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Phase 3 Double-Blind, Placebo-Controlled Crossover Trial on the Safety and Efficacy of Sustained-Release Dalfampridine in Transverse Myelitis

Phase 4
18 Years
65 Years
Open (Enrolling)
Transverse Myelitis

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Trial Information

Phase 3 Double-Blind, Placebo-Controlled Crossover Trial on the Safety and Efficacy of Sustained-Release Dalfampridine in Transverse Myelitis

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.

Inclusion Criteria:

1. Diagnosis of idiopathic transverse myelitis confirmed by MRI

2. Age 18-65

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).

Type of Study:


Study Design:

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

Outcome Measure:

Timed 25-foot walk

Outcome Description:

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.

Outcome Time Frame:

Every 2 weeks for 20 weeks

Safety Issue:


Principal Investigator

Michael Levy, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Johns Hopkins University


United States: Institutional Review Board

Study ID:




Start Date:

July 2012

Completion Date:

December 2013

Related Keywords:

  • Transverse Myelitis
  • Transverse myelitis
  • Myelitis
  • Myelitis, Transverse



Johns Hopkins HospitalBaltimore, Maryland  21287