Safety and Efficacy of Sustained Release Dalfampridine in Transverse Myelitis

Transverse Myelitis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01446575
• Other study ID #: Ampyra-TM-1
• Status: Terminated
• Phase: Phase 4
• First received: September 27, 2011
• Last updated: April 16, 2015
• Start date: July 2012
• Est. completion date: November 2013

Study information

• Verified date: April 2015
• Source: Johns Hopkins University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 6
• Est. completion date: November 2013
• Est. primary completion date: November 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

1. Diagnosis of idiopathic transverse myelitis confirmed by MRI

2. Age 18-70

Exclusion Criteria:

1. Diagnosis of any other recurrent CNS disease including, but not limited to, multiple sclerosis, recurrent myelitis, or neuromyelitis optica.

2. History of seizure(s).

3. Pregnancy or positive pregnancy test (mandatory test for all women aged 18-55 to be done at first screening visit).

4. Known allergy to dalfampridine or any other formulation of 4-aminopyridine.

5. Patients unable to walk.

6. Patients with history of severe alcohol or drug abuse, severe psychiatric illness like 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).

7. 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).

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Myelitis
• Myelitis, Transverse
• Transverse Myelitis

Intervention

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

Locations

Country	Name	City	State
United States	Johns Hopkins Hospital	Baltimore	Maryland

Sponsors (2)

Lead Sponsor	Collaborator
Johns Hopkins University	Acorda Therapeutics

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Timed 25-foot walk	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.	Every 2 weeks for 24 weeks	No
Secondary	Transcranial magnetic stimulation	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 during each arm of the study for a total of 3 measures.	Three times over the course of 24 weeks	No
Secondary	Lower extremity muscle strength measurements	Lower extremity muscle strength measurements, using a hand held dynamometer	Every 6 weeks for 24 weeks	No
Secondary	Expanded Disability Severity Scale	A standardized measure of disability used commonly in multiple sclerosis and related disorders.	Every 6 weeks for 24 weeks	No