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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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.

Conditions
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Multiple Sclerosis, Multiple Sclerosis, Relapsing-Remitting

Intervention / Treatment
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* Drug: Dosing Interruption of Natalizumab


Participation Criteria
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Eligibility Criteria
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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: 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. At least 18 years old at the time of informed consent. 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. Must weigh between 50 and 110 kg, inclusive. Patients must be considered clinically stable and scheduled for their pre-planned annual dose interruption of 2 consecutive skipped doses. 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 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. If subject consumes alcohol within 24 hours of blood specimen collection.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Interruption<br>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<br>* Planned 12 week dosing interruption of natalizumab<br>* Other names: Dosing Interruption of Tysabri;|
| No Intervention: Standard Treatment<br>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?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Leukocyte Type and Quantity in CSF | 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 | 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 |  | 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 |  | 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 | 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 |  | Change of John Cunningham Virus Extracellular Vesicles in CSF in pre- and post-interruption of treatment through study completion, an average of 6 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Natalizumab, Drug Holiday, Alternative Dosing, Extended Dosing