Ampyra for Optic Neuritis in Multiple Sclerosis
Condition: Multiple Sclerosis; Optic Neuritis
MeSH terms: Multiple Sclerosis; Neuritis; Optic Neuritis; Sclerosis
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Fifty subjects will be enrolled in this Phase II, investigator-initiated, randomized and
      blinded cross-over trial of dalfampridine of 8 weeks duration The study will test the
      hypothesis that dalfampridine, when administered to subjects with incomplete visual recovery
      after optic neuritis from MS, will result in symptomatic improvement in visual function. The
      study will consist of one screening/baseline visit, one visit during treatment with active
      drug, and one visit on placebo. After the baseline visit, subjects will be randomly assigned
      to receive study medication or placebo for the first three weeks, followed by a two week
      wash-out, and then treatment reallocation for the latter three weeks.
    

Detailed description: 
      Optic neuritis (ON) is the presenting feature of multiple sclerosis (MS) in 15% of cases, and
      occurs over the disease course in 50% of patients.1-3 Vision remains a major concern for MS
      patients, as visual dysfunction leads to lower quality of life.4-6 Despite the high
      prevalence of ON in MS, treatment and management options remain limited. Although intravenous
      glucocorticoids are employed to aid recovery of an acute episode of ON, no convincing
      evidence supports their efficacy in altering the degree of long-term recovery.7 Although some
      individuals with ON can have a dramatic recovery from blindness, ON often impairs visual
      function permanently. In the Optic Neuritis Treatment Trial, 63% reported that vision had not
      returned to normal after 6 months, and 20% had vision worse than 20/20 after 5 years of
      follow-up.8, 9 Visual impairment creates difficulties at home and work, leading to decreased
      independence and impaired mobility within the community. Visual dysfunction in combination
      with MS impairments within cerebellar and proprioceptive systems can be particularly
      disabling.

      Optic neuritis classically impairs one's ability to read print or a computer screen, to drive
      in bright or low light, and to appreciate colors and contrasts. Unfortunately, when optic
      neuritis results in lasting impairment, there are no pharmacologic therapies to restore
      vision. Low vision specialists may provide magnifying glasses, brighter lights, and advice to
      optimize the position of objects at home and in the workplace. Better treatment options are
      needed to improve visual function.

      Ampyra (dalfampridine) is a potassium-channel antagonist, with a mechanism-of-action to
      improve nerve conduction in demyelinated axons, resulting in an electrophysiologic and
      clinical benefit.10-22 Demyelinated axons within the anterior visual pathway would be a prime
      and ideal target to study the effects of Ampyra. In fact, Stefoski et al demonstrated visual
      function benefit in an open-label study of IV 4-aminopyridine in 12 subjects.21 The optic
      nerves are a well-defined white-matter tract, commonly affected in MS, and with clear
      clinical outcome measures. In addition, visual evoked potentials (VEPs) can be included
      within the study design as a secondary endpoint, to confirm improved nerve conduction.
      Because VEPs are such a precise, reliable, and accepted measure of demyelination, the
      anterior visual pathway is the ideal in vivo human system to study the electro-physiologic
      effects of a therapeutic such as Ampyra.

      Hypothesis 1: Dalfampridine treatment will improve visual function, measured by the 5% ETDRS
      contrast sensitivity chart, in subjects with long-term visual impairment secondary to optic
      neuritis from MS.

      Hypothesis 2: Dalfampridine treatment will reduce visual evoked potential P100 latency
      following remote optic neuritis.

      Hypothesis 3: Dalfampridine treatment will result in an improvement in secondary endpoints,
      including visual fields, high contrast visual acuity, color vision, and quality of life.

      The study will be conducted at the Department of Neurology and Neurosurgery, Washington
      University School of Medicine, St. Louis, the institution at which Dr. Naismith is based. The
      MS patients will come from the 1800 active MS patients in our clinic and the 3500 in the St.
      Louis area.

      Fifty subjects will be enrolled in this Phase II, investigator-initiated, randomized and
      blinded cross-over trial of dalfampridine of 8 weeks duration (Table 1). The study will test
      the hypothesis that dalfampridine, when administered to subjects with incomplete visual
      recovery after optic neuritis from MS, will result in symptomatic improvement in visual
      function. The study will consist of one screening/baseline visit, one visit during treatment
      with active drug, and one visit on placebo. After the baseline visit, subjects will be
      randomly assigned to receive study medication or placebo for the first three weeks, followed
      by a two week wash-out, and then treatment reallocation for the latter three weeks.
    

Intervention name(s): Dalfampridine/Placebo; Placebo/Dalfampridine
Intervention type(s): Drug; Drug
Intervention description(s): Weeks 1-3: Dalfampridine 10mg (1 tablet) every 12 hours for 3 weeks. Weeks 4-5: 2 weeks of wash-out. Weeks 5-8: Placebo (sugar pill) 1 tablet every 12 hours for 3 weeks.; Weeks 1-3: Placebo (sugar pill) 1 tablet every 12 hours for 3 weeks. Weeks 4-5: 2 weeks of wash-out. Weeks 6-8: Dalfampridine 10mg (1 tablet) every 12 hours for 3 weeks.
Other intervention name(s): Ampyra (R); Fampridine; Ampyra (R); Fampridine
Intervention MeSH terms: 4-Aminopyridine
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: Multiple Sclerosis; Optic Neuritis; Ampyra; Dalfampridine; Fampridine; Remote Optic Neuritis; Contrast Sensitivity; Treatment