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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04048577
Recruitment Status : Not yet recruiting
First Posted : August 7, 2019
Last Update Posted : August 7, 2019
Sponsor:
Collaborators:
Biogen
Cedars-Sinai Medical Center
Information provided by (Responsible Party):
Regina Radner Berkovich, Berkovich, Regina MD, PhD Inc.

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Multiple Sclerosis Multiple Sclerosis, Relapsing-Remitting Drug: Dosing Interruption of Natalizumab Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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.
Estimated Study Start Date : September 1, 2019
Estimated Primary Completion Date : February 1, 2020
Estimated Study Completion Date : March 1, 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Natalizumab

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 Name: 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).



Primary Outcome Measures :
  1. 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.

  2. 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.


Secondary Outcome Measures :
  1. 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. ]
  2. 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. ]
  3. 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.

  4. 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. ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   21 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04048577


Contacts
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Contact: Regina R Berkovich, MD, PhD 3104749595 reginaberkovichmd@gmail.com

Locations
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United States, California
Regina Berkovich MD, PhD Inc.
West Hollywood, California, United States, 90048
Contact: Michael W Fernandez, BS    310-474-9595    berkovichresearch@gmail.com   
Sponsors and Collaborators
Berkovich, Regina MD, PhD Inc.
Biogen
Cedars-Sinai Medical Center
Investigators
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Principal Investigator: Regina R Berkovich, MD, PhD Regina Berkovich MD, PhD Inc.

Publications:
Foley J, Zhovtis Ryerson L, Chang I, Kister I, Cutter G, Metzger R, Goldberg JD, Li X, Riddle E, Kasliwal R, Ren Z, Hotermans C, Ho PR, Campbell N. Progressive multifocal leukoencephalopathy occurring with extended interval dosing of natalizumab: Analysis of cases in the TOUCH database. CMSC 2018; 5698.
Foley J, Metzger R, Hoyt T, Christensen A. Optimizing the natalizumab dose interval to reduce PML risk - lessons from the pharmacokinetics of therapy discontinuation. AAN 2015; P4.032.
Zhovtis Ryerson L, Foley J, Chang I, Kister I, Cutter G, Metzger R, Goldberg JD, Li X, Riddle E, Yu B, Ren Z, Hotermans C, Ho PR, Campbell N. Natalizumab extended interval dosing is associated with a reduction in progressive multifocal leukoencephalopathy risk in the TOUCH registry. ACTRIMS 2018; LB250.

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Responsible Party: Regina Radner Berkovich, Director, Berkovich, Regina MD, PhD Inc.
ClinicalTrials.gov Identifier: NCT04048577    
Other Study ID Numbers: 001-BIO-CSF
First Posted: August 7, 2019    Key Record Dates
Last Update Posted: August 7, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by Regina Radner Berkovich, Berkovich, Regina MD, PhD Inc.:
Natalizumab
Drug Holiday
Alternative Dosing
Extended Dosing
Additional relevant MeSH terms:
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Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Natalizumab
Immunologic Factors
Physiological Effects of Drugs