Ampyra for Optic Neuritis in MS

Condition(s) targeted: Multiple Sclerosis; Optic Neuritis

Intervention: Dalfampridine/Placebo (Drug); Placebo/Dalfampridine (Drug)

Phase: Phase 2/Phase 3

Status: Recruiting

Sponsored by: Washington University School of Medicine

Official(s) and/or principal investigator(s):
Robert T Naismith, MD, Principal Investigator, Affiliation: Washington University School of Medicine

Overall contact:
Samantha L Lancia, MS, Phone: 314-747-5576, Email: lancias@neuro.wustl.edu

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.

Official title: Dalfampridine After Optic Neuritis to Improve Visual Function in Multiple Sclerosis

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment

Primary outcome: Efficacy of Dalfampridine on visual function (contrast sensitivity).

Secondary outcome:

Dalfampridine reduce visual evoked potential P100 latency.

Dalfampridine improvement in other vision testing (acuity, color, and fields).

Dalfampridine affect on quality of life.

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.

Minimum age: 18 Years. Maximum age: 55 Years. Gender(s): Both.

Criteria:

Inclusion criteria are:

1. At least one previous clinical episode of optic neuritis,

2. the last episode of ON must have occurred at least 12 months prior to study entry,

3. clinically definite MS, defined by the revised McDonald criteria, 23

4. ages 18-55,

5. visual acuity greater than or equal to 20/30 but less than or equal to 20/200,

6. must be able to read at least 2 of the 5 letters on the top line of the 5% ETDRS chart (logMAR 0. 96), and

7. must have sufficient cognitive function to understand the consent process and to reliably perform all clinical assessments

Exclusion criteria are:

1. Any ophthalmologic condition, other than ON, which can affect vision, including nystagmus in primary position of gaze,

2. history of seizures or spells with altered level of consciousness,

3. pregnancy or breast feeding,

4. an MS exacerbation or use of glucocorticoids within 3 months of entry,

5. a history of moderate to severe renal insufficiency,

6. previous use of 4-aminopyridine, in any formulation, in the prior 4 weeks.

Samantha L Lancia, MS, Phone: 314-747-5576, Email: lancias@neuro.wustl.edu

Washington University (John L. Trotter MS Center), St. Louis, Missouri 63110, United States; Recruiting
Samantha L Lancia, MS, Phone: 314-747-5576, Email: lancias@neuro.wustl.edu
Nhial Tutlam, MPH, Phone: 314-362-3402, Email: tutlamn@neuro.wustl.edu
Robert T Naismith, MD, Principal Investigator

John L. Trotter MS Center, Washington University School of Medicine & Barnes Jewish Hosiptal

Related publications:

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Arnold AC. Evolving management of optic neuritis and multiple sclerosis. Am J Ophthalmol. 2005 Jun;139(6):1101-8. Review.

Balcer LJ. Clinical practice. Optic neuritis. N Engl J Med. 2006 Mar 23;354(12):1273-80. Review. No abstract available.

Ma SL, Shea JA, Galetta SL, Jacobs DA, Markowitz CE, Maguire MG, Balcer LJ. Self-reported visual dysfunction in multiple sclerosis: new data from the VFQ-25 and development of an MS-specific vision questionnaire. Am J Ophthalmol. 2002 May;133(5):686-92.

Noble J, Forooghian F, Sproule M, Westall C, O'Connor P. Utility of the National Eye Institute VFQ-25 questionnaire in a heterogeneous group of multiple sclerosis patients. Am J Ophthalmol. 2006 Sep;142(3):464-8.

Mowry EM, Loguidice MJ, Daniels AB, Jacobs DA, Markowitz CE, Galetta SL, Nano-Schiavi ML, Cutter GR, Maguire MG, Balcer LJ. Vision related quality of life in multiple sclerosis: correlation with new measures of low and high contrast letter acuity. J Neurol Neurosurg Psychiatry. 2009 Jul;80(7):767-72. Epub 2009 Feb 23.

Beck RW, Cleary PA, Anderson MM Jr, Keltner JL, Shults WT, Kaufman DI, Buckley EG, Corbett JJ, Kupersmith MJ, Miller NR, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Engl J Med. 1992 Feb 27;326(9):581-8.

[No authors listed] Visual function 5 years after optic neuritis: experience of the Optic Neuritis Treatment Trial. The Optic Neuritis Study Group. Arch Ophthalmol. 1997 Dec;115(12):1545-52.

Cleary PA, Beck RW, Bourque LB, Backlund JC, Miskala PH. Visual symptoms after optic neuritis. Results from the Optic Neuritis Treatment Trial. J Neuroophthalmol. 1997 Mar;17(1):18-23; quiz 24-8.

Goodman AD, Brown TR, Krupp LB, Schapiro RT, Schwid SR, Cohen R, Marinucci LN, Blight AR; Fampridine MS-F203 Investigators. Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial. Lancet. 2009 Feb 28;373(9665):732-8.

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Bever CT Jr, Young D, Anderson PA, Krumholz A, Conway K, Leslie J, Eddington N, Plaisance KI, Panitch HS, Dhib-Jalbut S, et al. The effects of 4-aminopyridine in multiple sclerosis patients: results of a randomized, placebo-controlled, double-blind, concentration-controlled, crossover trial. Neurology. 1994 Jun;44(6):1054-9.

Polman CH, Bertelsmann FW, van Loenen AC, Koetsier JC. 4-aminopyridine in the treatment of patients with multiple sclerosis. Long-term efficacy and safety. Arch Neurol. 1994 Mar;51(3):292-6.

van Diemen HA, Polman CH, van Dongen MM, Nauta JJ, Strijers RL, van Loenen AC, Bertelsmann FW, Koetsier JC. 4-Aminopyridine induces functional improvement in multiple sclerosis patients: a neurophysiological study. J Neurol Sci. 1993 Jun;116(2):220-6.

van Diemen HA, Polman CH, van Dongen TM, van Loenen AC, Nauta JJ, Taphoorn MJ, van Walbeek HK, Koetsier JC. The effect of 4-aminopyridine on clinical signs in multiple sclerosis: a randomized, placebo-controlled, double-blind, cross-over study. Ann Neurol. 1992 Aug;32(2):123-30.

Stefoski D, Davis FA, Fitzsimmons WE, Luskin SS, Rush J, Parkhurst GW. 4-Aminopyridine in multiple sclerosis: prolonged administration. Neurology. 1991 Sep;41(9):1344-8.

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Davis FA, Stefoski D, Rush J. Orally administered 4-aminopyridine improves clinical signs in multiple sclerosis. Ann Neurol. 1990 Feb;27(2):186-92.

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Beck RW, Ruchman MC, Savino PJ, Schatz NJ. Contrast sensitivity measurements in acute and resolved optic neuritis. Br J Ophthalmol. 1984 Oct;68(10):756-9.

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Naismith RT, Tutlam NT, Xu J, Klawiter EC, Shepherd J, Trinkaus K, Song SK, Cross AH. Optical coherence tomography differs in neuromyelitis optica compared with multiple sclerosis. Neurology. 2009 Mar 24;72(12):1077-82.

Naismith RT, Tutlam NT, Xu J, Shepherd JB, Klawiter EC, Song SK, Cross AH. Optical coherence tomography is less sensitive than visual evoked potentials in optic neuritis. Neurology. 2009 Jul 7;73(1):46-52.

Naismith RT, Xu J, Tutlam NT, Trinkaus K, Cross AH, Song SK. Radial diffusivity in remote optic neuritis discriminates visual outcomes. Neurology. 2010 May 25;74(21):1702-10.

Naismith RT, Xu J, Tutlam NT, Scully PT, Trinkaus K, Snyder AZ, Song SK, Cross AH. Increased diffusivity in acute multiple sclerosis lesions predicts risk of black hole. Neurology. 2010 May 25;74(21):1694-701. Erratum in: Neurology. 2010 Sep 7;75(10):938.

Naismith RT, Xu J, Tutlam NT, Snyder A, Benzinger T, Shimony J, Shepherd J, Trinkaus K, Cross AH, Song SK. Disability in optic neuritis correlates with diffusion tensor-derived directional diffusivities. Neurology. 2009 Feb 17;72(7):589-94. Epub 2008 Dec 10.

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Starting date: May 2011
Last updated: May 13, 2011