Dimethyl Fumarate Treatment of Primary Progressive Multiple Sclerosis

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
Dimethyl Fumarate Treatment of Primary Progressive Multiple Sclerosis

Conditions
-----------------
Primary Progressive Multiple Sclerosis

Intervention / Treatment
-----------------
* Drug: Dimethyl fumarate
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active drug<br>Dimethyl fumarate, 240mg twice daily for 48 weeks | Drug: Dimethyl fumarate<br> <br> * Other names: BG-12;|
| Placebo Comparator: Placebo<br>Placebo Oral Capsules, 2 tablets twice daily for 48 weeks | Drug: Placebo<br>* Manufactured to mimic Dimethyl Fumarate capsules<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neurofilament light chain in the cerebrospinal fluid (CSF) | CSF Neurofilament Light Chain (NFL) is measured twice over a course of 48 weeks. Patients will have a spinal tap performed at baseline and again at week 48. | 0-48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Expanded Disability Status Scale (EDSS) | We will analyze the difference in EDSS change from screening visit to week 48 between the treatment and placebo group. EDSS is performed by a certified physician, primarily the PI. | 0-48 weeks | 
| Timed 25-Foot Walk (T25FW) | We will analyze the difference in T25FW change from screening visit to week 48 between the treatment and placebo group. T25FW is evaluated by the principal investigator or a delegated member of the study team. | 0-48 weeks | 
| Nine hole peg test (9HPT) | We will analyze the difference in 9HPT change from screening visit to week 48 between the treatment and placebo group. 9HPT is evaluated by the principal investigator or a delegated member of the study team. | 0-48 weeks | 
| Symbol digit modalities test (SDMT) | We will analyze the difference in the SDMT change from screening visit to week 48 between the treatment and placebo group using a general linear model with treatment allocation as factor and the screening SDMT value as covariate. SDMT is evaluated by the principal investigator or a delegated member of the study team. | 0-48 weeks | 
| CSF/Serum Immunoglobulin type G index | Is assessed from a sample of the cerebrospinal fluid at baseline and at week 48 and change is recorded. The analysis will be performed by the routine diagnostics department at the hospital where the spinal tap is performed. | 0-48 weeks | 
| Cerebrospinal fluid-serum albumin quotient | We will analyze the difference in change in CSF-serum albumin quotient from screening visit to week 48 between the treatment and placebo group. The analysis will be performed by the routine diagnostics department at the hospital where the spinal tap is performed. | 0-48 weeks | 
| soluble CD14 (sCD14) | We will analyze the difference in change in sCD14 concentration from screening visit to week 48 between the treatment and placebo group. The analysis is performed by a multiplex luminex assay (R&D systems). | 0-48 weeks | 
| soluble CD27 (sCD27) | We will analyze the difference in change in sCD27 concentration from screening visit to week 48 between the treatment and placebo group. The analysis is performed by a multiplex luminex assay (R&D systems). | 0-48 weeks | 
| BCMA | We will analyze the difference in change in BCMA concentration from screening visit to week 48 between the treatment and placebo group. The analysis is performed by a multiplex luminex assay (R&D systems). | 0-48 weeks | 
| Chitinase 3-like-1 | We will analyze the difference in change in CHI3L1 concentration from screening visit to week 48 visit between the treatment and placebo group. The analysis is performed by a multiplex luminex assay (R&D systems). | 0-48 weeks | 
| Myelin Basic protein (MBP) | We will analyze the difference in change in MBP concentration from screening visit to week 48 between the treatment and placebo group. The analysis is performed by a enzyme-linked immunosorbent assay (ELISA) (R&D DuoSet). | 0-48 weeks | 
| Number of new or enlarged T2 lesions | We will analyze the number of new or enlarging T2 lesions from screening visit to W48 between the treatment and placebo group. This analysis will be performed by our collaborator at Hvidovre Hospital (Danish Research Center for Magentic Resonance) | 0-48 weeks | 
| Fractional anisotropy (FA) in Normal Appearing White Matter (NAWM) | We will analyze the difference in change from screening to W48 of FA in NAWM between the treatment and placebo group. This analysis will be performed by our collaborator at Hvidovre Hospital (Danish Research Center for Magentic Resonance) | 0-48 weeks | 
| Change in lesion volume | We will analyze the change from screening to W48 in lesion volume. This analysis will be performed by our collaborator at Hvidovre Hospital (Danish Research Center for Magentic Resonance) | 0-48 weeks | 
| Change from screening in in magnetization transfer ratio (MTR) of T2 lesions | We will analyze the difference in change from screening to W48 in MTR of T2 lesions between the treatment and placebo group. This analysis will be performed by our collaborator at Hvidovre Hospital (Danish Research Center for Magentic Resonance). | 0-48 weeks | 
| Thalamic volume | We will analyze the difference in change from screening to W48 of thalamic volume between the treatment and placebo group. This analysis will be performed by our collaborator at Hvidovre Hospital (Danish Research Center for Magentic Resonance). | 0-48 weeks | 
| Percent brain volume change (PBVC) | We will analyze the difference in percentage change in brain volume from screening visit to week 48 between the treatment and placebo group. This analysis will be performed by our collaborator at Hvidovre Hospital (Danish Research Center for Magentic Resonance). | 0-48 weeks |