Clinical trial NCT02959658: Dimethyl Fumarate Treatment of Primary Progressive Multiple Sclerosis
Official title: Dimethyl Fumarate Treatment of Primary Progressive Multiple Sclerosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Primary Progressive Multiple Sclerosis
Lead sponsor: Rigshospitalet, Denmark
Sponsor class: OTHER
Collaborators: name: Biogen
First posted: 2016-11-09
Enrollment: 54
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Neurofilament light chain in the cerebrospinal fluid (CSF)
timeFrame: 0-48 weeks
Secondary outcomes:
measure: Expanded Disability Status Scale (EDSS)
timeFrame: 0-48 weeks
measure: Timed 25-Foot Walk (T25FW)
timeFrame: 0-48 weeks
measure: Nine hole peg test (9HPT)
timeFrame: 0-48 weeks
measure: Symbol digit modalities test (SDMT)
timeFrame: 0-48 weeks
measure: CSF/Serum Immunoglobulin type G index
timeFrame: 0-48 weeks
measure: Cerebrospinal fluid-serum albumin quotient
timeFrame: 0-48 weeks
measure: soluble CD14 (sCD14)
timeFrame: 0-48 weeks
measure: soluble CD27 (sCD27)
timeFrame: 0-48 weeks
measure: BCMA
timeFrame: 0-48 weeks
measure: Chitinase 3-like-1
timeFrame: 0-48 weeks
measure: Myelin Basic protein (MBP)
timeFrame: 0-48 weeks
measure: Number of new or enlarged T2 lesions
timeFrame: 0-48 weeks
measure: Fractional anisotropy (FA) in Normal Appearing White Matter (NAWM)
timeFrame: 0-48 weeks
measure: Change in lesion volume
timeFrame: 0-48 weeks
measure: Change from screening in in magnetization transfer ratio (MTR) of T2 lesions
timeFrame: 0-48 weeks
measure: Thalamic volume
timeFrame: 0-48 weeks
measure: Percent brain volume change (PBVC)
timeFrame: 0-48 weeks
Other outcomes:
measure: BVMTR
timeFrame: 0-48 weeks & 48-96 weeks
measure: California Verbal Learning Test 2 (CVLT-II)
timeFrame: 0-48 weeks & 48-96 weeks
measure: UDI
timeFrame: 0-48 weeks & 48-96 weeks
measure: FSMC
timeFrame: 0-48 weeks & 48-96 weeks
measure: MSIS-29
timeFrame: 0-48 weeks & 48-96 weeks
measure: Number of Gadolinium (Gd) enhancing lesions on MRI
timeFrame: 0-48 weeks & 48-96 weeks
measure: Number of new T2 lesions
timeFrame: 48-96 weeks
measure: Number of enlarged T2 lesions
timeFrame: 48-96 weeks
measure: Brain volume change
timeFrame: 0-48 weeks & 48-96 weeks
measure: Change in Magnetization Transfer Ratio (MTR).
timeFrame: 0-48 weeks & 48-96 weeks
measure: Change in diffusion tensor imaging (DTI) measures (FA and mean diffusivity).
timeFrame: 0-48 weeks & 48-96 weeks
measure: Cross sectional area at C2 level of the cervical spinal cord on MRI
timeFrame: 0-48 weeks & 48-96 weeks
measure: Circle drawing test at the time of the MRI
timeFrame: 0-48 weeks & 48-96 weeks
measure: Change in Serum Neurofilament Light Chain (serum NFL)
timeFrame: 0-48 weeks & 48-96 weeks
Locations:
city: Copenhagen
country: Denmark
facility: Danish Multiple Sclerosis Center, Department of neurology
Study officials:
affiliation: Rigshospitalet, Denmark
name: Jacob Lando Talbot, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hojsgaard Chow H, Talbot J, Lundell H, Gobel Madsen C, Marstrand L, Lange T, Mahler MR, Buhelt S, Holm Hansen R, Blinkenberg M, Romme Christensen J, Soelberg Sorensen P, Rode von Essen M, Siebner HR, Sellebjerg F. Dimethyl Fumarate Treatment in Patients With Primary Progressive Multiple Sclerosis: A Randomized, Controlled Trial. Neurol Neuroimmunol Neuroinflamm. 2021 Aug 24;8(5):e1037. doi: 10.1212/NXI.0000000000001037. Print 2021 Sep.