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

Primary Purpose

Multiple Sclerosis, Multiple Sclerosis, Relapsing-Remitting

Status
Withdrawn
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Dimethyl Fumarate
Sponsored by
Washington University School of Medicine
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Multiple Sclerosis focused on measuring Cerebral Spinal Fluid, Dimethyl Fumarate, Tecfidera, Multiple Sclerosis, Relapsing MS, RRMS, Mechanism of Action

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Washington University (John L. Trotter MS Center)
  • Swedish Neuroscience Institute

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Dimethyl Fumarate

Arm Description

Open label dimethyl fumarate (Tecfidera) at the US approved dose of 120mg BID for 7 days and then 240mg BID thereafter for 12 months.

Outcomes

Primary Outcome Measures

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)
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
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)
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)

Secondary Outcome Measures

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.

Full Information

First Posted
January 11, 2016
Last Updated
July 19, 2016
Sponsor
Washington University School of Medicine
Collaborators
Biogen
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1. Study Identification

Unique Protocol Identification Number
NCT02675413
Brief Title
Mechanisms of Action of Dimethyl Fumarate (Tecfidera) in Relapsing MS
Official Title
Mechanisms of Action of Dimethyl Fumarate in Relapsing MS
Study Type
Interventional

2. Study Status

Record Verification Date
July 2016
Overall Recruitment Status
Withdrawn
Why Stopped
Principal Investigator decided to withdraw.
Study Start Date
April 2016 (undefined)
Primary Completion Date
April 2016 (Actual)
Study Completion Date
April 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Washington University School of Medicine
Collaborators
Biogen

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Sclerosis, Multiple Sclerosis, Relapsing-Remitting
Keywords
Cerebral Spinal Fluid, Dimethyl Fumarate, Tecfidera, Multiple Sclerosis, Relapsing MS, RRMS, Mechanism of Action

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
0 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Dimethyl Fumarate
Arm Type
Experimental
Arm Description
Open label dimethyl fumarate (Tecfidera) at the US approved dose of 120mg BID for 7 days and then 240mg BID thereafter for 12 months.
Intervention Type
Drug
Intervention Name(s)
Dimethyl Fumarate
Other Intervention Name(s)
Tecfidera
Intervention Description
Open-label
Primary Outcome Measure Information:
Title
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
Description
Mean difference in Nitrate, nitrite (um/L), Glutathione (uM), and F2-isoprostanes (pg/ml)
Time Frame
24 months
Title
Mean differences in markers of axonal damage to assess whether DMF protects against neurodegeneration at baseline and 12 months
Description
mean differences in neurofilament heavy and light chains, and tau protein in blood and spinal fluid
Time Frame
24 months
Title
Mean differences in MS-relevant cytokines, chemokines and osteopontin to examine the immunologic consequences of DMF therapy during autoimmune CNS inflammation.
Description
Mean differences in CXCL13 (pg/ml), CCL2 (pg/ml), TNF (pg/ml), IFNg (pg/ml),IL-17 (pg/ml), Osteopontin (pg/ml)
Time Frame
24 months
Title
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.
Description
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)
Time Frame
24 months
Secondary Outcome Measure Information:
Title
Correlation of Biomarkers with Imaging and Clinical Outcome Measures
Description
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.
Time Frame
24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Anne Cross, MD
Organizational Affiliation
Washington University School of Medicine
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Laura Piccio, MD
Organizational Affiliation
Washington University School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Washington University (John L. Trotter MS Center)
City
St. Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Swedish Neuroscience Institute
City
Seattle
State/Province
Washington
ZIP/Postal Code
98122
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Undecided
IPD Sharing Plan Description
Unclear what results may be available for sharing. We plan to publish group analysis.

Learn more about this trial

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

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