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Central and Peripheral Nervous System Changes as Markers of Disease Progression in Multiple Sclerosis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03401307
Recruitment Status : Active, not recruiting
First Posted : January 17, 2018
Last Update Posted : July 21, 2020
Sponsor:
Collaborator:
Region of Southern Denmark
Information provided by (Responsible Party):
Sepehr Mamoei, University of Southern Denmark

Brief Summary:

OBJECTIVE To investigate neurodegeneration and demyelination in the central and peripheral nervous system in multiple sclerosis linked to disease progression and mechanisms that can explain different responses to Fampridine treatment in MS patients with walking disability.

METHOD The study is a prospective cohort follow-up study with 98 participants with MS and walking disability. Participants are identified as responders or non-responders to Fampridine treatment prior to the study. Participants will undergo MRI of the cerebrum with lesion load quantification, neurophysiological tests comprised of motor evoked potentials and electroneurographic examination, blood samples examining KIR4.1 antibodies, brain derived neurotrophic factor (BDNF), myelin protein zero (MPZ), peripheral myelin protein 22 (PMP22), p75-nerve growth factor receptor (p75NGFR) and anti-myelin associated glycoprotein (anti-MAG). The presence of SORCS-3 gene mutation will also be examined, as will cerebrospinal fluid levels of myelin basic protein, neurofilament heavy and light chains. Functional test of Timed 25-foot walk test (T25FW) will identify response to Fampridine treatment. A functional test battery will further detail function of upper extremities and cognition.

CONCLUSION This study will add to the understanding of neurodegeneration and demyelination in CNS and PNS in patients with MS having walking disability. This will impact clinical decision-making by improving organization of immunomodulatory treatment, identifying biomarkers thus facilitating earlier treatment and improving patient control, information and education.


Condition or disease
Multiple Sclerosis Neurodegeneration Central Nervous System Lesion Peripheral Nervous System Problem Neurologic Deficits Drug Effect Genetic Disease Neurophysiologic Abnormality

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Study Type : Observational
Estimated Enrollment : 82 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Central and Peripheral Nervous System Changes as Markers of Disease Progression in Multiple Sclerosis
Actual Study Start Date : August 1, 2017
Actual Primary Completion Date : June 20, 2020
Estimated Study Completion Date : November 1, 2020

Resource links provided by the National Library of Medicine


Group/Cohort
Responders to Fampridine Treatment
Participants, who are classified as responders to Fampridine treatment, have already been identified in the MS-centers in the Region of Southern Denmark, where they undergo outpatient treatment and clinical controls. A 2-week Fampridine treatment phase, as described in the trial outline section, has been used to identify responders to Fampridine. Participants who improve with ≥20% on the T25FW are categorized as responders.
Non-Responders to Fampridine Treatment
Participants, who are classified as non-responders to Fampridine treatment, have already been identified in the MS-centers in the Region of Southern Denmark, where they undergo outpatient treatment and clinical controls. A 2-week Fampridine treatment phase, as described in the trial outline section, has been used to identify non-responders to Fampridine. Participants who do not improve with ≥20% on the T25FW are categorized as non-responders.



Primary Outcome Measures :
  1. Timed 25-Foot Walk Test (T25FW) [ Time Frame: Baseline up to 6, 12 and 18 months. ]
    The patient walks 25 feet as fast as possible. The test is repeated twice and the mean is used as the test result. This functional test measures walking speed and acceleration. This functional test has a high inter-rater and test-retest reliability and shows evidence of good concurrent validity. Hobart et al. have estimated the MCID for T25FW as an improvement >20% and Jensen et al. have recently estimated it to 17.8% when based on data distribution approach.


Secondary Outcome Measures :
  1. Twelve Item MS Walking Scale (MSWS-12) [ Time Frame: Baseline up to 6, 12 and 18 months. ]
    Questionnaire regarding assessment of walking speed from the perspective of the patient.

  2. Guys Neurological Disability Scale (GNDS) [ Time Frame: Baseline up to 6, 12 and 18 months. ]
    The Guy's Neurological Disability Scale (GNDS) is a clinical disability scale which encompass disabilities seen in multiple sclerosis. It has 12 separate categories which include cognition, mood, vision, speech, swallowing, upper limb function, lower limb function, bladder function, bowel function, sexual function, fatigue, and 'others'.

  3. 5-Times-Sit-to-Stand Test (5-STS) [ Time Frame: Baseline up to 6, 12 and 18 months. ]
    The patient sits on a chair and stands up as fast as possible. This is repeated 5 times. Time stops when the patient has sat down up for the 5th time. This functional test measures strength and balance in lower extremities. The 5-STS shows validity and good test-retest and interobserver reliability. A 25.5% improvement on the 5-STS has been suggested to indicate true change and Jensen et al. have estimated the MCID to be 34.6%.

  4. The Six Spot Step Test (SSST) [ Time Frame: Baseline up to 6, 12 and 18 months. ]
    The patient walks in a crisscross pattern to six wooden markings on the floor as fast as possible while kicking each wooden disc to the side. The test is repeated twice with each leg and the mean is used as the test result. This functional test measures coordination, acceleration, speed and balancing. The re-test reliability and measurement error of the SSST is equally good as the T25FW. However, the sensitivity and discriminatory power of the SSST is better than that of the T25FW. Jensen et al. have estimated an MCID of 16.7%.

  5. Antibodies [ Time Frame: Baseline up to 12 months. ]
    Blood samples will be taken examining blood levels of KIR4.1 antibodies, brain derived neurotrophic factor (BDNF), myelin protein zero (MPZ), peripheral myelin protein 22 (PMP22), p75-nerve growth factor receptor (p75NGFR) and anti-myelin associated glycoprotein (anti-MAG). The aforementioned are know to have a role in (de)myelination in the PNS.

  6. 9-Hole Peg Test (9-HPT) [ Time Frame: Baseline up to 6, 12 and 18 months. ]
    The patient undergoes this test with the dominant upper extremity and afterwards by the non-dominant upper extremity. 9 small pegs are placed into 9 holes and are removed and placed in a bowl as fast as possible. Time stops when the last peg is removed from the hole. The test is repeated twice for each upper limb and the mean is used as the test result for each upper limb. This functional test measures coordination and fine motor skills in the upper extremities. This test has high test-retest reliability. Jensen et al. have estimated an MCID of 15.3%.

  7. Symbol Digit Modalities Test (SDMT) [ Time Frame: Baseline up to 6, 12 and 18 months. ]
    The patient is presented to nine symbols, each representing a number from 0-9. A sheet containing 100 symbols should be paired with the corresponding numbers as fast as possible in 90 seconds. The amount of correct answers is the test result. This functional test measures cognition and more specifically processing speed. SDMT is sensitive for the detection of cognitive deterioration over time and is a reliable test over multiple test-retest intervals. Blum et al. have estimated the MCID for the SDMT as 5.1 arbitrary units (a.u.) and Jensen et al. have estimated an MCID as 17.1% and 6.2 a.u..

  8. MRI of the brain [ Time Frame: Baseline up to 12 months. ]
    MRI with T2-weighted sequences of the brain will be used to estimate the lesion load in the CNS, which will be compared to the clinical neurologic symptoms while serving as a reference to the MRI a year after. The locations of the T2 lesions and lesion load in the CNS will be compared between responders and non-responders to Fampridine treatment.

  9. Neurophysiologic examinations [ Time Frame: Baseline up to 12 months. ]
    MEP, combined with ENG, will be performed in order to investigate nerve conduction in the motor pathways of the CNS and PNS.


Biospecimen Retention:   Samples With DNA
DNA samples from blood for gene testing of the SORCS-3 gene.


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Sampling Method:   Non-Probability Sample
Study Population

Participants in this cohort will be recruited from the four Multiple Sclerosis Centers in the Region of Southern Denmark (Sønderborg, Odense, Vejle/Kolding and Esbjerg), which (as of January 2016) have approximately 3600 patients with MS.

Participants, who are classified as responders to Fampridine treatment, have already been identified in the MS-centers in the Region of Southern Denmark, where they undergo outpatient treatment and clinical controls. A 2-week Fampridine treatment phase, as described in the trial outline section, has been used to identify responders to Fampridine. Participants who improve with ≥20% on the T25FW are categorized as responders.

Criteria

Inclusion Criteria:

  • Participants are diagnosed with MS according to the McDonald criteria.
  • Categorized as responder or non-responder to Fampridine treatment.
  • Age in the range of 18-65 years.
  • Extended Disability Status Scale (EDSS) 4-7 points.
  • Pyramidal Functions Score ≥ 2 in the Kurtzke Functional Systems Scores (FSS).

Exclusion Criteria:

  • MS-attack and/or change in immunomodulatory treatment within 60 days before inclusion.
  • Simultaneous use of medications that inhibit the organic cation transporter (OCT2).
  • History of epileptic seizures.
  • Clinically manifest heart-, liver-, kidney- (glomerular filtration rate < 80 ml/min), pulmonary disease, diabetes, alcohol intake exceeding the National Institute of Health's recommendations and pregnancy.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03401307


Locations
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Denmark
Department of Neurology (Skleroseklinikken), Sygehus Sønderjylland
Sønderborg, Jylland, Denmark, 6400
Sponsors and Collaborators
University of Southern Denmark
Region of Southern Denmark
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Sepehr Mamoei, M.D., Ph.D.-Fellow, University of Southern Denmark
ClinicalTrials.gov Identifier: NCT03401307    
Other Study ID Numbers: SDUSF-2016-106 - (660)
First Posted: January 17, 2018    Key Record Dates
Last Update Posted: July 21, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Multiple Sclerosis
Neurologic Manifestations
Genetic Diseases, Inborn
Sclerosis
Disease Progression
Nerve Degeneration
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Disease Attributes