Investigation of the Effect of Dimethyl Fumarate on T Cells in Patients With Relapsing Remitting Multiple Sclerosis
Investigation of the Effect of Dimethyl Fumarate on T Cells in Patients With Relapsing Remitting Multiple Sclerosis
This is an exploratory study, which allows analysis of multiple immune parameters derived
 from peripheral blood mononuclear cells (PBMCs) from patients with relapsing remitting
 multiple sclerosis before and during immune-modulatory treatment with dimethyl fumarate in
 comparison to PBMCs from healthy subjects.
The purpose of the trial is to shed more light on the mechanisms of action of dimethyl
 fumarate in patients with relapsing remitting multiple sclerosis. More specifically the
 influence of dimethyl fumarate on peripheral immune cells will be addressed to evaluate
 changes in cytokine production by the distinct T cell subsets and the differentiation
 capacity of naïve T cells. Furthermore, the impact of dimethyl fumarate treatment on the
 migratory capacity of T cells as well as the evaluation of changes in the suppressive
 capacity of regulatory T cells will be evaluated. To put the obtained results into context,
 response data of dimethyl fumarate-treated patients will be compared with data from healthy
 subjects.
Inclusion Criteria:

 Healthy subjects:

 -  H-1. Written informed consent must be obtained before any assessment is performed.

 -  H-2. Male and female subjects aged 18 - 60 years.

 -  H-3. No history of multiple sclerosis or clinically isolated syndrome.

 -  H-4. No history of other autoimmune diseases, which has been treated systemically with
 corticosteroids, immunomodulators or immunosuppressive drugs at any time point.

 RRMS patients:

 -  MS-1. Written informed consent must be obtained before any assessment is performed.

 -  MS-2. Male and female subjects aged 18 - 60 years.

 -  MS-3. Patients with RRMS, defined by 2010 revised McDonald criteria.

 -  MS-4. Patients with an Expanded Disability Status Scale (EDSS) score of 0-6.0.

 -  MS-5. Patients with one of the following treatment status:

 -  Naïve to disease modifying (DM) treatment (i.e. no DM treatment for at least 1
 month),

 -  Currently on MS therapy with interferon β-1 or glatiramer acetate and willing to
 switch to dimethyl fumarate (Tecfidera®).

 -  MS-6. MRI-scan of the brain ≤ 3 months at screening.

 Exclusion Criteria:

 RRMS patients:

 -  MS-1. Known hypersensitivity to dimethyl fumarate or any ingredients of Tecfidera®
 (microcrystalline cellulose; croscarmellose-sodium; talcum; high dispersion,
 hydrophobic silicon dioxide; magnesiumstearate (Ph. Eur.); triethylcitrate;
 methacrylic acid-methacrylate copolymer (1:1) (Ph. Eur.); methacrylic
 acid-ethylacrylate copolymer (1:1)-dispersion 30% (Ph. Eur.), simeticon,
 sodiumdodecylsulfate, polysorbate 80, gelantine, titanium oxide (E171), brilliant blue
 (E133), hydrated Iron(III)-oxide hydroxide (E172), shellac, potassium hydroxide.

 -  MS-2. A MS-relapse within 30 days prior to screening.

 -  MS-3. Known history of active tuberculosis or active tuberculosis determined by a
 positive QuantiFERON® TB Gold test (i.e. a negative test result has to be provided at
 screening unless a negative test result exists from the last 3 months prior to
 screening).

 -  MS-4. Moderate to severe impairment of liver function or persisting elevations > 2 x
 ULN (confirmed by retest) of serum glutamic pyruvic transaminase/ alanine
 aminotransferase (SGPT/ALT) or serum glutamic oxaloacetic transaminase/aspartate
 aminotransferase (SGOT/AST), except patients with confirmed Gilbert´s syndrome
 (Meulengracht´s disease).

 -  MS-5. Moderate to severe impairment of renal function, as shown by serum creatinine >
 133 μmol/L (or > 1.5 mg/dL).

 -  MS-6. Patients with significantly impaired bone marrow function or significant anemia,
 leukopenia, neutropenia or thrombocytopenia.

 -  MS-7. Women of childbearing potential not utilizing highly effective contraception.

 Both populations:

 -  MS/H-1. Mental condition rendering the subject unable to understand the nature, scope,
 and possible consequences of the study.

 -  MS/H-2. Subjects unlikely to comply with protocol as determined by investigator, e.g.,
 uncooperative attitude, inability to return for follow-up visits (e.g. major physical
 disability), and known unlikelihood of completing the study.

 -  MS/H-3. Clinically relevant cardiovascular, neurological, endocrine, or other major
 systemic disease making implementation of the protocol or interpretation of the study
 results difficult or that would put the subject at risk by participating in the study.

 -  MS/H-4. Subjects with ulcerative colitis or Crohn´s disease.

 -  MS/H-5. Subjects with a congenital or acquired severe immunodeficiency, a history of
 cancer (except for basal or squamous cell skin lesions which have been surgically
 excised, with no evidence of metastasis), lymph proliferative disease, or any subject
 who has received lymphoid irradiation.

 -  MS/H-6. Human immunodeficiency virus (HIV) positive, hepatitis B virus positive or
 hepatitis C virus positive subjects (i.e. a negative test result has to be provided at
 screening. In the presence of a negative test result from the last 3 months prior to
 screening, the test has not to be repeated at screening.).

 -  MS/H-7. Acute or chronic infection.

 -  MS/H-8. History of drug or alcohol abuse.

 -  MS/H-9. Use of adrenocorticotrophic hormone (ACTH) or systemic corticosteroids for 4
 weeks prior to screening.

 -  MS/H-10. Prior or concomitant use of cytokine therapy or intravenous immunoglobulins
 in the 3 months prior to screening.

 -  MS/H-11. Prior use of alemtuzumab or cladribine.

 -  MS/H-12. Prior use (within 1 year) of fingolimod (Gilenya®) or natalizumab (Tysabri®).

 -  MS/H-13. Prior use (within 2 years) of mitoxantrone, or other immunosuppressant agents
 such as azathioprine, cyclophosphamide, cyclosporine, methotrexate or mycophenolate
 mofetil.

 -  MS/H-14. Prior treatment with teriflunomide or leflunomide, unless successful
 wash-out, confirmed by plasma concentration of < 0.02 μg/ml.

 -  MS/H-15. Prior use of any investigational drug in the 6 months preceding screening.

 -  MS/H-16. Pregnant or breast-feeding women.