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

NCT02253264 | Completed Phase 1 DMC

• 1 other identifier: IRB00027318
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Primary Progressive Multiple Sclerosis; Secondary Progressive Multiple Sclerosis

Outcome Measures

Primary Outcomes (1)

• 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.

  1 year

Study Arms (1)

Intrathecal rituximab

EXPERIMENTAL

25 mg of rituximab will be administered intrathecally by direct infusion over 10 minutes at two time points, two weeks apart.

Drug: Rituximab

Interventions

Rituximab DRUG

Also known as: Rituxan

Intrathecal rituximab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

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

Sponsors & Collaborators

• Johns Hopkins University: lead

Study Sites (1)

The Johns Hopkins Hospital

Baltimore, Maryland, 21287, United States

Location

MeSH Terms

Conditions

Multiple Sclerosis, Chronic Progressive

Interventions

Rituximab

Condition Hierarchy (Ancestors)

Multiple Sclerosis; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Ellen M Mowry, MD, MCR

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 29, 2014
• First Posted: October 1, 2014
• Study Start: November 1, 2014
• Primary Completion: August 1, 2017
• Study Completion: August 1, 2017
• Last Updated: August 30, 2017

Record last verified: 2017-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)