Ampyra for Optic Neuritis in Multiple Sclerosis

• Sponsor: Washington University School of Medicine (Other)
• Overall Status: Completed
• CT.gov ID: NCT01337986
• Collaborator: Acorda Therapeutics (Industry)
• Enrollment: 53
• Location: 1
• Arms: 2
• Duration (Months): 31
• Patients Per Site Per Month: 1.7

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis; Optic Neuritis	Drug: Dalfampridine/Placebo; Drug: Placebo/Dalfampridine	Phase 2/Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 53 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Single (Participant)
• Primary Purpose: Treatment
• Official Title: Dalfampridine After Optic Neuritis to Improve Visual Function in Multiple Sclerosis
• Study Start Date: May 1, 2011
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Group B: Dalfampridine First 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.	Drug: 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.; Other Names: Ampyra (R) Fampridine
Active Comparator: Group A: Dalfampridine Second 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	Drug: 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.; Other Names: Ampyra (R) Fampridine

Outcome Measures

Primary Outcome Measures

1. Efficacy of Dalfampridine on Visual Function by Early Diabetic Treatment Retinopathy Study (EDTRS) 5% Contrast Sensitivity Scores [Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8)]

   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.

2. Efficacy of Dalfampridine on Visual Function Assessed by Change From Baseline in Raw Letters by EDTRS 5% Contrast Sensitivity [Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8)]

   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

3. Difference in EDTRS 5% Contrast Sensitivity (LogMAR Score) at Visits 2 and 3 Relative to Visit 1 [Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8)]

   Intent to treat analysis of treatment effect in primary endpoint EDTRS 5% Contrast Sensitivity. Improvement from baseline scores.

4. Change From Baseline in Raw Letters by EDTRS 5% Contrast Sensitivity [Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8)]

   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.

Secondary Outcome Measures

1. 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)]

2. Percentage of Eyes That Improved by One-line (5 Letters) [Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8)]

   Percentage of eyes that improved by one-line (5 letters) on the 5% contrast sensitivity chart

3. Visual Evoked Potential P100 Latency Per Treatment Arm [Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8)]

   Visual evoked potential 60min P100 latency on dalfampridine vs. placebo.

4. Odds Ratio Quartile of Visual Field Index [Visit 1 (Week 0 - baseline), Visit 2 (Week 3 - post intervention 1) and Visit 3 (Week 8 - post intervention 2)]

   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.

5. Changes in Color Vision Total Error Score From Baseline Based Upon the Farnsworth Munsell Hue 100 Sort Test (FM100). [Visit 1 (Week 0 - baseline), Visit 2 (Week 3 - postintervention 1) and Visit 3 (Week 8 - post intervention 2)]

   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.

6. Dalfampridine Effect on Quality of Life Change From Baseline. [Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8)]

   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).

7. Difference in Pelli- Robson Score at Visits 2 and 3 Relative to Visit 1 [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 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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 18-70,

5. visual acuity greater than or equal to 20/30

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) at 3 meters, 2 meters or 1 meter, 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Washington University (John L. Trotter MS Center)	Saint Louis	Missouri	United States	63110

Sponsors and Collaborators

• Washington University School of Medicine
• Acorda Therapeutics

Investigators

• Principal Investigator: Robert T Naismith, MD, Washington University School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

• Acorda Therapeutics. AMPRYA package insert (2010).
• Arnold AC. Evolving management of optic neuritis and multiple sclerosis. Am J Ophthalmol. 2005 Jun;139(6):1101-8. Review.
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• 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.
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• 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.
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• 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.
• 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.
• 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.
• 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.
• 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.
• 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. 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. doi: 10.1212/01.wnl.0000335766.22758.cd. Epub 2008 Dec 10.
• 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.
• 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.
• 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.
• 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. Review.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT01337986
• Other Study ID Numbers: Ampyra Vision 2011 RTN; WU HRPO# : 201104126
• First Posted: Apr 19, 2011
• Last Update Posted: Jan 30, 2020
• Last Verified: Jan 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Washington University School of Medicine: Multiple Sclerosis; Optic Neuritis; Ampyra; Dalfampridine; Fampridine; Remote Optic Neuritis; Contrast Sensitivity; Treatment
• Additional relevant MeSH terms: Multiple Sclerosis; Neuritis; Optic Neuritis; Sclerosis; 4-Aminopyridine

Study Results

Participant Flow

Recruitment Details	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.
Pre-assignment Detail	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.

Arm/Group Title	Group B: Dalfampridine/Placebo	Group A: Placebo/Dalfampridine
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	23	23
COMPLETED	20	18
NOT COMPLETED	3	5

Baseline Characteristics

Arm/Group Title	Group B: Dalfampridine/Placebo	Group A: Placebo/Dalfampridine	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	20	18	38
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	18 90%	17 94.4%	35 92.1%
>=65 years	2 10%	1 5.6%	3 7.9%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44.5 (10.7)	50.7 (10.2)	47.6 (10.5)
Sex: Female, Male (Count of Participants)
Female	14 70%	14 77.8%	28 73.7%
Male	6 30%	4 22.2%	10 26.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	4 20%	5 27.8%	9 23.7%
White	16 80%	13 72.2%	29 76.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	20 100%	18 100%	38 100%
MS Subtype (participants) [Number]
Relapsing Remitting MS (RRMS)	17 85%	15 83.3%	32 84.2%
Secondary Progressive MS (SPMS)	3 15%	3 16.7%	6 15.8%
Clinical Episodes of ON (Number of episodes) [Median (Full Range) ]
Median (Full Range) [Number of episodes]	1	1	1
Baseline 5% Sloan Chart (Number of Letters) [Median (Full Range) ]
Median (Full Range) [Number of Letters]	22	20	21

Outcome Measures

1. Primary Outcome

Title	Efficacy of Dalfampridine on Visual Function by Early Diabetic Treatment Retinopathy Study (EDTRS) 5% Contrast Sensitivity Scores
Description	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.
Time Frame	Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8)

Outcome Measure Data

Analysis Population Description

Per protocol analysis

Arm/Group Title	Group B: Dalfampridine	Group B: Placebo	Group A: Placebo	Group A: Dalfampridine
Arm/Group Description	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.	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.	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.	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.
Measure Participants	20	20	18	18
Measure eligible eyes	30	30	29	29
Mean (Standard Deviation) [LogMAR Score]	-0.04 (0.02)	-0.06 (0.02)	-0.08 (0.02)	-0.06 (0.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group B: Dalfampridine, Group B: Placebo, Group A: Placebo, Group A: Dalfampridine
	Comments	Per protocol Analysis
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.84
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Group B: Dalfampridine, Group B: Placebo, Group A: Placebo, Group A: Dalfampridine
	Comments	Change in EDTRS between Visits 2 and 3.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	.29
	Comments
	Method	Mixed Models Analysis
	Comments

2. Primary Outcome

Title	Efficacy of Dalfampridine on Visual Function Assessed by Change From Baseline in Raw Letters by EDTRS 5% Contrast Sensitivity
Description	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
Time Frame	Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8)

Outcome Measure Data

Analysis Population Description

Per protocol analysis

Arm/Group Title	Group B: Dalfampridine	Group B: Placebo	Group A: Placebo	Group A: Dalfampridine
Arm/Group Description	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.	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.	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.	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.
Measure Participants	20	20	18	18
Measure eligible eyes	30	30	29	29
Mean (Standard Deviation) [letters]	2 (1)	2 (1)	4 (1)	3 (1)

3. Primary Outcome

Title	Difference in EDTRS 5% Contrast Sensitivity (LogMAR Score) at Visits 2 and 3 Relative to Visit 1
Description	Intent to treat analysis of treatment effect in primary endpoint EDTRS 5% Contrast Sensitivity. Improvement from baseline scores.
Time Frame	Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8)

Outcome Measure Data

Analysis Population Description

Intent To Treat Population, scores from morning and afternoon were averaged.

Arm/Group Title	Dalfampridine	Placebo
Arm/Group Description	Patient Assessments while on Dalfampridine	Patient Assessments while on Dalfampridine
Measure Participants	46	46
Mean (Standard Deviation) [5% Contrast LogMAR Score]	0.06 (0.02)	0.05 (0.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group B: Dalfampridine, Group B: Placebo
	Comments	Null hypothesis: there will be no difference in the change relevant to baseline (visit 1) in EDTRS 5% contrast sensitivity with dalfampridine vs placebo.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	.64
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.008
	Confidence Interval	(2-Sided) 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.01
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Group B: Dalfampridine, Group B: Placebo
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.11
	Comments
	Method	Mixed Models Analysis
	Comments

4. Secondary Outcome

Title	Percentage of Eyes That Improved by 2 Lines (10 Letters) on the Sloan 5% Contrast Sensitivity Chart
Time Frame	Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dalfampridine	Placebo	Both	None
Arm/Group Description	Improvement while on Dalfampridine (not placebo)	Improvement while on Placebo (not dalfampridine)	Improvement when taking Dalfampridine or Placebo (improvement with any treatment)	No Improvement on Dalfampridine/Placebo.
Measure Participants	46	46	46	46
Measure Number of Eyes	72	72	72	72
Number (95% Confidence Interval) [Percentages of eyes that improved]	9.7	11.1	11.1	68.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group B: Dalfampridine, Group B: Placebo, Group A: Placebo, Group A: Dalfampridine
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.93
	Comments
	Method	Regression, Logistic
	Comments

5. Secondary Outcome

Title	Percentage of Eyes That Improved by One-line (5 Letters)
Description	Percentage of eyes that improved by one-line (5 letters) on the 5% contrast sensitivity chart
Time Frame	Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8)

Outcome Measure Data

Analysis Population Description

Proportion as the Percent of Eyes Improved by 1 Line

Arm/Group Title	Dalfampridine	Placebo	Both	Neither
Arm/Group Description	Improvement while on Dalfampridine	Improvement while on Placebo	Improvement on Dalfampridine and Placebo	No Improvement on Dalfampridine or Placebo
Measure Participants	38	38	38	38
Measure Number of Eyes	72	72	72	72
Number (95% Confidence Interval) [Percent of Eyes]	11.1	15.3	37.5	36.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group B: Dalfampridine, Group B: Placebo, Group A: Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	.34
	Comments
	Method	Regression, Logistic
	Comments

6. Secondary Outcome

Title	Visual Evoked Potential P100 Latency Per Treatment Arm
Description	Visual evoked potential 60min P100 latency on dalfampridine vs. placebo.
Time Frame	Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8)

Outcome Measure Data

Analysis Population Description

per protocol

Arm/Group Title	Dalfampridine	Placebo
Arm/Group Description	Patient Assessments while on Dalfampridine	Patient Assessments while on Dalfampridine
Measure Participants	38	38
Mean (Standard Deviation) [milliseconds]	121.6 (2.4)	120.2 (2.4)

7. Secondary Outcome

Title	Odds Ratio Quartile of Visual Field Index
Description	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.
Time Frame	Visit 1 (Week 0 - baseline), Visit 2 (Week 3 - post intervention 1) and Visit 3 (Week 8 - post intervention 2)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dalfampridine Then Placebo	Placebo Then Dalfampridine
Arm/Group Description	Weeks 1-3 Dalfampridine 10 mg Twice Daily, Weeks 6-8 Placebo Twice Daily	Weeks 1-3 Placebo Twice Daily, Weeks 6-8 Dalfampridine 10 mg Twice Daily
Measure Participants	20	18
Measure eligible eyes	30	29
Baseline (Visit 1)	77.53 (29.84)	85.38 (86.65)
Post Intervention 1 (Visit 2)	78.50 (28.30)	86.65 (22.64)
Post Intervention 2 (Visit 3)	79.71 (28.57)	86.00 (22.75)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group B: Dalfampridine, Group B: Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.04
	Comments	Probability of being in the lowest quartile for Visual Field Index deficits.
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.46
	Confidence Interval	(2-Sided) 95%; 1.02 to 2.10
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds Ratio for Visual Field Index

8. Secondary Outcome

Title	Changes in Color Vision Total Error Score From Baseline Based Upon the Farnsworth Munsell Hue 100 Sort Test (FM100).
Description	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.
Time Frame	Visit 1 (Week 0 - baseline), Visit 2 (Week 3 - postintervention 1) and Visit 3 (Week 8 - post intervention 2)

Outcome Measure Data

Analysis Population Description

per protocol

Arm/Group Title	Dalfampridine	Placebo
Arm/Group Description	Patient Assessments while on Dalfampridine	Patient Assessments while on Dalfampridine
Measure Participants	38	38
Mean (Full Range) [FM100 Total Error Score]	-13.0	-10.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group B: Dalfampridine, Group B: Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.94
	Comments
	Method	Regression, Logistic
	Comments

9. Secondary Outcome

Title	Dalfampridine Effect on Quality of Life Change From Baseline.
Description	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).
Time Frame	Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dalfampridine	Placebo
Arm/Group Description	Study participants on dalfampridine	Study participants on placebo
Measure Participants	38	38
Median (Full Range) [NEI VFQ percentage]	0	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group B: Dalfampridine, Group B: Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.39
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

10. Secondary Outcome

Title	Difference in Pelli- Robson Score at Visits 2 and 3 Relative to Visit 1
Description	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).
Time Frame	Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8)

Outcome Measure Data

Analysis Population Description

per protocol

Arm/Group Title	Dalfampridine	Placebo
Arm/Group Description	Patient Assessments while on Dalfampridine	Patient Assessments while on Dalfampridine
Measure Participants	38	38
Measure Number of Eyes	60	60
Mean (Standard Deviation) [units on a scale]	0.07 (0.02)	0.06 (0.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group B: Dalfampridine, Group B: Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.72
	Comments
	Method	Regression, Linear
	Comments

11. Primary Outcome

Title	Change From Baseline in Raw Letters by EDTRS 5% Contrast Sensitivity
Description	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.
Time Frame	Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8)

Outcome Measure Data

Analysis Population Description

Intent To Treat Population, scores from morning and afternoon were averaged.

Arm/Group Title	Dalfampridine	Placebo
Arm/Group Description	Patient Assessments while on Dalfampridine	Patient Assessments while on Dalfampridine
Measure Participants	46	46
Mean (Standard Deviation) [letters]	3 (1)	2.5 (1)

Adverse Events

Time Frame	8 weeks
Adverse Event Reporting Description	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.
Arm/Group Title	Dalfampridine		Placebo
Arm/Group Description	Participants assigned to received dalfampridine.		Participants assigned to received placebo.
All Cause Mortality
	Dalfampridine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/46 (0%)		0/46 (0%)
Serious Adverse Events
	Dalfampridine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/46 (0%)		0/46 (0%)
Other (Not Including Serious) Adverse Events
	Dalfampridine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/46 (8.7%)		0/46 (0%)
Nervous system disorders
Dizziness	4/46 (8.7%)	4	0/46 (0%)	0

Limitations/Caveats

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.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.