A Pilot Study to Characterize the Biological Effect of a Pre-planned 12 Week Dose Interruption of Natalizumab

July 20, 2021 updated by: Regina Radner Berkovich, Berkovich, Regina MD, PhD Inc.

The Impact of a Planned 12-week Dosing Interruption of Natalizumab on Immune Cell Trafficking, Pharmacokinetic (PK)/Pharmacodynamic (PD) Parameters, and Multiple Sclerosis (MS) Disease Stability.

This is an open-label study of patients with relapsing forms of MS is designed to assess the biochemical, immunological, and kinetic profiles of natalizumab being used with specific brief dosing interruption. The study will be conducted at one site in the US. Ten subjects currently treated with natalizumab will be enrolled and will be evaluated for both PK/PD and cell trafficking in blood and/or CSF during standard dosing of natalizumab and at the end of a planned 12-week dosing interruption. MS disease activity will be carefully monitored clinically and by MRI and NfL.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Study Title:

The impact of a planned 12-week dosing interruption of natalizumab on immune cell trafficking, PK/PD parameters, and MS disease stability.

Objectives:

Hypothesis: An interruption in the dosing of natalizumab results in a lower risk of progressive multifocal leukoencephalopathy (PML) while maintaining MS disease control by selective immune surveillance.

Primary endpoints: To measure the re-establishment of immune surveillance by measuring leukocyte cell binding to the blood brain barrier and trafficking into the central nervous system (CNS) during a planned 12-week dosing interruption of natalizumab. This will be done by measuring leukocytes in the CSF. Concurrently, MS disease activity will be monitoring with MRI.

Secondary endpoints:

  • To characterize the difference in PK/PD parameters in patients during standard 28-day dosing intervals vs. at the end of a planned 12-week dosing interruption
  • To measure natalizumab drug concentrations, Soluble Vascular Cell Adhesion Molecule (sVCAM), Soluble Mucosal Vascular Addressin Cell Adhesion Molecule (sMAdCAM), Very Late Antigen-4 (VLA4) expression, and receptor occupancy measured in blood.
  • To measure neurofilament light (NfL) in CSF and serum as a sensitive measure of MS disease stability.
  • Using MRI and clinical parameters, to determine impact of a planned 12-week dosing interruption of natalizumab on MS disease stability.
  • MRI's will be obtained for each patient at the end of the dose interruption and 3 months after the re-initiation of natalizumab dosing.

Design:

Single site, open-label, consenting patients with relapsing forms of Multiple Sclerosis who are scheduled for a dose interruption of natalizumab. Patients will provide biological samples (blood and CSF) and have MRIs post-dose interruption.

Patient Population:

Patients with relapsing forms of Multiple Sclerosis who are currently on natalizumab therapy with stable MS disease and who are scheduled for a planned 12-week dosing interruption.

Treatment Groups:

Duration of Study Participation: Up to 9 months Study Location: 8727 Beverly Blvd, West Hollywood, California (CA) 90048 United States (US) Study Phase: Pilot exploratory study. Number of Planned Subjects: 10 Sample Size Determination: This is an exploratory study. No formal sample size calculation was performed.

Study Type

Interventional

Enrollment (Anticipated)

10

Phase

  • Phase 4

Contacts and Locations

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

Study Contact

Study Locations

  • United States
    • California
      • West Hollywood, California, United States, 90048
        • Recruiting
        • Regina Berkovich MD, PhD Inc.
        • Contact:

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

19 years to 63 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

To be eligible for entry into this study, candidates must meet all of the following eligibility criteria at the time of randomization:

Screening Visit:

  1. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI) in accordance with national and local subject privacy regulations.
  2. At least 18 years old at the time of informed consent.
  3. Must be a patient with a relapsing form of Multiple Sclerosis enrolled in the TOUCH Prescribing Program who is not expected to discontinue Tysabri® therapy prior to completion of the requirements of this study.
  4. Must weigh between 50 and 110 kg, inclusive.
  5. Patients must be considered clinically stable and scheduled for their pre-planned annual dose interruption of 2 consecutive skipped doses.
  6. No evidence of disease activity with on standard (28-day interval) dosing of natalizumab.

Exclusion Criteria:

Candidates will be excluded from study entry if any of the following exclusion criteria exist at the time of screening:

Medical History

  1. If subject answers 'Yes" to any question on the PML questionnaire that is not resolved prior to infusion as per standard operating procedure for natalizumab infusion.
  2. If subject consumes alcohol within 24 hours of blood specimen collection.

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: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Dose Interruption
All subjects will continue to receive their prescribed Tysabri® 300 mg IV infusions at their approved infusion sites. The patients will receive Tysabri at standard intervals (28-days) except during the pre-planned dose interruption of 2 consecutive skipped doses.
Drug: Dosing Interruption of Natalizumab
Planned 12 week dosing interruption of natalizumab
Other Names:
  • Dosing Interruption of Tysabri
No Intervention: Standard Treatment
All subjects will continue to receive their prescribed Tysabri® 300 mg IV infusions at their approved infusion sites. The patients will receive Tysabri at standard intervals (28-days).

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Leukocyte Type and Quantity in CSF
Time Frame: Change of Leukocyte types and quantity in CSF in pre- and post-interruption of treatment through study completion, an average of 6 months.
Types and quantities of leukocytes including T-cells, B-cells, macrophages, monocytes, etc. measured through flow cytometry.
Change of Leukocyte types and quantity in CSF in pre- and post-interruption of treatment through study completion, an average of 6 months.
MS Activity through CSF, Blood, and MRI
Time Frame: Change of MS Activity in pre- and post-interruption of treatment through study completion, an average of 6 months.
Soluble factors related to MS activity include Neurofilament Light Chain Levels in Blood and CSF measured through flow cytometry. MRI of brain, cervical, and thoracic cavity will be closely monitored for MS disease activity.
Change of MS Activity in pre- and post-interruption of treatment through study completion, an average of 6 months.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Natalizumab Concentrations in Blood
Time Frame: Change of Natalizumab Concentrations in Blood in pre- and post-interruption of treatment through study completion, an average of 6 months.
Change of Natalizumab Concentrations in Blood in pre- and post-interruption of treatment through study completion, an average of 6 months.
immunoglobulin G4 Levels in Blood
Time Frame: Change of immunoglobulin G4 Levels in Blood in pre- and post-interruption of treatment through study completion, an average of 6 months.
Change of immunoglobulin G4 Levels in Blood in pre- and post-interruption of treatment through study completion, an average of 6 months.
Soluble Vascular Cell Adhesion Molecules and Soluble Mucosal Vascular Addressin Cell Adhesion Molecule Levels (sVCAM sMAdCAM) in Blood
Time Frame: Change of sVCAM sMAdCAM in blood in pre- and post-interruption of treatment through study completion, an average of 6 months.
sVCAM sMAdCAM are ligands that are released into the bloodstream as marker of inflammation. The measurements will be done with Luminex technology using VCAM1 and MAdCAM1 specific antibodies to measure the levels in serum.
Change of sVCAM sMAdCAM in blood in pre- and post-interruption of treatment through study completion, an average of 6 months.
John Cunningham Virus Extracellular Vesicle Antibody Levels in CSF
Time Frame: Change of John Cunningham Virus Extracellular Vesicles in CSF in pre- and post-interruption of treatment through study completion, an average of 6 months.
Change of John Cunningham Virus Extracellular Vesicles in CSF in pre- and post-interruption of treatment through study completion, an average of 6 months.

Collaborators and Investigators

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

Sponsor

Berkovich, Regina MD, PhD Inc.

Collaborators

Biogen
Cedars-Sinai Medical Center

Investigators

  • Principal Investigator: Regina R Berkovich, MD, PhD, Regina Berkovich MD, PhD Inc.

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)

July 3, 2019

Primary Completion (Anticipated)

November 1, 2021

Study Completion (Anticipated)

December 1, 2021

Study Registration Dates

First Submitted

April 15, 2019

First Submitted That Met QC Criteria

August 5, 2019

First Posted (Actual)

August 7, 2019

Study Record Updates

Last Update Posted (Actual)

July 22, 2021

Last Update Submitted That Met QC Criteria

July 20, 2021

Last Verified

July 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 001-BIO-CSF

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

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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