Clinical trial NCT02675413: Mechanisms of Action of Dimethyl Fumarate (Tecfidera) in Relapsing MS
Official title: Mechanisms of Action of Dimethyl Fumarate in Relapsing MS
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE4
Conditions: Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Keywords: Cerebral Spinal Fluid
Dimethyl Fumarate
Tecfidera
Multiple Sclerosis
Relapsing MS
RRMS
Mechanism of Action
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: Biogen
First posted: 2016-02-05
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

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.

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.

Primary outcomes:
measure: 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
timeFrame: 24 months
measure: Mean differences in markers of axonal damage to assess whether DMF protects against neurodegeneration at baseline and 12 months
timeFrame: 24 months
measure: Mean differences in MS-relevant cytokines, chemokines and osteopontin to examine the immunologic consequences of DMF therapy during autoimmune CNS inflammation.
timeFrame: 24 months
measure: 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.
timeFrame: 24 months
Secondary outcomes:
measure: Correlation of Biomarkers with Imaging and Clinical Outcome Measures
timeFrame: 24 months
Other outcomes:
Locations:
city: St. Louis
country: United States
facility: Washington University (John L. Trotter MS Center)
state: Missouri
city: Seattle
country: United States
facility: Swedish Neuroscience Institute
state: Washington
Study officials:
affiliation: Washington University School of Medicine
name: Anne Cross, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Washington University School of Medicine
name: Laura Piccio, MD
role: PRINCIPAL_INVESTIGATOR
References: