitingEBV-Related Post-Transplant Lymphoproliferative Disorder | Monomorphic Post-Transplant Lymphoproliferative Disorder | Polymorphic Post-Transplant Lymphoproliferative Disorder | Recurrent Monomorphic Post-Transplant Lymphoproliferative Disorder | Recurrent Polymorphic Post-Transplant Lymphoproliferative... and other conditionsUnited States
-
Academic and Community Cancer Research UnitedNational Cancer Institute (NCI)Active, not recruitingRecurrent Grade 1 Follicular Lymphoma | Recurrent Grade 2 Follicular Lymphoma | Recurrent Mantle Cell Lymphoma | Recurrent Marginal Zone Lymphoma | Refractory B-Cell Non-Hodgkin Lymphoma | Recurrent Small Lymphocytic Lymphoma | Recurrent B-Cell Non-Hodgkin Lymphoma | Recurrent Grade 3a Follicular... and other conditionsUnited States
-
M.D. Anderson Cancer CenterNational Cancer Institute (NCI)RecruitingAnn Arbor Stage I Grade 1 Follicular Lymphoma | Ann Arbor Stage I Grade 2 Follicular Lymphoma | Ann Arbor Stage II Grade 1 Follicular Lymphoma | Ann Arbor Stage II Grade 2 Follicular LymphomaUnited States
-
National Cancer Institute (NCI)CompletedAnn Arbor Stage III Grade 1 Follicular Lymphoma | Ann Arbor Stage III Grade 2 Follicular Lymphoma | Ann Arbor Stage IV Grade 1 Follicular Lymphoma | Ann Arbor Stage IV Grade 2 Follicular Lymphoma | Ann Arbor Stage II Grade 3 Contiguous Follicular Lymphoma | Ann Arbor Stage II Grade 3 Non-Contiguous... and other conditionsUnited States
-
M.D. Anderson Cancer CenterNational Cancer Institute (NCI)Active, not recruitingRecurrent Small Lymphocytic Lymphoma | Prolymphocytic Leukemia | Recurrent Chronic Lymphocytic LeukemiaUnited States
-
National Cancer Institute (NCI)Celgene CorporationActive, not recruitingAnn Arbor Stage III Grade 1 Follicular Lymphoma | Ann Arbor Stage III Grade 2 Follicular Lymphoma | Ann Arbor Stage IV Grade 1 Follicular Lymphoma | Ann Arbor Stage IV Grade 2 Follicular Lymphoma | Ann Arbor Stage II Grade 3 Contiguous Follicular Lymphoma | Ann Arbor Stage II Grade 3 Non-Contiguous... and other conditionsUnited States
-
PfizerCompletedRheumatoid ArthritisUnited States, Australia, Canada, Israel, Mexico, Colombia, Germany, Russian Federation, South Africa, United Kingdom
-
Mabion SAParexelWithdrawn
-
National Cancer Institute (NCI)Active, not recruitingRecurrent Mantle Cell Lymphoma | Refractory B-Cell Non-Hodgkin Lymphoma | Recurrent B-Cell Non-Hodgkin Lymphoma | Refractory Mantle Cell LymphomaUnited States
-
M.D. Anderson Cancer CenterNational Cancer Institute (NCI)RecruitingChronic Lymphocytic Leukemia/Small Lymphocytic LymphomaUnited States