Dimethyl Fumarate Treatment of Primary Progressive Multiple Sclerosis

Dimethyl Fumarate Treatment of Primary Progressive Multiple Sclerosis

This study aims to evaluate safety and efficacy of dimethyl fumarate treatment in patients with primary progressive multiple sclerosis (PPMS).

Half of the patients will receive dimethyl fumarate and the other half will receive placebo.

Multiple sclerosis (MS) is a chronic, inflammatory disease of the central nervous system and is presumed to be caused by T cell-mediated autoimmune processes. PPMS has no registered treatment options only symptomatic treatment exists. Progressive forms of MS are characterized clinically by gradual symptom development with or without superimposed relapses.

Fumarates have long been known to have disease-attenuating effects in psoriasis. They have been in routine use in dermatology in Germany for several decades. Dimethyl fumarate has the interesting property of combining immunological effects, at least partly mediated by interference with nuclear factor kappa B and other transcription factors, and also anti-oxidative and neuroprotective effects mediated by activation of the transcription factor Nuclear factor (erythroid-derived 2)-Related Factor 2 (NRF2). Dimethyl fumarate is currently approved for treatment of relapsing-remitting MS by the European medicines Agency in a dose of 240 mg twice per day.

Neurofilament light chain (NFL) is a treatment responsive biomarker of neuronal and axonal death when appearing in the cerebrospinal fluid (CSF) and it has been associated with long-term prognosis in MS. The concentration is often elevated in progressive MS patients. Treatment effect is measured by measuring changes in neurofilament light chain concentration over the course of 48 weeks of treatment with either active drug or placebo.

Inclusion Criteria:

• Age 18 to 65 years
• PPMS according to the McDonald (2010) and Lublin (2014) criteria
• Disease duration at least one year
• EDSS ≤ 6.5
• Written informed consent to study participation
• No other signs of significant disease judged by the investigator
• Eligible for randomization to active treatment or placebo as assessed by CSF NFL levels above 380ng/L
• Not eligible for randomization as assessed by CSF biomarker studies but accepts follow-up and open-label treatment per protocol
• Patients not eligible for randomization due to low NFL concentrations in CSF at screening can be followed up after 48 weeks, and are eligible for open-label treatment if they fulfil one of the following clinical criteria of disease progression:
• 1 point increase in EDSS score from screening to week 48 if screening EDSS <6
• 0.5 point increase in EDSS score from screening to week 48 if screening EDSS>5.5
• 2 point increase in a physical functional system
• Worsening in SDMT, 9HPT or T25FW >20% from screening to week 48

Exclusion Criteria:

• Pregnancy or breast feeding
• Lack of effective contraception for women of child-bearing potential
• Relapse within 6 months of inclusion
• Methylprednisolone treatment within 3 months of inclusion
• Treatment with interferon-beta, glatiramer acetate, immunoglobulin G or other immunomodulatory treatment within 6 months of inclusion
• Treatment with mitoxantrone, cyclophosphamide, azathioprine or other immunosuppressive treatment within 6 months of inclusion
• Findings on the screening MRI judged to preclude participation by the treating physician
• Other diseases associated with immunodeficiency
• Other diseases judged to be relevant by the treating physician
• Anticoagulant therapy other than platelet inhibitors
• Active malignant disease in the previous 5 years
• Renal insufficiency or blood creatinine > 150 μmol/l
• Present or chronic infection with hepatitis B virus, hepatitis C virus, HIV (tested in the screening blood samples) or other infections found to be relevant by the treating physician.
• Psychiatric disorders or other disorders impairing the patient's ability to participate in the trial
• Contraindication to MRI
• Known allergy or hypersensitivity to dimethyl fumarate