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| ID | Type | Description | Link |
|---|---|---|---|
| WU HRPO# : 201104126 | Other Identifier | Washington University HRPO |
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| Name | Class |
|---|---|
| Acorda Therapeutics | INDUSTRY |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group B: Dalfampridine First | Active Comparator | Dalfampridine/Placebo: 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. |
|
| Group A: Dalfampridine Second | Active Comparator | Placebo/Dalfampridine: 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 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dalfampridine/Placebo | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Efficacy of Dalfampridine on Visual Function by Early Diabetic Treatment Retinopathy Study (EDTRS) 5% Contrast Sensitivity Scores | Per Protocol Analysis to assess differences in EDTRS 5% Contrast Sensitivity (LogMAR) Scores at visits 2 and 3 Relative to Visit 1 on patients taking Dalfampridine vs Placebo. | Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8) |
| Efficacy of Dalfampridine on Visual Function Assessed by Change From Baseline in Raw Letters by EDTRS 5% Contrast Sensitivity | Per Protocol Analysis to assess difference in number of letters on the EDTRS 5% Contrast Sensitivity (LogMAR) Chart scores at visits 2 and 3 Relative to Visit 1 | Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8) |
| Difference in EDTRS 5% Contrast Sensitivity (LogMAR Score) at Visits 2 and 3 Relative to Visit 1 | Intent to treat analysis of treatment effect in primary endpoint EDTRS 5% Contrast Sensitivity. Improvement from baseline scores. | Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8) |
| Change From Baseline in Raw Letters by EDTRS 5% Contrast Sensitivity | Intent to treat analysis of treatment effect in primary endpoint EDTRS 5% Contrast Sensitivity. Change in the number of letters able to read while on Dalfampridine and Placebo relative to their baseline scores. | Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8) |
| Measure | Description | Time Frame |
|---|---|---|
| Percentage of Eyes That Improved by 2 Lines (10 Letters) on the Sloan 5% Contrast Sensitivity Chart | Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8) | |
| Percentage of Eyes That Improved by One-line (5 Letters) | Percentage of eyes that improved by one-line (5 letters) on the 5% contrast sensitivity chart |
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Inclusion criteria are:
Exclusion criteria are:
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| Name | Affiliation | Role |
|---|---|---|
| Robert T Naismith, MD | Washington University School of Medicine | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Washington University (John L. Trotter MS Center) | St Louis | Missouri | 63110 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 15664543 | Background | Frohman EM, Frohman TC, Zee DS, McColl R, Galetta S. The neuro-ophthalmology of multiple sclerosis. Lancet Neurol. 2005 Feb;4(2):111-21. doi: 10.1016/S1474-4422(05)00992-0. | |
| 15953446 | Background | Arnold AC. Evolving management of optic neuritis and multiple sclerosis. Am J Ophthalmol. 2005 Jun;139(6):1101-8. doi: 10.1016/j.ajo.2005.01.031. |
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Patients whose vision did not meet study criteria at the first visit in the affected eye or who had had steroids within 3 months of study entry were considered screen failures (n =7).Treatment group was randomly assigned by the pharmacist using a randomization table generated by a probability model.
Subjects were recruited from the John L Trotter Multiple Sclerosis (MS) Clinic at Washington University and through email blasts from the Gateway (St. Louis) MS Chapter. 53 participants meet the pre-screening criteria and signed an informed consent to be screened for the study.
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| ID | Title | Description |
|---|---|---|
| FG000 | Group B: Dalfampridine/Placebo | Dalfampridine/Placebo: 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. |
| FG001 | Group A: Placebo/Dalfampridine | Placebo/Dalfampridine: 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. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
All patients that were randomized and included in the per-protocol analysis (compliantly completed 3 visits on assigned treatment).
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| ID | Title | Description |
|---|---|---|
| BG000 | Group B: Dalfampridine/Placebo | Dalfampridine/Placebo: 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. |
| BG001 | Group A: Placebo/Dalfampridine |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Efficacy of Dalfampridine on Visual Function by Early Diabetic Treatment Retinopathy Study (EDTRS) 5% Contrast Sensitivity Scores | Per Protocol Analysis to assess differences in EDTRS 5% Contrast Sensitivity (LogMAR) Scores at visits 2 and 3 Relative to Visit 1 on patients taking Dalfampridine vs Placebo. | Per protocol analysis | Posted | Mean | Standard Deviation | LogMAR Score | Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8) | eligible eyes | eligible eyes |
|
8 weeks
Only unexpected and and reasonably related events were recorded. Adverse events related to known side effects of dalfampridine (listed in the package insert) or the patients prior medical history are not recorded. There were no events that warranted modification to the consent for the duration of the study. All adverse events (four) occurred while taking dalfmapridine during this cross-over study.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Dalfampridine | Participants assigned to received dalfampridine. | 0 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dizziness | Nervous system disorders | CTCAE (3.0) | Non-systematic Assessment |
Pilot study with relatively small number of patients compared to a phase III study. Cross-over design may be inferior to placebo-controlled parallel cohort study.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Robert Naismith, MD | Washington Univerisity St. Louis | 314-747-5576 | naismithr@wustl.edu |
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| ID | Term |
|---|---|
| D009103 | Multiple Sclerosis |
| D009902 | Optic Neuritis |
| ID | Term |
|---|---|
| D020278 | Demyelinating Autoimmune Diseases, CNS |
| D020274 | Autoimmune Diseases of the Nervous System |
| D009422 | Nervous System Diseases |
| D003711 | Demyelinating Diseases |
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| ID | Term |
|---|---|
| D015761 | 4-Aminopyridine |
| ID | Term |
|---|---|
| D000631 | Aminopyridines |
| D000588 | Amines |
| D009930 | Organic Chemicals |
| D011725 | Pyridines |
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|
| Placebo/Dalfampridine | Drug | 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. |
|
|
| Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8) |
| Visual Evoked Potential P100 Latency Per Treatment Arm | Visual evoked potential 60min P100 latency on dalfampridine vs. placebo. | Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8) |
| Odds Ratio Quartile of Visual Field Index | The Visual Field Index (VFI) is a global index that assigns a number between 1% to 100% based on an aggregate percentage of visual function, with 100% being a perfect age-adjusted visual field. Probability of falling in the best quartile for visual field (VFI) measures (Q1), relative to the three next quartiles for worse VFIs (Q2-4), while on Dalfampridine vs Placebo. Due to the clustered observations at different times in a cross-over design, the visual field data is not suited to a normal theory model and should not be expressed as a continuous variable. Thus, a categorical model that uses a multinomial distribution for measurement of 4 categories was selected for proper statistical modeling, with results expressed as odds ratios. | Visit 1 (Week 0 - baseline), Visit 2 (Week 3 - post intervention 1) and Visit 3 (Week 8 - post intervention 2) |
| Changes in Color Vision Total Error Score From Baseline Based Upon the Farnsworth Munsell Hue 100 Sort Test (FM100). | Dalfampridine will change color vision Total Error Scores from baseline on the Farnsworth Munsell 100 Hue Sort Test. Farnsworth Munsell 100 Hue Test requires placing 100 color palettes in the correct order based upon color hue. Scores are determined by the frequency and severity of any displacement in the correct order. One error equates to one misplaced hue, by one step or position. An error score greater than 500 indicates virtually no color discrimination. An error score of 0 indicates no errors in ordering the hues. A Total Error Score of 0 to 128 could be seen in a normal population. | Visit 1 (Week 0 - baseline), Visit 2 (Week 3 - postintervention 1) and Visit 3 (Week 8 - post intervention 2) |
| Dalfampridine Effect on Quality of Life Change From Baseline. | Dalfampridine treatment will result in change in quality of life. The National Eye Institute Visual Function Questionnaire consists of 25 questions characterizing visual function at home and in the community. Score ranges from 100 (best) to 0 (worst). | Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8) |
| Difference in Pelli- Robson Score at Visits 2 and 3 Relative to Visit 1 | Difference in Pelli- Robson Score at Visits 2 and 3 Relative to Visit 1 on Dalfampridine vs Placebo. Pelli-Robson is scored based upon the numbers read on the chart converted to LogMAR units. The scale is 0.00 (worst) to 2.35 (best). | Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8) |
| 16554529 | Background | Balcer LJ. Clinical practice. Optic neuritis. N Engl J Med. 2006 Mar 23;354(12):1273-80. doi: 10.1056/NEJMcp053247. No abstract available. |
| 11992867 | Background | 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. doi: 10.1016/s0002-9394(02)01337-5. |
| 16935592 | Background | 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. doi: 10.1016/j.ajo.2006.04.051. |
| 19240050 | Background | 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. doi: 10.1136/jnnp.2008.165449. Epub 2009 Feb 23. |
| 1734247 | Background | 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. doi: 10.1056/NEJM199202273260901. |
| 9400788 | Background | 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. |
| 9093956 | Background | 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. doi: 10.1016/s0002-9394(14)70814-1. |
| 19249634 | Background | 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. doi: 10.1016/S0140-6736(09)60442-6. |
| 9700711 | Background | Fujihara K, Miyoshi T. The effects of 4-aminopyridine on motor evoked potentials in multiple sclerosis. J Neurol Sci. 1998 Jul 15;159(1):102-6. doi: 10.1016/s0022-510x(98)00143-9. |
| 9109861 | Background | Schwid SR, Petrie MD, McDermott MP, Tierney DS, Mason DH, Goodman AD. Quantitative assessment of sustained-release 4-aminopyridine for symptomatic treatment of multiple sclerosis. Neurology. 1997 Apr;48(4):817-21. doi: 10.1212/wnl.48.4.817. |
| 7755367 | Background | Davis FA, Stefoski D, Quandt FN. Mechanism of action of 4-aminopyridine in the symptomatic treatment of multiple sclerosis. Ann Neurol. 1995 May;37(5):684. doi: 10.1002/ana.410370524. No abstract available. |
| 8208399 | Background | 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. doi: 10.1212/wnl.44.6.1054. |
| 8129642 | Background | 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. doi: 10.1001/archneur.1994.00540150090022. |
| 8336169 | Background | 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. doi: 10.1016/0022-510x(93)90329-w. |
| 1510353 | Background | 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. doi: 10.1002/ana.410320203. |
| 1891078 | Background | 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. doi: 10.1212/wnl.41.9.1344. |
| 2082971 | Background | Polman CH, van Diemen HA, van Dongen MM, Koetsier JC, van Loenen AC, van Walbeek HK. 4-Aminopyridine in multiple sclerosis. Ann Neurol. 1990 Oct;28(4):589. doi: 10.1002/ana.410280421. No abstract available. |
| 2317014 | Background | Davis FA, Stefoski D, Rush J. Orally administered 4-aminopyridine improves clinical signs in multiple sclerosis. Ann Neurol. 1990 Feb;27(2):186-92. doi: 10.1002/ana.410270215. |
| 16283615 | Background | Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz LM, McFarland HF, O'Connor PW, Sandberg-Wollheim M, Thompson AJ, Weinshenker BG, Wolinsky JS. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol. 2005 Dec;58(6):840-6. doi: 10.1002/ana.20703. |
| 6631441 | Background | Jones RE, Heron JR, Foster DH, Snelgar RS, Mason RJ. Effects of 4-aminopyridine in patients with multiple sclerosis. J Neurol Sci. 1983 Aug-Sep;60(3):353-62. doi: 10.1016/0022-510x(83)90145-4. |
| 19922891 | Background | Vollmer T, Henney HR 3rd. Pharmacokinetics and tolerability of single escalating doses of fampridine sustained-release tablets in patients with multiple sclerosis: a Phase I-II, open-label trial. Clin Ther. 2009 Oct;31(10):2206-14. doi: 10.1016/j.clinthera.2009.10.008. |
| 19922892 | Background | Vollmer T, Blight AR, Henney HR 3rd. Steady-state pharmacokinetics and tolerability of orally administered fampridine sustained-release 10-mg tablets in patients with multiple sclerosis: a 2-week, open-label, follow-up study. Clin Ther. 2009 Oct;31(10):2215-23. doi: 10.1016/j.clinthera.2009.10.007. |
| 6477856 | Background | 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. doi: 10.1136/bjo.68.10.756. |
| 8610798 | Background | Trobe JD, Beck RW, Moke PS, Cleary PA. Contrast sensitivity and other vision tests in the optic neuritis treatment trial. Am J Ophthalmol. 1996 May;121(5):547-53. doi: 10.1016/s0002-9394(14)75429-7. |
| Background | Farnsworth D. The Farnsworth-Munsell 100-hue and dichotomous tests for color vision. J Opt Soc Am 1943;33:568-574. |
| 19307541 | Background | 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. doi: 10.1212/01.wnl.0000345042.53843.d5. |
| 19564583 | Background | 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. doi: 10.1212/WNL.0b013e3181aaea32. |
| 20498438 | Background | 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. doi: 10.1212/WNL.0b013e3181e0434d. |
| 20498437 | Background | 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. doi: 10.1212/WNL.0b013e3181e042c4. |
| 19073948 | Background | 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. doi: 10.1212/01.wnl.0000335766.22758.cd. Epub 2008 Dec 10. |
| 19667226 | Background | Naismith RT, Shepherd JB, Weihl CC, Tutlam NT, Cross AH. Acute and bilateral blindness due to optic neuropathy associated with copper deficiency. Arch Neurol. 2009 Aug;66(8):1025-7. doi: 10.1001/archneurol.2009.70. |
| 9373488 | Background | Vanden Bosch ME, Wall M. Visual acuity scored by the letter-by-letter or probit methods has lower retest variability than the line assignment method. Eye (Lond). 1997;11 ( Pt 3):411-7. doi: 10.1038/eye.1997.87. |
| Background | Acorda Therapeutics. AMPRYA package insert (2010). |
| Protocol Violation |
|
Placebo/Dalfampridine: 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. |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| MS Subtype | Number | participants |
|
| Clinical Episodes of ON | Median | Full Range | Number of episodes |
|
| Baseline 5% Sloan Chart | Median | Full Range | Number of Letters |
|
Dalfampridine/Placebo: 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. |
| OG002 | Group A: Placebo | Placebo/Dalfampridine: 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. |
| OG003 | Group A: Dalfampridine | Placebo/Dalfampridine: 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. |
|
|
|
| Primary | Efficacy of Dalfampridine on Visual Function Assessed by Change From Baseline in Raw Letters by EDTRS 5% Contrast Sensitivity | Per Protocol Analysis to assess difference in number of letters on the EDTRS 5% Contrast Sensitivity (LogMAR) Chart scores at visits 2 and 3 Relative to Visit 1 | Per protocol analysis | Posted | Mean | Standard Deviation | letters | Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8) | eligible eyes | eligible eyes |
|
|
|
| Primary | Difference in EDTRS 5% Contrast Sensitivity (LogMAR Score) at Visits 2 and 3 Relative to Visit 1 | Intent to treat analysis of treatment effect in primary endpoint EDTRS 5% Contrast Sensitivity. Improvement from baseline scores. | Intent To Treat Population, scores from morning and afternoon were averaged. | Posted | Mean | Standard Deviation | 5% Contrast LogMAR Score | Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8) |
|
|
|
|
| Secondary | Percentage of Eyes That Improved by 2 Lines (10 Letters) on the Sloan 5% Contrast Sensitivity Chart | Posted | Number | 95% Confidence Interval | Percentages of eyes that improved | Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8) | Number of Eyes | Number of Eyes |
|
|
|
|
| Secondary | Percentage of Eyes That Improved by One-line (5 Letters) | Percentage of eyes that improved by one-line (5 letters) on the 5% contrast sensitivity chart | Proportion as the Percent of Eyes Improved by 1 Line | Posted | Number | 95% Confidence Interval | Percent of Eyes | Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8) | Number of Eyes | Number of Eyes |
|
|
|
|
| Secondary | Visual Evoked Potential P100 Latency Per Treatment Arm | Visual evoked potential 60min P100 latency on dalfampridine vs. placebo. | per protocol | Posted | Mean | Standard Deviation | milliseconds | Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8) |
|
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| Secondary | Odds Ratio Quartile of Visual Field Index | The Visual Field Index (VFI) is a global index that assigns a number between 1% to 100% based on an aggregate percentage of visual function, with 100% being a perfect age-adjusted visual field. Probability of falling in the best quartile for visual field (VFI) measures (Q1), relative to the three next quartiles for worse VFIs (Q2-4), while on Dalfampridine vs Placebo. Due to the clustered observations at different times in a cross-over design, the visual field data is not suited to a normal theory model and should not be expressed as a continuous variable. Thus, a categorical model that uses a multinomial distribution for measurement of 4 categories was selected for proper statistical modeling, with results expressed as odds ratios. | Posted | Mean | Standard Deviation | Visual Field Index % of normal vision | Visit 1 (Week 0 - baseline), Visit 2 (Week 3 - post intervention 1) and Visit 3 (Week 8 - post intervention 2) | eligible eyes | eligible eyes |
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| Secondary | Changes in Color Vision Total Error Score From Baseline Based Upon the Farnsworth Munsell Hue 100 Sort Test (FM100). | Dalfampridine will change color vision Total Error Scores from baseline on the Farnsworth Munsell 100 Hue Sort Test. Farnsworth Munsell 100 Hue Test requires placing 100 color palettes in the correct order based upon color hue. Scores are determined by the frequency and severity of any displacement in the correct order. One error equates to one misplaced hue, by one step or position. An error score greater than 500 indicates virtually no color discrimination. An error score of 0 indicates no errors in ordering the hues. A Total Error Score of 0 to 128 could be seen in a normal population. | per protocol | Posted | Mean | Full Range | FM100 Total Error Score | Visit 1 (Week 0 - baseline), Visit 2 (Week 3 - postintervention 1) and Visit 3 (Week 8 - post intervention 2) |
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| Secondary | Dalfampridine Effect on Quality of Life Change From Baseline. | Dalfampridine treatment will result in change in quality of life. The National Eye Institute Visual Function Questionnaire consists of 25 questions characterizing visual function at home and in the community. Score ranges from 100 (best) to 0 (worst). | Posted | Median | Full Range | NEI VFQ percentage | Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8) |
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| Secondary | Difference in Pelli- Robson Score at Visits 2 and 3 Relative to Visit 1 | Difference in Pelli- Robson Score at Visits 2 and 3 Relative to Visit 1 on Dalfampridine vs Placebo. Pelli-Robson is scored based upon the numbers read on the chart converted to LogMAR units. The scale is 0.00 (worst) to 2.35 (best). | per protocol | Posted | Mean | Standard Deviation | units on a scale | Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8) | Number of Eyes | Number of Eyes |
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| Primary | Change From Baseline in Raw Letters by EDTRS 5% Contrast Sensitivity | Intent to treat analysis of treatment effect in primary endpoint EDTRS 5% Contrast Sensitivity. Change in the number of letters able to read while on Dalfampridine and Placebo relative to their baseline scores. | Intent To Treat Population, scores from morning and afternoon were averaged. | Posted | Mean | Standard Deviation | letters | Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8) |
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| 46 |
| 0 |
| 46 |
| 4 |
| 46 |
| EG001 | Placebo | Participants assigned to received placebo. | 0 | 46 | 0 | 46 | 0 | 46 |
Not provided
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D009901 | Optic Nerve Diseases |
| D003389 | Cranial Nerve Diseases |
| D005128 | Eye Diseases |
| D006573 |
| Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| eligible eyes |
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Null hypothesis for period effect: there will be no difference in the change relevant to baseline (visit 1) in EDTRS 5% contrast sensitivity for those who started on dalfampridine and crossed over to placebo, compared to those who started on placebo and crossed over to dalfampridine. |
| Mixed Models Analysis |
| 0.11 |
| Superiority or Other (legacy) |
| Post Intervention 2 (Visit 3) |
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