Safety and Efficacy of Sustained Release Dalfampridine in Transverse Myelitis
Transverse myelitis is an inflammatory disorder of the spinal cord that leads to disabilities of gait. Dalfampridine, a sustained-release potassium channel blocker that has been shown to be effective in improving gait and other neurologic functions in multiple sclerosis. Dalfampridine has the potential to improve gait and neurologic function in patients with transverse myelitis as this rare disorder shares a similar pathogenic process with multiple sclerosis. The investigators propose a clinical trial to test the efficacy of dalfampridine in this particular cohort of patients.
The clinical trial that the investigators propose to conduct will focus on monophasic idiopathic Transverse Myelitis (TM) and will evaluate the efficacy of dalfampridine in primary neurologic outcome, 25-foot timed walk, and several secondary outcomes including valid behavioral and neurophysiological measures. To better understand the mechanisms underlying the proposed behavioral gains, the investigators will use Transcranial Magnetic Stimulation as the neurophysiologic measure to identify changes in corticomotor excitability in the spinal cord.
Drug: Placebo controlled
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
|Official Title:||Phase 3 Double-Blind, Placebo-Controlled Crossover Trial on the Safety and Efficacy of Sustained-Release Dalfampridine in Transverse Myelitis|
- Timed 25-foot walk [ Time Frame: Every 2 weeks for 20 weeks ] [ Designated as safety issue: No ]Timed 25-foot walking trials will be assessed every 2 weeks while on therapy as the primary outcome. The Timed 25 Foot Walk Test is a quantitative measure of lower extremity function.
- Motor evoked potentials [ Time Frame: Once in the first arm, and again in the second arm ] [ Designated as safety issue: No ]This measure will be used as an indicator of the health of the tract in terms of neuronal conduction. To be done at baseline and end of study on a subset of responders.
- Lower extremity muscle strength measurements [ Time Frame: Every 2 weeks for 20 weeks ] [ Designated as safety issue: No ]Lower extremity muscle strength measurements, using a hand held dynamometer
- Expanded Disability Severity Scale [ Time Frame: Every 2 weeks for 20weeks ] [ Designated as safety issue: No ]A standardized measure of disability used commonly in multiple sclerosis and related disorders.
|Study Start Date:||July 2012|
|Estimated Study Completion Date:||December 2013|
|Estimated Primary Completion Date:||July 2013 (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. At the conclusion of this first 10-week trial, subjects will be crossed over to the other therapy for another 8 weeks and 25-foot timed walking assessments will again be made every 2 weeks.
Dalfampridine 10 mg twice daily for 8 weeks
Other Name: Ampyra
Placebo Comparator: Placebo controlled
Placebo controlled arm.
Drug: Placebo controlled
Placebo pill 1 tablet twice daily
Fampridine (4-aminopyridine) is a potassium channel blocker that has been studied since the 1970s for its effect on amplifying conductivity in demyelinated peripheral nerves, potentiating neurotransmitter release in muscles and increasing post-synaptic action potentials in the spinal cord. It was tested in various human neurologic conditions over the next two decades and was found to have a markedly limited therapeutic window due to the stimulation of seizure activity. Interest in fampridine for treatment of multiple sclerosis (MS) stemmed from small case series of patients who found therapeutic benefit in many different neurologic functions including vision, oculomotor function and motor activity. The first randomized, placebo-controlled, double-blinded study of fampridine in MS in 1992 enrolled 70 patients into a cross over study found significant improvements in a number of neurophysiological parameters while on fampridine that were not seen in patients while on placebo. Since then, at least six additional studies on oral fampridine in MS were conducted and found to have some significant benefits in 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, which maintains stable 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 a limited cohort of multiple sclerosis with noted improvements in gait and lower extremity muscle strength. Seizures were only seen in high doses of 30 mg twice daily or more whereas benefits were evident at the now standard 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 the improvement in gait in the responder cohort of patients rather than the entire study population. This method of analysis focused on those who reported some benefit from dalfampridine in an initial 4-week trial period and re-assigned those who did not see benefit to the non-responder group. About 35% of study subjects fell into the responder group and on average, this group improved their walking speed by 25%.
The investigators interest in dalfampridine is focused more narrowly on a subset of patients with a demyelinating disorder that is restricted to the spinal cord. This disorder, transverse myelitis (TM), was not included in any previous human trials of dalfampridine. In contrast to MS, which affects the entire central nervous system, this restricted demyelinating disease affects the spinal cord largely spares the brain and is not associated with an increased risk of seizures. In addition to being a potentially safer cohort of patients for dalfampridine, TM is a more homogenous disease model in which to test the dalfampridine's mechanism of action.
Transverse myelitis, more correctly identified as monophasic idiopathic transverse myelitis is defined as a single episode of inflammation within the spinal 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 and the single lesion is the cause of all of their symptoms. The goal of using dalfampridine in these patients is to amplify axonal conductance across this single lesion that would manifest in improved neurologic function involving the lower extremities including gait. This is the most straightforward proof of concept experimental model proving the mechanism of action of dalfampridine.
|Contact: Maureen Mealy, RNemail@example.com|
|United States, Maryland|
|Johns Hopkins Hospital||Recruiting|
|Baltimore, Maryland, United States, 21287|
|Contact: Maureen Mealy, RN firstname.lastname@example.org|
|Sub-Investigator: Carlos Pardo, MD|
|Sub-Investigator: Kathleen Zackowski, PhD|
|Sub-Investigator: Daniel Becker, MD|
|Principal Investigator:||Michael Levy, MD, PhD||Johns Hopkins University|