A Phase 1 Trial of Intrathecal Rituximab for Progressive Multiple Sclerosis Patients

Completed · Phase 1

Conditions studied: Primary Progressive Multiple Sclerosis, Secondary Progressive Multiple Sclerosis

In brief

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.

Key facts

Study ID: NCT02253264
Run by: Johns Hopkins University
People needed: 8
Starts: 2014-11-01
Expected to finish: 2017-08-01
Last updated by the study team: 2017-08-30

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

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

You may not qualify if…

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

Where it is running

The Johns Hopkins Hospital — Baltimore, Maryland, United States

Full record on ClinicalTrials.gov

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