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Neuromyelitis Optica

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Myelitis, Transverse

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Neuromyelitis Optica Spectrum Disorder

Transverse Myelitis

Channel Blockers

All Drugs and Chemicals

4-Aminopyridine

Potassium Channel Blockers

All subjects were randomized for the first double-blinded 8-week part of the study to the dalfampridine group. Then subjects were crossed over to the placebo arm for another 8 weeks.

All subjects were randomized for the first double-blinded 8-week part of the study to the placebo arm. Then subjects were crossed over to the dalfampridine arm for another 8 weeks.

Dalfampridine 10 mg twice daily for 8 weeks

Dalfampridine

Placebo pill 1 tablet twice daily for 8 weeks

Placebo

Michael Levy, MD, PhD

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.

Safety and Efficacy of Sustained Release Dalfampridine in Transverse Myelitis (Re-Launch)

Double-Blind, Placebo-Controlled Crossover Trial on the Safety and Efficacy of Sustained-Release Dalfampridine in Transverse Myelitis (Re-Launch)

In this cross-over study, walking speed was recorded 4 times for each subject while in both the dalfampridine and placebo arms. The results average all of the times while on damfampridine and compares them to the average of the times while on placebo.

Upper and lower extremity muscle strength measurements, using a hand held dynamometer, at the beginning and end of each arm. Change in muscle strength between baseline and end (8 weeks) of each intervention are provided.

Acorda Therapeutics

Johns Hopkins University

All subjects will be randomized for the first double-blinded 8-week part of the study with 25-foot timed walking assessments every 2 weeks. Then subjects will be crossed over to the other therapy (drug or placebo) for another 8 weeks.

Dalfampridine: Dalfampridine 10 mg twice daily for 8 weeks

Placebo controlled arm.

Placebo: Placebo pill 1 tablet twice daily for 8 weeks

This is a crossover trial. At baseline prior to randomization into an intervention, the baseline measures are provided.

Whole Study Population

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Duration of Disease

In this scale, 0 is normal and 10 is dead. Additional information can be found here: https://www.mstrust.org.uk/a-z/expanded-disability-status-scale-edss

Expanded Disability Status Scale score

Lesion location within spinal cord

Vertebral length is defined as the number of vertebrae between the top of the T2 hyper intense lesion by MRI and the bottom of the lesion visualized on the middle sagittal section.

Lesion length by MRI

24 participants consented, 8 were excluded = 16 enrolled. Of the 16 enrollees, 3 withdrew = 13 completers.

Michael Levy, Principal Investigator

Change from baseline to 2 weeks

Change from baseline to 4 weeks

Change from baseline to 6 weeks

Change from baseline to 8 weeks

Walking Speed During Timed 25-foot Walk

Supine Left Hip Flexor

Supine Right Hip Flexor

Prone Left Hip Flexor

Prone Right Hip Flexor

Left Grip

Right Grip

Upper and Lower Extremity Muscle Strength Measurements

All subjects were randomized for the first double-blinded 8-week part of the study to the dalfampridine group. Then subjects were crossed over to the placebo arm for another 8 weeks.

Dalfampridine: Dalfampridine 10 mg twice daily for 8 weeks Placebo: Placebo pill 1 tablet twice daily for 8 weeks

Dalfampridine Then Placebo

All subjects were randomized for the first double-blinded 8-week part of the study to the placebo arm. Then subjects were crossed over to the dalfampridine arm for another 8 weeks.

Placebo: Placebo pill 1 tablet twice daily for 8 weeks Dalfampridine: Dalfampridine 10 mg twice daily for 8 weeks

Placebo Then Dalfampridine

Screening and Randomization

Intervention - Phase 1

Intervention - Phase 2 (After Crossover)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Safety and Efficacy of Sustained Release Dalfampridine in Transverse Myelitis (Re-Launch)	NCT02166346	Transverse Myel... Neuromyelitis O... Idiopathic Tran... Myelitis NOS	Dalfampridine Placebo	18 Years - 70 Years	Johns Hopkins University
Safety and Efficacy of Sustained Release Dalfampridine in Transverse Myelitis (Re-Launch)	NCT02166346	Transverse Myel... Neuromyelitis O... Idiopathic Tran... Myelitis NOS	Dalfampridine Placebo	18 Years - 70 Years	Johns Hopkins University
Safety and Efficacy of Sustained Release Dalfampridine in Transverse Myelitis (Re-Launch)	NCT02166346	Transverse Myel... Neuromyelitis O... Idiopathic Tran... Myelitis NOS	Dalfampridine Placebo	18 Years - 70 Years	Johns Hopkins University

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