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Multiple SclerosisPhase 2/3NCT01337986

Ampyra for Optic Neuritis in Multiple Sclerosis

A Phase 2/3 study of Multiple Sclerosis and Optic Neuritis, run by Washington University School of Medicine at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 to 55 years
Conditions the study is for
Multiple Sclerosis, Optic Neuritis
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
53 participants
Where
1 siteUnited States
Study dates
May 2011to Dec 2013
Phase
Phase 2/3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 55 years
  • All sexes
  • No healthy volunteers
  • Adult

Who may be able to join

  • At least one previous clinical episode of optic neuritis,
  • the last episode of ON must have occurred at least 12 months prior to study entry,
  • clinically definite MS, defined by the revised McDonald criteria, 23
  • ages 18-70,
  • visual acuity greater than or equal to 20/30
  • 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
  • must have sufficient cognitive function to understand the consent process and to reliably perform all clinical assessments

Who cannot join

  • Any ophthalmologic condition, other than ON, which can affect vision, including nystagmus in primary position of gaze,
  • history of seizures or spells with altered level of consciousness,
  • pregnancy or breast feeding,
  • an MS exacerbation or use of glucocorticoids within 3 months of entry,
  • a history of moderate to severe renal insufficiency,
  • previous use of 4-aminopyridine, in any formulation, in the prior 4 weeks.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Washington University (John L. Trotter MS Center)

    St Louis, Missouri, 63110

Other trials in United States

About this study

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

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.

Read the 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.

Being tested
Dalfampridine/Placebo, Placebo/Dalfampridine
Keywords
Multiple Sclerosis, Optic Neuritis, Ampyra, Dalfampridine, Fampridine, Remote Optic Neuritis, Contrast Sensitivity, Treatment
Medical subject headings
Multiple Sclerosis, Optic Neuritis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Dalfampridine/PlaceboDrug

    Also called Ampyra (R), Fampridine

    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/DalfampridineDrug

    Also called Ampyra (R), Fampridine

    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.

Study groups in NCT01337986
Study groupRoleWhat they receive
Group B: Dalfampridine FirstActive comparatorDalfampridine/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.
Receives: Drug: Dalfampridine/Placebo
Group A: Dalfampridine SecondActive comparatorPlacebo/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
Receives: Drug: Placebo/Dalfampridine

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8)

  2. 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

    Measured: Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8)

  3. 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.

    Measured: Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8)

  4. 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.

    Measured: Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8)

Secondary outcomes (7)

  1. Percentage of Eyes That Improved by 2 Lines (10 Letters) on the Sloan 5% Contrast Sensitivity Chart

    Measured: Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8)

  2. 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

    Measured: Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8)

  3. Visual Evoked Potential P100 Latency Per Treatment Arm

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

    Measured: Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8)

  4. 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.

    Measured: Visit 1 (Week 0 - baseline), Visit 2 (Week 3 - post intervention 1) and Visit 3 (Week 8 - post intervention 2)

  5. 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.

    Measured: Visit 1 (Week 0 - baseline), Visit 2 (Week 3 - postintervention 1) and Visit 3 (Week 8 - post intervention 2)

  6. 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).

    Measured: Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8)

  7. 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).

    Measured: Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted19 Apr 2011 (estimated)
  2. Study startMay 2011
  3. Primary completionDec 2013
  4. Study completionDec 2013

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2/3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Crossover
Masking
Single blind
Who is masked
Participant
Enrolment
53 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01337986
Sponsor's protocol ID
Ampyra Vision 2011 RTN
Other IDs
WU HRPO# : 201104126
Status last verified
Jan 2020
First submitted
13 Apr 2011
Last updated
30 Jan 2020
Data monitoring committee
No
Individual data sharing
No

Publications

  • 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.

    PubMed 15664543

  • 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.

    PubMed 15953446

  • Balcer LJ. Clinical practice. Optic neuritis. N Engl J Med. 2006 Mar 23;354(12):1273-80. doi: 10.1056/NEJMcp053247. No abstract available.

    PubMed 16554529

  • 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.

    PubMed 11992867

  • 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.

    PubMed 16935592

  • 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.

    PubMed 19240050

  • 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.

    PubMed 1734247

  • 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.

    PubMed 9400788

  • 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.

    PubMed 9093956

  • 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.

    PubMed 19249634

  • 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.

    PubMed 9700711

  • 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.

    PubMed 9109861

  • 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.

    PubMed 7755367

  • 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.

    PubMed 8208399

  • 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.

    PubMed 8129642

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study of Multiple Sclerosis and Optic Neuritis, run by Washington University School of Medicine at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 30 Jan 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 30 Jan 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Efficacy of Dalfampridine on Visual Function by Early Diabetic Treatment Retinopathy Study (EDTRS) 5% Contrast Sensitivity Scores (time frame: Visit 1 (Week 0), Visit 2 (Week 3) and Visit 3 (Week 8)). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01337986, which also lists 35 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Jan 2020.

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Ampyra for Optic Neuritis in Multiple Sclerosis | AzTrials