Ignite Creation Date:
2024-05-06 @ 11:00 AM
Last Modification Date:
2024-10-26 @ 12:38 PM
Study NCT ID:
NCT03401307
Status:
COMPLETED
Last Update Posted:
2021-10-14
First Post:
2018-01-04
Brief Title:
Central and Peripheral Nervous System Changes as Markers of Disease Progression in Multiple Sclerosis
Sponsor:
University of Southern Denmark
Organization:
University of Southern Denmark
Study Overview
Official Title:
Central and Peripheral Nervous System Changes as Markers of Disease Progression in Multiple Sclerosis
Status:
COMPLETED
Status Verified Date:
2021-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 KIR41 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
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 KIR41 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
Detailed Description:
BACKGROUND Multiple Sclerosis MS is an autoimmune inflammatory demyelinating disease targeting myelinated axons in the Central Nervous System CNS It is the most common nontraumatic cause of disability in young people Most MS patients are diagnosed between the ages of 20 and 40 years Denmark has a prevalence of approximately 155 MS patients per 100000 inhabitants which is among the highest in the world The etiology of MS is not known however a combination of genetic and environmental factors is likely to be involved in triggering the disease
CLINICAL PRESENTATION MS damages the CNS and causes progressive disability Clinical symptoms of the patient depend on the location of the lesions that can occur anywhere in the CNS Consequently the neurological impairments are very variable and consist of sensory motor visual urinary coordination and cognitive deficits MS is divided into several categories based on disease progression relapse-remitting multiple sclerosis RRMS secondary progressive multiple sclerosis SPMS and primary progressive multiple sclerosis PPMS Clinically isolated syndrome CIS is a single relapse compatible with MS accompanied by paraclinical evidence of demyelination with more than 80 percent of patients with CIS developing MS at a later stage
WORKUP
McDonald criteria are used for diagnosing MS They are based on clinical findings supported by paraclinical tests mentioned below The aim is to demonstrate neurological impairments disseminated in time lesions in the CNS are of different age and localization in the CNS while excluding other conditions
1 Magnetic Resonance Imaging MRI of the brain and spinal cord is used to demonstrate lesions in the CNS
2 Lumbar puncture is performed in order to demonstrate inflammation in the CNS Analysis of the CSF can also exclude infection in the CNS
3 Blood Samples are drawn to assess IgG glucose and albumin in order to assess levels on both sides of the blood brain barrier BBB and to exclude other conditions
4 Evoked Potentials are useful at identifying subclinical lesions
Visual Evoked Potentials VEP assess the anterior visual pathways where delays in latencies indicates demyelination
Somatosensory Evoked Potentials SSEP assess the posterior column of the spinal cord brainstem and somatosensory cortex
OTHER ASPECTS OF CURRENT WORKUP
The other aspects of the workup that are mentioned below are not a part of the established workup on diagnosing or monitoring MS
Blood Samples Currently there are no established peripheral blood biomarkers for MS A study has demonstrated the SORCS3-gene as a potential MS risk gene It has not been evaluated as a peripheral blood biomarker for MS as of yet despite being potentially important in the pathogenesis of MS
Furthermore a study has screened serum samples aiming to identify CNS-specific antibodies in MS
Antibodies to the glial potassium channel KIR41 Inward-rectifier potassium ion channel was present in a subgroup of MS patients while being absent among patients with other neurological conditions and healthy controls
Brain Derived Neurotrophic Factor BDNF is suggested to play a neuroprotective role in MS BDNF concentrations has been shown to be lower in patients with RRMS compared to healthy controls
There are currently biomarkers being indicative of demyelination in the PNS Myelin protein zero MPZ is a cell surface component of myelin which decreases in the tissue when demyelination occurs in the PNS Peripheral myelin protein 22 PMP22 is a glycoprotein component of myelin only found in the PNS where it accounts for 2-5 of the myelin protein content
The P75 nerve growth factor receptor p75 NGFR also known as P75 neurotrophin receptor p75NTR or low-affinity nerve growth factor receptor LNGFR is a ligand which plays a role in Schwann cell migration and myelination during development apoptosis and axonal regeneration Anti-myelin associated glycoprotein Anti-MAG is a myelin marker that is rather specific for the PNS
Neurophysiological tests Motor Evoked Potentials MEP assess the motor pathways by stimulating the precentral gyrus It is valuable in evaluating descending motor pathways PNS and muscles Electroneurographic examination ENG assesses the nerve conduction speed in the PNS and is not usually applied for patients with MS Few studies that have evaluated examining nerve conduction speeds in the PNS among MS patients show that deficits in the PNS may be common among MS patients
TREATMENT
There are three aspects of MS-treatment
1 Immunomodulatory treatment with the aim of reducingpreventing relapses and slowing disease progression Patients who are initiated in immunomodulatory treatment can be classified into two groups responders or non-responders The former profits from treatment while the latter does not respond or has marginal response to treatment Responders can become non-responders after a while Currently the aim of immunomodulatory treatment among MS patients with RRMS is no evidence of disease activity NEDA where the patient has no relapses no increase in disability and no new active lesions on MRI
2 Symptomatic treatment of walking disabilities urinary tract problems pain depression sexual problems spasticity and fatigue Neurorehabilitation is also an important part of the symptomatic treatment
3 Treatment of relapses using high dose corticosteroids
FAMPRIDINE Fampridine AmpyraDalfampridine4-aminopyridine is the first oral agent approved by the Food and Drug Administration FDA and European Medicines Agency EMA for the treatment of walking disability in MS It was approved in 2011 in Denmark for treatment of MS patients with walking disability
Fampridine is a potassiumchannel blocker with a primary mechanism of action of blocking voltage-gated potassium channels It blocks potassium from entering the channel which leads to smoother nerve conduction and a subsequent improved amplitude and duration of the action potential Fampridine acts at both the CNS and PNS and enhances nerve conduction in demyelinated axons and improves walking ability in a subset of MS patients Furthermore a study has demonstrated improvement in cognition and upper extremity functioning as a result of Fampridine treatment Patients who do not profit from Fampridine treatment are classified as non-responders Currently the mechanism behind non-response to Fampridine and conversion from response to non-response has not been studied The functional test of T25FW is widely used to discriminate patients as responders or non-responders as well as to monitor response to treatment with Fampridine When Fampridine treatment is indicated patients will undergo a short-term treatment period while undergoing the T25FW in order to establish if there is response to treatment or non-response If patients are classified as the latter treatment will be stopped During long-term treatment with Fampridine the initial responders are yearly evaluated as to whether they are continuous responders
SUMMARY OF STUDY RATIONALE Walking impairment is one of the most common symptoms of MS and has been reported as one of the most impactful symptoms on quality of life MS patients with walking impairments receive the potassium-channel blocker Fampridine if they respond to this treatment It has been established that approximately 35 of MS patients with walking disabilities are responders to this treatment and thus have improvements in their walking speed and acceleration The response status is established using the functional test T25FW The presence of a specific potassiumchannel antibody KIR 41 has been demonstrated in a subtype of MS patients while being absent in healthy controls Antibodies affecting the PNS and thus aggravating walking abilities have been studied but their links to MS remain to be investigated
MS patients undergo neurodegeneration in the CNS with progressive neurological disability associated with axonal and neuronal damage which is a major contributor to walking impairment The involvement of the PNS in the dysfunction of the lower extremities as well as the role of the PNS as a potential marker of disease progression in MS remains to be fully elucidated The effect of Fampridine in relation to the PNS has also not been examined and the mechanism behind non-response to Fampridine treatment and conversion from response to non-response remains to be elucidated
Consequently the overall research question of the present study proposal is to further clarify disease mechanisms involved in MS Moreover the overall aim of this project is to expand the knowledge on 1 neurodegeneration and demyelination in the central and peripheral nervous system in MS linked to disease progression over time and 2 to examine mechanisms that can explain the different responses to Fampridine treatment Below the specific study aims and hypotheses are outlined
STUDY AIMS
Overall one main study is conducted which has three inherent sub-studies The aims of the main study Central and Peripheral Nervous System Changes as Markers of Disease Progression in Multiple Sclerosis are therefore
1 to investigate the progression-rate and the corresponding changes in patients with MS undertaking Fampridine treatment in regards to a magnetic resonance imaging-verified lesions in the central nervous system and b neurophysiologic examinations of the peripheral nervous system Study I
2 to investigate the response of potential peripheral blood biomarkers to Fampridine treatment in patients with MS Study II
3 to compare motor pathways in the central nervous system and peripheral nervous system in patients with MS who are responders to non-responders of Fampridine treatment
Null hypotheses are
Over time among MS patients there is neurodegeneration in the central nervous system while there is no neurodegeneration in the peripheral nervous system
There is no difference in biomarkers of the CNS and the PNS in MS patients
There are no differences in the motor pathways of the central and peripheral nervous system in patients with MS who respond and do not respond to treatment with Fampridine
Responders to Fampridine treatment do not convert to non-responders over time
Participants will undergo MRI blood samples neurophysiologic examinations and the functional testing as described in the trial outline section in order to evaluate response to treatment with Fampridine and markers of disease progression In addition to the widely used T25FW additional functional tests will also be performed to have a more detailed overview of the function of the lower and upper extremities while also examining cognition over time The T25FW test will also be used for identification of responders to treatment with Fampridine
CLINICAL PRESENTATION MS damages the CNS and causes progressive disability Clinical symptoms of the patient depend on the location of the lesions that can occur anywhere in the CNS Consequently the neurological impairments are very variable and consist of sensory motor visual urinary coordination and cognitive deficits MS is divided into several categories based on disease progression relapse-remitting multiple sclerosis RRMS secondary progressive multiple sclerosis SPMS and primary progressive multiple sclerosis PPMS Clinically isolated syndrome CIS is a single relapse compatible with MS accompanied by paraclinical evidence of demyelination with more than 80 percent of patients with CIS developing MS at a later stage
WORKUP
McDonald criteria are used for diagnosing MS They are based on clinical findings supported by paraclinical tests mentioned below The aim is to demonstrate neurological impairments disseminated in time lesions in the CNS are of different age and localization in the CNS while excluding other conditions
1 Magnetic Resonance Imaging MRI of the brain and spinal cord is used to demonstrate lesions in the CNS
2 Lumbar puncture is performed in order to demonstrate inflammation in the CNS Analysis of the CSF can also exclude infection in the CNS
3 Blood Samples are drawn to assess IgG glucose and albumin in order to assess levels on both sides of the blood brain barrier BBB and to exclude other conditions
4 Evoked Potentials are useful at identifying subclinical lesions
Visual Evoked Potentials VEP assess the anterior visual pathways where delays in latencies indicates demyelination
Somatosensory Evoked Potentials SSEP assess the posterior column of the spinal cord brainstem and somatosensory cortex
OTHER ASPECTS OF CURRENT WORKUP
The other aspects of the workup that are mentioned below are not a part of the established workup on diagnosing or monitoring MS
Blood Samples Currently there are no established peripheral blood biomarkers for MS A study has demonstrated the SORCS3-gene as a potential MS risk gene It has not been evaluated as a peripheral blood biomarker for MS as of yet despite being potentially important in the pathogenesis of MS
Furthermore a study has screened serum samples aiming to identify CNS-specific antibodies in MS
Antibodies to the glial potassium channel KIR41 Inward-rectifier potassium ion channel was present in a subgroup of MS patients while being absent among patients with other neurological conditions and healthy controls
Brain Derived Neurotrophic Factor BDNF is suggested to play a neuroprotective role in MS BDNF concentrations has been shown to be lower in patients with RRMS compared to healthy controls
There are currently biomarkers being indicative of demyelination in the PNS Myelin protein zero MPZ is a cell surface component of myelin which decreases in the tissue when demyelination occurs in the PNS Peripheral myelin protein 22 PMP22 is a glycoprotein component of myelin only found in the PNS where it accounts for 2-5 of the myelin protein content
The P75 nerve growth factor receptor p75 NGFR also known as P75 neurotrophin receptor p75NTR or low-affinity nerve growth factor receptor LNGFR is a ligand which plays a role in Schwann cell migration and myelination during development apoptosis and axonal regeneration Anti-myelin associated glycoprotein Anti-MAG is a myelin marker that is rather specific for the PNS
Neurophysiological tests Motor Evoked Potentials MEP assess the motor pathways by stimulating the precentral gyrus It is valuable in evaluating descending motor pathways PNS and muscles Electroneurographic examination ENG assesses the nerve conduction speed in the PNS and is not usually applied for patients with MS Few studies that have evaluated examining nerve conduction speeds in the PNS among MS patients show that deficits in the PNS may be common among MS patients
TREATMENT
There are three aspects of MS-treatment
1 Immunomodulatory treatment with the aim of reducingpreventing relapses and slowing disease progression Patients who are initiated in immunomodulatory treatment can be classified into two groups responders or non-responders The former profits from treatment while the latter does not respond or has marginal response to treatment Responders can become non-responders after a while Currently the aim of immunomodulatory treatment among MS patients with RRMS is no evidence of disease activity NEDA where the patient has no relapses no increase in disability and no new active lesions on MRI
2 Symptomatic treatment of walking disabilities urinary tract problems pain depression sexual problems spasticity and fatigue Neurorehabilitation is also an important part of the symptomatic treatment
3 Treatment of relapses using high dose corticosteroids
FAMPRIDINE Fampridine AmpyraDalfampridine4-aminopyridine is the first oral agent approved by the Food and Drug Administration FDA and European Medicines Agency EMA for the treatment of walking disability in MS It was approved in 2011 in Denmark for treatment of MS patients with walking disability
Fampridine is a potassiumchannel blocker with a primary mechanism of action of blocking voltage-gated potassium channels It blocks potassium from entering the channel which leads to smoother nerve conduction and a subsequent improved amplitude and duration of the action potential Fampridine acts at both the CNS and PNS and enhances nerve conduction in demyelinated axons and improves walking ability in a subset of MS patients Furthermore a study has demonstrated improvement in cognition and upper extremity functioning as a result of Fampridine treatment Patients who do not profit from Fampridine treatment are classified as non-responders Currently the mechanism behind non-response to Fampridine and conversion from response to non-response has not been studied The functional test of T25FW is widely used to discriminate patients as responders or non-responders as well as to monitor response to treatment with Fampridine When Fampridine treatment is indicated patients will undergo a short-term treatment period while undergoing the T25FW in order to establish if there is response to treatment or non-response If patients are classified as the latter treatment will be stopped During long-term treatment with Fampridine the initial responders are yearly evaluated as to whether they are continuous responders
SUMMARY OF STUDY RATIONALE Walking impairment is one of the most common symptoms of MS and has been reported as one of the most impactful symptoms on quality of life MS patients with walking impairments receive the potassium-channel blocker Fampridine if they respond to this treatment It has been established that approximately 35 of MS patients with walking disabilities are responders to this treatment and thus have improvements in their walking speed and acceleration The response status is established using the functional test T25FW The presence of a specific potassiumchannel antibody KIR 41 has been demonstrated in a subtype of MS patients while being absent in healthy controls Antibodies affecting the PNS and thus aggravating walking abilities have been studied but their links to MS remain to be investigated
MS patients undergo neurodegeneration in the CNS with progressive neurological disability associated with axonal and neuronal damage which is a major contributor to walking impairment The involvement of the PNS in the dysfunction of the lower extremities as well as the role of the PNS as a potential marker of disease progression in MS remains to be fully elucidated The effect of Fampridine in relation to the PNS has also not been examined and the mechanism behind non-response to Fampridine treatment and conversion from response to non-response remains to be elucidated
Consequently the overall research question of the present study proposal is to further clarify disease mechanisms involved in MS Moreover the overall aim of this project is to expand the knowledge on 1 neurodegeneration and demyelination in the central and peripheral nervous system in MS linked to disease progression over time and 2 to examine mechanisms that can explain the different responses to Fampridine treatment Below the specific study aims and hypotheses are outlined
STUDY AIMS
Overall one main study is conducted which has three inherent sub-studies The aims of the main study Central and Peripheral Nervous System Changes as Markers of Disease Progression in Multiple Sclerosis are therefore
1 to investigate the progression-rate and the corresponding changes in patients with MS undertaking Fampridine treatment in regards to a magnetic resonance imaging-verified lesions in the central nervous system and b neurophysiologic examinations of the peripheral nervous system Study I
2 to investigate the response of potential peripheral blood biomarkers to Fampridine treatment in patients with MS Study II
3 to compare motor pathways in the central nervous system and peripheral nervous system in patients with MS who are responders to non-responders of Fampridine treatment
Null hypotheses are
Over time among MS patients there is neurodegeneration in the central nervous system while there is no neurodegeneration in the peripheral nervous system
There is no difference in biomarkers of the CNS and the PNS in MS patients
There are no differences in the motor pathways of the central and peripheral nervous system in patients with MS who respond and do not respond to treatment with Fampridine
Responders to Fampridine treatment do not convert to non-responders over time
Participants will undergo MRI blood samples neurophysiologic examinations and the functional testing as described in the trial outline section in order to evaluate response to treatment with Fampridine and markers of disease progression In addition to the widely used T25FW additional functional tests will also be performed to have a more detailed overview of the function of the lower and upper extremities while also examining cognition over time The T25FW test will also be used for identification of responders to treatment with Fampridine
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None