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

NCT04048577 | Unknown Phase 4 FDA Drug

• 1 other identifier: 001-BIO-CSF
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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.

Conditions

Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting

Keywords

Natalizumab; Drug Holiday; Alternative Dosing; Extended Dosing

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (4)

• 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

  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.

Study Arms (2)

Dose Interruption

EXPERIMENTAL

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

Standard Treatment

NO INTERVENTION

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).

Interventions

Dosing Interruption of Natalizumab DRUG

Planned 12 week dosing interruption of natalizumab

Also known as: Dosing Interruption of Tysabri

Dose Interruption

Eligibility Criteria

• Age: 21 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Berkovich, Regina MD, PhD Inc.: lead
• Biogen: collaborator
• Cedars-Sinai Medical Center: collaborator

Study Sites (1)

Regina Berkovich MD, PhD Inc.

West Hollywood, California, 90048, United States

RECRUITING

Related 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.

  PMID: 26000328 BACKGROUND

• 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.

  PMID: 22591293 BACKGROUND

• Disanto G, Barro C, Benkert P, Naegelin Y, Schadelin 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.

  PMID: 28512753 BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

• 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.

  PMID: 28969984 BACKGROUND

• 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.

  PMID: 19188571 BACKGROUND

• 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.

  PMID: 30737333 BACKGROUND

• Novakova L, Zetterberg H, Sundstrom P, Axelsson M, Khademi M, Gunnarsson M, Malmestrom 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.

  PMID: 29079686 BACKGROUND

• 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.

  PMID: 25273271 BACKGROUND

• 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 Seze 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.

  PMID: 28916537 BACKGROUND

• 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.

  BACKGROUND

• 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.

  PMID: 26917698 BACKGROUND

MeSH Terms

Conditions

Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases

Study Officials

• Regina R Berkovich, MD, PhD

  Regina Berkovich MD, PhD Inc.

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Regina R Berkovich, MD, PhD

CONTACT

3104749595; reginaberkovichmd@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director

Study Record Dates

• First Submitted: April 15, 2019
• First Posted: August 7, 2019
• Study Start: July 3, 2019
• Primary Completion: November 1, 2021
• Study Completion: December 1, 2021
• Last Updated: July 22, 2021

Record last verified: 2021-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)