Clinical trial NCT02166346: Safety and Efficacy of Sustained Release Dalfampridine in Transverse Myelitis (Re-Launch)
Official title: Double-Blind, Placebo-Controlled Crossover Trial on the Safety and Efficacy of Sustained-Release Dalfampridine in Transverse Myelitis (Re-Launch)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Transverse Myelitis
Neuromyelitis Optica
Idiopathic Transverse Myelitis
Myelitis NOS
Keywords: Transverse myelitis
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
Collaborators: name: Acorda Therapeutics
First posted: 2014-06-18
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of transverse myelitis confirmed by MRI
* Gait impairment defined as a baseline timed 25-foot walk of at least 5 seconds and no more than 60 seconds.
* Age 18-70.

Exclusion Criteria:

* Diagnosis of any of the following concurrent conditions: spinal dural arteriovenous malformation, multiple sclerosis, infectious myelitis and recurrent transverse myelitis of any etiology. Subjects with a positive NMO-Immunoglobulin G (IgG) biomarker test will be permitted to join the study as long as the there is only a history of monophasic, and not recurrent, TM.
* History of seizure(s).
* Pregnancy or positive pregnancy test (mandatory test for all women aged 18-55 to be done at first screening visit).
* Known use or allergy to dalfampridine or any other formulation of 4-aminopyridine.
* Patients unable to walk.
* Patients with history of severe alcohol or drug abuse, severe psychiatric illness such as severe depression, poor motivational capacity, or severe language disturbances, particularly of receptive nature or with serious cognitive deficits (defined as equivalent to a mini-mental state exam score of 23 or less).
* Patients with severe uncontrolled medical problems (e.g. hypertension, cardiovascular disease, severe rheumatoid arthritis, active joint deformity of arthritic origin, active cancer or renal disease, any kind of end-stage pulmonary or cardiovascular disease, claudication, uncontrolled epilepsy or others).

Primary outcomes:
measure: Walking Speed During Timed 25-foot Walk
timeFrame: Every 2 weeks during each 8 week intervention
Secondary outcomes:
measure: Upper and Lower Extremity Muscle Strength Measurements
timeFrame: baseline and end (8 weeks) of each intervention
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
Study officials:
affiliation: Johns Hopkins University
name: Michael Levy, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: