Dimethyl Fumarate Treatment of Primary Progressive Multiple Sclerosis

Primary Progressive Multiple Sclerosis Clinical Trial

— FUMAPMS  

Official title:

Dimethyl Fumarate Treatment of Primary Progressive Multiple Sclerosis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02959658
• Other study ID #: FUMAPMS2016
• Status: Completed
• Phase: Phase 2
• Start date: December 2016
• Est. completion date: December 9, 2020

Study information

• Verified date: December 2020
• Source: Rigshospitalet, Denmark
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 54
• Est. completion date: December 9, 2020
• Est. primary completion date: December 21, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Chronic Progressive
• Primary Progressive Multiple Sclerosis
• Sclerosis

Intervention

Drug:
• Dimethyl fumarate

• Placebo
Manufactured to mimic Dimethyl Fumarate capsules

Locations

Country	Name	City	State
Denmark	Danish Multiple Sclerosis Center, Department of neurology	Copenhagen

Sponsors (2)

Lead Sponsor	Collaborator
Rigshospitalet, Denmark	Biogen

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	BVMTR	Change from screening for Brief Visuospatial Memory Test Revised (BVMTR) The test is performed by the principal investigator or a delegated member of the study team.	0-48 weeks & 48-96 weeks
Other	California Verbal Learning Test 2 (CVLT-II)	Change from screening for California Verbal Learning Test 2 (CVLT-II). The test is performed by the principal investigator or a delegated member of the study team.	0-48 weeks & 48-96 weeks
Other	UDI	The questionnaire is handed out at screening visit, week 48 and week 96.	0-48 weeks & 48-96 weeks
Other	FSMC	The questionnaire is handed out at screening visit, week 48 and week 96.	0-48 weeks & 48-96 weeks
Other	MSIS-29	The questionnaire is handed out at screening visit, week 48 and week 96.	0-48 weeks & 48-96 weeks
Other	Number of Gadolinium (Gd) enhancing lesions on MRI	Change from screening/W48 in number of Gd-enhancing lesions.	0-48 weeks & 48-96 weeks
Other	Number of new T2 lesions	Change from screening in number of new T2 lesions	48-96 weeks
Other	Number of enlarged T2 lesions	Change from screening in number of enlarged T2 lesions	48-96 weeks
Other	Brain volume change	Change from screening/W48 in volume of cortical grey matter (CGM), normal appearing white matter (NAWM), thalamus, putamen and lesion volume.	0-48 weeks & 48-96 weeks
Other	Change in Magnetization Transfer Ratio (MTR).	Change from screening/W48 in Magnetization Transfer Ratio (MTR) of CGM, NAWM, the putamen and thalamic nuclei	0-48 weeks & 48-96 weeks
Other	Change in diffusion tensor imaging (DTI) measures (FA and mean diffusivity).	Change from screening/W48 in diffusion tensor imaging (DTI) measures (FA and mean diffusivity) of CGM, NAWM (except FA in NAWM from screening to week 48), lesions, the putamen and thalamic nuclei.	0-48 weeks & 48-96 weeks
Other	Cross sectional area at C2 level of the cervical spinal cord on MRI	Change from screening/W48 in the cross sectional area at the C2 level of the cervical spinal cord on MRI.	0-48 weeks & 48-96 weeks
Other	Circle drawing test at the time of the MRI	At the time of MRI (screening, week 48 and week 96) a circle drawing test will be performed.	0-48 weeks & 48-96 weeks
Other	Change in Serum Neurofilament Light Chain (serum NFL)	Is assessed from a blood sample at screening visit, W48 visit, and W96 visit. The analysis is performed by the neuroimmunology laboratory with a commercially available SIMOA-assay (Quanterix).	0-48 weeks & 48-96 weeks
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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