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

Multiple Sclerosis Clinical Trial

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.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04048577
• Other study ID #: 001-BIO-CSF
• Status: Recruiting
• Phase: Phase 4
• Start date: July 3, 2019
• Est. completion date: December 1, 2021

Study information

• Verified date: July 2021
• Source: Berkovich, Regina MD, PhD Inc.
• Contact: Regina R Berkovich, MD, PhD
• Phone: 3104749595
• Email: reginaberkovichmd[@]gmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 10
• Est. completion date: December 1, 2021
• Est. primary completion date: November 1, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Relapsing-Remitting
• Sclerosis

Intervention

Drug:
• Dosing Interruption of Natalizumab
Planned 12 week dosing interruption of natalizumab

Locations

Country	Name	City	State
United States	Regina Berkovich MD, PhD Inc.	West Hollywood	California

Sponsors (3)

Lead Sponsor	Collaborator
Berkovich, Regina MD, PhD Inc.	Biogen, Cedars-Sinai Medical Center

Country where clinical trial is conducted

United States, 

References & Publications (13)

Berkovich R, Togasaki DM, Cen SY, Steinman L. CD4 cell response to interval therapy with natalizumab. Ann Clin Transl Neurol. 2015 May;2(5):570-4. doi: 10.1002/acn3.190. Epub 2015 Mar 6. — View Citation

Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, Lee S, Plavina T, Scanlon JV, Sandrock A, Bozic C. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012 May 17;366(20):1870-80. doi: 10.1056/NEJMoa1107829. — View Citation

Disanto G, Barro C, Benkert P, Naegelin Y, Schädelin S, Giardiello A, Zecca C, Blennow K, Zetterberg H, Leppert D, Kappos L, Gobbi C, Kuhle J; Swiss Multiple Sclerosis Cohort Study Group. Serum Neurofilament light: A biomarker of neuronal damage in multiple sclerosis. Ann Neurol. 2017 Jun;81(6):857-870. doi: 10.1002/ana.24954. — View Citation

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.

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.

Ho PR, Koendgen H, Campbell N, Haddock B, Richman S, Chang I. Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies. Lancet Neurol. 2017 Nov;16(11):925-933. doi: 10.1016/S1474-4422(17)30282-X. Epub 2017 Sep 29. — View Citation

Khatri BO, Man S, Giovannoni G, Koo AP, Lee JC, Tucky B, Lynn F, Jurgensen S, Woodworth J, Goelz S, Duda PW, Panzara MA, Ransohoff RM, Fox RJ. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology. 2009 Feb 3;72(5):402-9. doi: 10.1212/01.wnl.0000341766.59028.9d. — View Citation

Kuhle J, Kropshofer H, Haering DA, Kundu U, Meinert R, Barro C, Dahlke F, Tomic D, Leppert D, Kappos L. Blood neurofilament light chain as a biomarker of MS disease activity and treatment response. Neurology. 2019 Mar 5;92(10):e1007-e1015. doi: 10.1212/WNL.0000000000007032. Epub 2019 Feb 8. — View Citation

Novakova L, Zetterberg H, Sundström P, Axelsson M, Khademi M, Gunnarsson M, Malmeström C, Svenningsson A, Olsson T, Piehl F, Blennow K, Lycke J. Monitoring disease activity in multiple sclerosis using serum neurofilament light protein. Neurology. 2017 Nov 28;89(22):2230-2237. doi: 10.1212/WNL.0000000000004683. Epub 2017 Oct 27. — View Citation

Plavina T, Muralidharan KK, Kuesters G, Mikol D, Evans K, Subramanyam M, Nestorov I, Chen Y, Dong Q, Ho PR, Amarante D, Adams A, De Sèze J, Fox R, Gold R, Jeffery D, Kappos L, Montalban X, Weinstock-Guttman B, Hartung HP, Cree BAC. Reversibility of the effects of natalizumab on peripheral immune cell dynamics in MS patients. Neurology. 2017 Oct 10;89(15):1584-1593. doi: 10.1212/WNL.0000000000004485. Epub 2017 Sep 15. Erratum in: Neurology. 2020 Oct 6;95(14):661. — View Citation

Plavina T, Subramanyam M, Bloomgren G, Richman S, Pace A, Lee S, Schlain B, Campagnolo D, Belachew S, Ticho B. Anti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol. 2014 Dec;76(6):802-12. doi: 10.1002/ana.24286. Epub 2014 Oct 24. — View Citation

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.

Zhovtis Ryerson L, Frohman TC, Foley J, Kister I, Weinstock-Guttman B, Tornatore C, Pandey K, Donnelly S, Pawate S, Bomprezzi R, Smith D, Kolb C, Qureshi S, Okuda D, Kalina J, Rimler Z, Green R, Monson N, Hoyt T, Bradshaw M, Fallon J, Chamot E, Bucello M, Beh S, Cutter G, Major E, Herbert J, Frohman EM. Extended interval dosing of natalizumab in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2016 Aug;87(8):885-9. doi: 10.1136/jnnp-2015-312940. Epub 2016 Feb 25. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.
Primary	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	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.
Secondary	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.
Secondary	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.
Secondary	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.