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.
|Transverse Myelitis Neuromyelitis Optica Idiopathic Transverse Myelitis Myelitis NOS||Drug: Dalfampridine Drug: Placebo||Phase 2|
|Study Design:||Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Double-Blind, Placebo-Controlled Crossover Trial on the Safety and Efficacy of Sustained-Release Dalfampridine in Transverse Myelitis (Re-Launch)|
- Timed 25-foot walk [ Time Frame: Every 2 weeks for 26 weeks ]Timed 25-foot walking trials will be assessed every 2 weeks while on therapy as the primary outcome. The Timed 25 foot walk is a quantitative measure of lower extremity function.
- Transcranial magnetic stimulation [ Time Frame: Four times over the course of 26 weeks ]This measure will be used as an indicator of the health of the tract in terms of neuronal conduction. To be done at beginning and end of each arm of the study for a total of 4 measures.
- Lower extremity muscle strength measurements [ Time Frame: Four times over the course of 26 weeks ]Lower extremity muscle strength measurements, using a hand held dynamometer, at the beginning and end of each arm.
- Expanded Disability Severity Scale [ Time Frame: Four times over the course of 26 weeks ]A standardized measure of disability used commonly in multiple sclerosis and related disorders done at the beginning and end of each arm.
|Study Start Date:||February 2014|
|Estimated Study Completion Date:||May 2017|
|Primary Completion Date:||November 2016 (Final data collection date for primary outcome measure)|
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 10 mg twice daily for 8 weeks
Other Name: Ampyra
Placebo Comparator: Placebo
Placebo controlled arm.
Placebo pill 1 tablet twice daily for 8 weeks
Other Name: Sugar pill
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 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02166346
|United States, Maryland|
|Johns Hopkins University|
|Baltimore, Maryland, United States, 21287|
|Principal Investigator:||Michael Levy, MD, PhD||Johns Hopkins University|