Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03401307 |
| Other study ID # |
SDUSF-2016-106 - (660) |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
August 1, 2017 |
| Est. completion date |
December 1, 2020 |
Study information
| Verified date |
October 2021 |
| Source |
University of Southern Denmark |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial 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.
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
100,000 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 KIR4.1 (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 reducing/preventing 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 (Ampyra/Dalfampridine/4-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 4.1) 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.
