Central and Peripheral Nervous System Changes as Markers of Disease Progression in Multiple Sclerosis
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|ClinicalTrials.gov Identifier: NCT03401307|
Recruitment Status : Active, not recruiting
First Posted : January 17, 2018
Last Update Posted : July 21, 2020
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|
|Study Type :||Observational|
|Estimated Enrollment :||82 participants|
|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|
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.
- 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.
- 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.
- 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'.
- 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%.
- 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%.
- 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.
- 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%.
- 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..
- 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.
- 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
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Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03401307
|Department of Neurology (Skleroseklinikken), Sygehus Sønderjylland|
|Sønderborg, Jylland, Denmark, 6400|