Intrathecal Rituximab in Progressive Multiple Sclerosis (EFFRITE)

October 2, 2019 updated by: Dr Mickaël BONNAN, Centre Hospitalier de PAU
The goal of investigators is to study the kinetics of action of a single dose of intrathecally-infused rituximab upon cerebro-spinal fluid (CSF) biological targets in progressive MS patients. Various markers of central nervous system inflammation (osteopontin, Tumor Necrosis Factor α, IgG secretion) and neurodegeneration (neurofilament) are studied at multiple time-points, assuming that a definitive action upon CSF biological targets would be strongly predictive of a delayed clinical action.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

• Background : Multiple sclerosis (MS) is the most frequent inflammatory disorder leading to impairment in young people. Although many drugs are now available to treat the early relapsing-remitting phase of MS (RR-MS), impairment is mostly linked to the secondary progressive phase of MS. Since no treatment proved to efficiently prevent or cure this progressive phase, treating this phase remains challenging. In fact, progressive phase is associated with a fence-ringed intrathecal compartmentalization of inflammation, leading to the unavailability of most immunosuppressive drugs. As a consequence, investigators here propose to shift the therapeutic paradigm in MS to a new paradigm based on intrathecal infusion of monoclonal antibodies (mAb) aimed at eradicate intrathecal inflammation. Rituximab is a mAb targeting CD20+ B-lymphocytes. Positive results in RR-MS were obtained after blood infusion of rituximab, but results were negative in progressive MS, probably due to the very low penetration of the blood brain barrier. Since intrathecal rituximab is already used in central nervous system (CNS) lymphomas, investigators propose to use it this way in progressive MS.

• Detailed description : An optimal dosage of rituximab for intrathecal infusion was choose using data already obtained in CNS lymphoma, acknowledging that 20mg offers the higher dosage with good tolerance profile. In order to isolate rituximab effect, a control group is treated by steroids since steroids are required before rituximab infusion. Moreover, B-lymphocytes depletion in CSF will probably be transient, as it is when rituximab is infused in blood. Assuming that CSF B-cells repopulation may be facilitated by peripheral B-cells, a group was assigned to receive also blood infusion of rituximab. CSF will be examined at multiple time points to assess the time frame of biological effect obtained in CSF.

Three groups of 4 patients are treated at day 0 :

  1. Control group : receive a single pulse of intravenous (IV) methylprednisolone (120mg) ;
  2. Rituximab intrathecal (IT) group : receive a single intrathecal infusion of rituximab (with IV methylprednisolone 120mg to avoid side effect) ;
  3. Rituximab IT + IV group : receive same as previous and IV rituximab (375mg/m2) the same day.

CSF and blood will be drawn for study at day 0 (before treatment), day 4, day 21 and day 180. B- lymphocytes monitoring in blood will be also be done at day 365. A detailed clinical monitoring (walking time, nine hole peg test, Expanded Disability Status Score (EDSS), Symbol Digit Modalities Test (SDMT), fatigue intensity scale) will be done at each time point from day 0 to 365, assessing tolerance and clinical effect. MRI will be done at screening, months 6 and 12.

  • Primary outcome : Change from baseline in Osteopontin level in CSF at day 4. CSF level is expected to normalize.
  • Secondary outcomes: Biological outcomes in CSF (IgG synthesis, Tumor Necrosis Factor α, neurofilament) at day 4; delay to regain pre-therapeutic levels of biological targets in CSF (day 21, day 180) ; clinical data (walking time, nine hole peg test, Expanded Disability Status Score (EDSS), Symbol Digit Modalities Test (SDMT), fatigue intensity scale) at each time point, and brain MRI volumetry at day 180 and day 365.
  • Study design : monocentric prospective randomized open clinical trial (phase II).
  • Eligibility criteria:

Inclusion criteria:

  • Age ≥45 years,
  • male or female ;
  • Secondary or primary progressive MS, in progressive phase since >2 years ;
  • EDSS ≥6.0 ;
  • Absence of alternative therapy.

Exclusion criteria:

  • Relapsing-remitting phase of MS;
  • Contraindication to MRI, lumbar puncture, Trendelenburg position ;
  • Active infection or immunosuppressive state or treatment (actual or less than 6 months);
  • Earlier treatment with rituximab;

  • Dementia or severe psychiatric disorder.

    • Arm number or label and arm type :

experimental = Rituximab IT and Rituximab IT + IV groups ; comparator = Control group (methylprednisolone).

  • Interventions : Three groups of 4 patients are treated at day 0 : 1) Control group : receive a single pulse of IV methylprednisolone (120mg) ; 2) Rituximab IT group : receive a single intrathecal infusion of rituximab (with IV methylprednisolone 120mg to avoid side effect) ; 3) Rituximab IT + IV group : receive same as previous and IV rituximab (375mg/m2) the same day.
  • Number of subjects : 4 per group, with a total of 12 patients.
  • Statistical analysis : target sample size was estimated based on an expected outcome of complete clearance of intrathecal inflammation from CNS compartment, which expected to normalize biological markers of CSF inflammation. The estimated size was 6.8 in treatment group and 3.4 in control group. We decided to include respectively 8 and 4 patients in treatment and control groups. Analyses will be performed at the 0.05 global level of significance, risk alpha = 0.05 and risk beta = 0.10. We will use the SAS 9.1.3 software.

Study Type

Interventional

Enrollment (Actual)

10

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Pau, France, 64000
        • Centre hospitalier F. Mitterrand (CH Pau)

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

45 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age ≥45 years, male or female ;
  • Secondary or primary progressive MS, in progressive phase since >2 years ;
  • EDSS ≥6.0 ;
  • Absence of alternative therapy.

Exclusion Criteria:

  • Relapsing-remitting phase of MS;
  • Contraindication to MRI, lumbar puncture, Trendelenburg position ;
  • Active infection or immunosuppressive state or treatment (actual or less than 6 months);
  • Earlier treatment with rituximab;
  • Dementia or severe psychiatric disorder.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Control group
receive a single pulse of methylprednisolone IV (120mg)
Drug: methylprednisolone IV
blood infusion of methylprednisolone IV (120mg)
Other Names:
  • Solumedrol
Experimental: Rituximab IT group
receive a single intrathecal infusion of rituximab (with IV methylprednisolone 120mg to avoid side effect)
Drug: methylprednisolone IV
blood infusion of methylprednisolone IV (120mg)
Other Names:
  • Solumedrol
Drug: Rituximab IT
CSF injection of intrathecal rituximab (20mg)
Other Names:
  • intrathecal rituximab (Mabthera)
Experimental: Rituximab IT + IV group
receive Rituximab IT as previous and Rituximab IV (375mg/m2) the same day
Drug: methylprednisolone IV
blood infusion of methylprednisolone IV (120mg)
Other Names:
  • Solumedrol
Drug: Rituximab IT
CSF injection of intrathecal rituximab (20mg)
Other Names:
  • intrathecal rituximab (Mabthera)
Drug: Rituximab IV
Blood infusion of rituximab (375mg/m2)
Other Names:
  • Mabthera

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Change in osteopontin level in CSF
Time Frame: at day 4, day 21, day 180
at day 4, day 21, day 180

Secondary Outcome Measures

Outcome Measure
Time Frame
Change in Tumor Necrosis Factor alpha level in CSF
Time Frame: day 4, day 21, day 180
day 4, day 21, day 180
Change in IgG synthesis in CSF
Time Frame: day 4, day 21, day 180
day 4, day 21, day 180
Change in neurofilament level in CSF
Time Frame: day 4, day 21, day 180
day 4, day 21, day 180

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in clinical parameters
Time Frame: day 4, day 21, day 180, day 365
Subjective appreciation and multiple clinical scales (walking time, nine hole peg test, EDSS, SDMT, Fatigue Intensity Scale)
day 4, day 21, day 180, day 365
Brain volume atrophy
Time Frame: day 180, day 365
Percent change in total brain volume (SIENA)
day 180, day 365

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Centre Hospitalier de PAU

Collaborators

University Hospital, Bordeaux

Investigators

  • Principal Investigator: Mickael Bonnan, MD, CH Pau

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 30, 2015

Primary Completion (Actual)

February 22, 2019

Study Completion (Actual)

September 2, 2019

Study Registration Dates

First Submitted

September 7, 2015

First Submitted That Met QC Criteria

September 8, 2015

First Posted (Estimate)

September 10, 2015

Study Record Updates

Last Update Posted (Actual)

October 3, 2019

Last Update Submitted That Met QC Criteria

October 2, 2019

Last Verified

April 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CHPAU2014/01

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.

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