Neuromyelitis Optica Clinical Trial
Official title:
Double-Blind, Placebo-Controlled Crossover Trial on the Safety and Efficacy of Sustained-Release Dalfampridine in Transverse Myelitis (Re-Launch)
Transverse myelitis (TM) is an inflammatory disorder of the spinal cord that leads to
disabilities of gait. Dalfampridine, a sustained-release potassium inhibitor has been shown
to be effective in improving gait and other neurologic functions in multiple sclerosis.
Dalfampridine has the potential to improve neurologic function in patients with transverse
myelitis as this rare disorder shares a similar pathogenic process with multiple sclerosis.
The in a clinical trial to test the efficacy of dalfampridine in TM.
The clinical trial that the investigators propose to conduct will focus on TM and will
evaluate the dalfampridine in primary neurologic outcome, 25-foot timed walk, and several
secondary outcomes including valid behavioral and neurophysiological tests.
This is a re-launch of the previous trial, which now includes additional behavioral and
clinical testing.
Fampridine (4-aminopyridine) is a potassium channel blocker that has been studied since the
1970s for its effect on amplifying conductivity in peripheral nerves, potentiating
neurotransmitter release in muscles and increasing post-synaptic action potentials in the
spinal cord. It was tested in other neurologic conditions over the next two decades and was
found to have a limited therapeutic window due to the stimulation of seizures at high doses.
The first randomized, placebo-controlled, double-blinded study of fampridine in 70 patients
found significant improvements in a number of neurophysiological parameters while on
fampridine compared to placebo. Since then, at least six additional studies on oral
fampridine in Multiple Sclerosis (MS) were conducted and found to have some significant
neurologic function. Although only a small incidence of seizure or altered mental status were
reported in these studies, the concern about fampridine causing seizures remained a barrier
in the acceptance of fampridine as an MS therapy in the general neurology community.
Recently, Biogen-Idec and Acorda have teamed up in the development of a sustained-release
formulation of fampridine, dalfampridine, in which plasma concentrations of the drug and
avoids toxic doses that lead to seizures. In two clinical trials, dalfampridine has been
shown to be beneficial in two large cohorts of multiple sclerosis patients with noted
improvements in gait and lower extremity muscle strength. Seizures were only seen in high
doses of 20 mg or more whereas benefits were evident at the approved dose of 10 mg twice
daily.
The Food and Drug Administration (FDA) approved dalfampridine for use in multiple sclerosis
in 2009 based on the key study that evaluated gait by timed 25-foot walk. About 35-40% of
study participants responded and this group improved their walking speed by about 20%.
The investigator's interest in dalfampridine is focused more narrowly on a subset of patients
with a demyelinating disorder that is restricted to the spinal cord, transverse myelitis
(TM), was not included in any previous human trials of dalfampridine. In contrast to MS,
which affects the entire system, transverse myelitis affects the spinal cord and largely
spares the brain. It is not associated with an increased risk of seizure.
Transverse myelitis is defined as an episode of inflammation in the spinal cord leading to
disability at the level of the lesion and below. The majority of TM lesions strike the
thoracic cord causing impairments in lower extremities. A single lesion is the cause of all
of their symptoms. The goal of using dalfampridine in these patients is to amplify axonal
conductance across the lesion. This would manifest as improved neurologic function involving
the lower extremities including gait. This is a straightforward proof of concept model
proving the mechanism of action of dalfampridine.
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