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Dimethyl Fumarate Treatment of Primary Progressive Multiple Sclerosis (FUMAPMS)

Primary Purpose

Primary Progressive Multiple Sclerosis

Status

Completed

Phase

Phase 2

Locations

Denmark

Study Type

Interventional

Intervention

Dimethyl fumarate

Placebo

About this trial

This is an interventional treatment trial for Primary Progressive Multiple Sclerosis

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Danish Multiple Sclerosis Center, Department of neurology

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Active drug

Placebo

Arm Description

Dimethyl fumarate, 240mg twice daily for 48 weeks

Placebo Oral Capsules, 2 tablets twice daily for 48 weeks

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

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.

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.

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.

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.

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).

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).

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).

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).

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).

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)

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)

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)

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).

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).

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).

Full Information

NCT ID

NCT02959658

First Posted

November 8, 2016

Last Updated

December 22, 2020

Sponsor

Rigshospitalet, Denmark

Collaborators

Biogen

1. Study Identification

Unique Protocol Identification Number

NCT02959658

Brief Title

Dimethyl Fumarate Treatment of Primary Progressive Multiple Sclerosis

Acronym

FUMAPMS

Official Title

Dimethyl Fumarate Treatment of Primary Progressive Multiple Sclerosis

Study Type

Interventional

2. Study Status

Record Verification Date

December 2020

Overall Recruitment Status

Completed

Study Start Date

December 2016 (Actual)

Primary Completion Date

December 21, 2019 (Actual)

Study Completion Date

December 9, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Rigshospitalet, Denmark

Collaborators

Biogen

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Primary Progressive Multiple Sclerosis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

54 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Active drug

Arm Type

Active Comparator

Arm Description

Dimethyl fumarate, 240mg twice daily for 48 weeks

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Placebo Oral Capsules, 2 tablets twice daily for 48 weeks

Intervention Type

Drug

Intervention Name(s)

Dimethyl fumarate

Other Intervention Name(s)

Tecfidera, BG-12

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Manufactured to mimic Dimethyl Fumarate capsules

Primary Outcome Measure Information:

Title

Neurofilament light chain in the cerebrospinal fluid (CSF)

Description

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.

Time Frame

0-48 weeks

Secondary Outcome Measure Information:

Title

Expanded Disability Status Scale (EDSS)

Description

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.

Time Frame

0-48 weeks

Title

Timed 25-Foot Walk (T25FW)

Description

Time Frame

0-48 weeks

Title

Nine hole peg test (9HPT)

Description

Time Frame

0-48 weeks

Title

Symbol digit modalities test (SDMT)

Description

Time Frame

0-48 weeks

Title

CSF/Serum Immunoglobulin type G index

Description

Time Frame

0-48 weeks

Title

Cerebrospinal fluid-serum albumin quotient

Description

Time Frame

0-48 weeks

Title

soluble CD14 (sCD14)

Description

Time Frame

0-48 weeks

Title

soluble CD27 (sCD27)

Description

Time Frame

0-48 weeks

Title

BCMA

Description

Time Frame

0-48 weeks

Title

Chitinase 3-like-1

Description

Time Frame

0-48 weeks

Title

Myelin Basic protein (MBP)

Description

Time Frame

0-48 weeks

Title

Number of new or enlarged T2 lesions

Description

Time Frame

0-48 weeks

Title

Fractional anisotropy (FA) in Normal Appearing White Matter (NAWM)

Description

Time Frame

0-48 weeks

Title

Change in lesion volume

Description

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)

Time Frame

0-48 weeks

Title

Change from screening in in magnetization transfer ratio (MTR) of T2 lesions

Description

Time Frame

0-48 weeks

Title

Thalamic volume

Description

Time Frame

0-48 weeks

Title

Percent brain volume change (PBVC)

Description

Time Frame

0-48 weeks

Other Pre-specified Outcome Measures:

Title

BVMTR

Description

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.

Time Frame

0-48 weeks & 48-96 weeks

Title

California Verbal Learning Test 2 (CVLT-II)

Description

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.

Time Frame

0-48 weeks & 48-96 weeks

Title

UDI

Description

The questionnaire is handed out at screening visit, week 48 and week 96.

Time Frame

0-48 weeks & 48-96 weeks

Title

FSMC

Description

The questionnaire is handed out at screening visit, week 48 and week 96.

Time Frame

0-48 weeks & 48-96 weeks

Title

MSIS-29

Description

The questionnaire is handed out at screening visit, week 48 and week 96.

Time Frame

0-48 weeks & 48-96 weeks

Title

Number of Gadolinium (Gd) enhancing lesions on MRI

Description

Change from screening/W48 in number of Gd-enhancing lesions.

Time Frame

0-48 weeks & 48-96 weeks

Title

Number of new T2 lesions

Description

Change from screening in number of new T2 lesions

Time Frame

48-96 weeks

Title

Number of enlarged T2 lesions

Description

Change from screening in number of enlarged T2 lesions

Time Frame

48-96 weeks

Title

Brain volume change

Description

Change from screening/W48 in volume of cortical grey matter (CGM), normal appearing white matter (NAWM), thalamus, putamen and lesion volume.

Time Frame

0-48 weeks & 48-96 weeks

Title

Change in Magnetization Transfer Ratio (MTR).

Description

Change from screening/W48 in Magnetization Transfer Ratio (MTR) of CGM, NAWM, the putamen and thalamic nuclei

Time Frame

0-48 weeks & 48-96 weeks

Title

Change in diffusion tensor imaging (DTI) measures (FA and mean diffusivity).

Description

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.

Time Frame

0-48 weeks & 48-96 weeks

Title

Cross sectional area at C2 level of the cervical spinal cord on MRI

Description

Change from screening/W48 in the cross sectional area at the C2 level of the cervical spinal cord on MRI.

Time Frame

0-48 weeks & 48-96 weeks

Title

Circle drawing test at the time of the MRI

Description

At the time of MRI (screening, week 48 and week 96) a circle drawing test will be performed.

Time Frame

0-48 weeks & 48-96 weeks

Title

Change in Serum Neurofilament Light Chain (serum NFL)

Description

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).

Time Frame

0-48 weeks & 48-96 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jacob Lando Talbot, MD

Organizational Affiliation

Rigshospitalet, Denmark

Official's Role

Principal Investigator

Facility Information:

Facility Name

Danish Multiple Sclerosis Center, Department of neurology

City

Copenhagen

ZIP/Postal Code

2100

Country

Denmark

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

34429340

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.

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Dimethyl Fumarate Treatment of Primary Progressive Multiple Sclerosis

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