Mechanisms of Action of Dimethyl Fumarate (Tecfidera) in Relapsing MS

Mechanisms of Action of Dimethyl Fumarate in Relapsing MS

This is a prospective study that will explore the mechanisms of efficacy of dimethyl fumarate (DMF) treatment in multiple sclerosis (MS). Investigators will enroll relapsing MS patients who are beginning therapy with DMF into a one-year longitudinal study in which blood and spinal fluid analyses, imaging and clinical studies will be performed to identify and measure changes associated with DMF therapy.

Study Overview

• Status: Withdrawn
• Conditions: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting
• Intervention / Treatment: Drug: Dimethyl Fumarate

Detailed Description

The emergence of Dimethyl Fumarate (DMF) as an oral agent for the treatment of relapsing multiple sclerosis (MS) has the potential to reduce the burden of neurologic disability while minimizing side effects and risks associated with more established therapies. However, at present there is a need for further understanding of the mechanisms of action for DMF. That is, it is not yet known whether the benefits observed in MS patients treated with DMF are due primarily to immunologic and anti-inflammatory effects or neuroprotective effects, or both. The main site(s) of DMF actions, whether in the CNS and/or the periphery, is also not known.

Dimethyl fumarate is believed to act centrally by enhancing the nuclear factor erythroid 2 related factor 2 (Nrf2) transcriptional pathway, which regulates enzymes to counter act oxidative stress . DMF may enhance the Nrf2 transcriptional pathway within the CNS, but this is unproven. DMF is also anti-inflammatory, and is known to inhibit NFB translocation to the nucleus [and chemokine-induced monocyte chemotaxis. Inhibition of NFB could occur systemically, or within the CNS, or both. Therefore, investigators intend to investigate antioxidant and immunologic changes within the central nervous system (CNS) and blood in relation to DMF therapy.

• Study Type: Interventional
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Washington University (John L. Trotter MS Center)
  • Washington
    • Seattle, Washington, United States, 98122
      • Swedish Neuroscience Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of Relapsing MS (2010 McDonald Criteria)
• Age greater than or equal to 18.
• Starting treatment with dimethyl fumarate (DMF). Enrolled patients will be either naive to disease modifying therapy (DMT) or will be enrolled after a greater than or equal to 30 days from last dose of prior DMT. If enrolled patients cannot tolerate DMF, the will be replaced by another subject. All subjects will serve as their own control.

Exclusion Criteria:

• Women of Childbearing Potential who are pregnant, breastfeeding, or planning to become pregnant or breastfeed for the duration of the study.
• Chronic diseases that will have effects on the laboratory, clinical and imaging parameters we will study: Insulin-dependent diabetes mellitus, stroke, Alzheimer's disease, auto-immune disorders such as rheumatoid arthritis, lupus, neuromyelitis optica, mixed connective disease, or sjogren's disease.
• Any prior treatment with mitoxantrone or alemtuzumab.
• Those undergoing DMT within the past 12 months with rituximab or daclizumab.
• Patients treated with chronic (monthly) systemic steroids.
• Patients treated with steroids (intravenous, intramuscular, oral or ACTH) with the intent to treat MS within 30 days of the baseline visit.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dimethyl Fumarate; Open label dimethyl fumarate (Tecfidera) at the US approved dose of 120mg BID for 7 days and then 240mg BID thereafter for 12 months.	Drug: Dimethyl Fumarate; Open-label; Other Names: Tecfidera

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean differences in Indicators of Oxidative stress (Nitrate, nitrite (um/L), Glutathione (uM), and F2-isoprostanes (pg/ml)) in blood and CSF at baseline and 12 months	Mean difference in Nitrate, nitrite (um/L), Glutathione (uM), and F2-isoprostanes (pg/ml)	24 months
Mean differences in markers of axonal damage to assess whether DMF protects against neurodegeneration at baseline and 12 months	mean differences in neurofilament heavy and light chains, and tau protein in blood and spinal fluid	24 months
Mean differences in MS-relevant cytokines, chemokines and osteopontin to examine the immunologic consequences of DMF therapy during autoimmune CNS inflammation.	Mean differences in CXCL13 (pg/ml), CCL2 (pg/ml), TNF (pg/ml), IFNg (pg/ml),IL-17 (pg/ml), Osteopontin (pg/ml)	24 months
Mean differences in the phenotype and activation status of adaptive and innate immune cells in the CSF and peripheral circulation at baseline and 12 months.	Mean differences in CD4 (% and cells/uL) , CD8 (% and cells/uL), CD117 (% and cells/uL), HLA-DR (% and cells/uL), CD123 (% and cells/uL), CD19 (% and cells/uL),CD14, monocytes (% and cells/uL), CD11c (% and cells/uL), BDCA2 (% and cells/uL), CD56 and CD16, NK cells (% and cells/uL), CD138, plasmablasts (% and cells/uL)	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation of Biomarkers with Imaging and Clinical Outcome Measures	A secondary goal is to correlate the biomarkers listed in the primary objectives with the number of gadolinium enhancing, T2W and T1W lesions seen at baseline and 12 months.	24 months

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: Biogen
• Investigators: Principal Investigator: Anne Cross, MD, Washington University School of Medicine; Principal Investigator: Laura Piccio, MD, Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start: April 1, 2016
• Primary Completion (Actual): April 1, 2016
• Study Completion (Actual): April 1, 2016

Study Registration Dates

• First Submitted: January 11, 2016
• First Submitted That Met QC Criteria: February 2, 2016
• First Posted (Estimate): February 5, 2016

Study Record Updates

• Last Update Posted (Estimate): July 20, 2016
• Last Update Submitted That Met QC Criteria: July 19, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Keywords: Multiple Sclerosis; RRMS; Dimethyl Fumarate; Tecfidera; Cerebral Spinal Fluid; Relapsing MS; Mechanism of Action
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Dimethyl Fumarate
• Other Study ID Numbers: 201511112

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: Unclear what results may be available for sharing. We plan to publish group analysis.