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Study and Treatment of Visual Dysfunction and Motor Fatigue in Multiple Sclerosis

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ClinicalTrials.gov Identifier: NCT02391961
Recruitment Status : Completed
First Posted : March 18, 2015
Last Update Posted : April 19, 2019
Sponsor:
Information provided by (Responsible Party):
VA Office of Research and Development

Tracking Information
First Submitted Date  ICMJE March 3, 2015
First Posted Date  ICMJE March 18, 2015
Last Update Posted Date April 19, 2019
Actual Study Start Date  ICMJE April 1, 2015
Actual Primary Completion Date January 31, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 7, 2015)
Eye movement assessment [ Time Frame: baseline, after 4 weeks, after 6 weeks, after 10 weeks ]
Changes in binocular horizontal conjugacy of saccades at baseline and following the saccadic fatigue test, before and after treatment, using: 1) abducting/adducting eye ratio for saccadic peak velocity (pulse size ratio); 2) time difference in occurrence of peak acceleration in the adducting vs. the abducting eye (pulse time delay).
Original Primary Outcome Measures  ICMJE
 (submitted: March 12, 2015)
Changes in binocular horizontal conjugacy of saccades [ Time Frame: baseline, after 4 weeks, after 6 weeks, after 10 weeks ]
Changes in binocular horizontal conjugacy at baseline and following the saccadic fatigue test, before and after treatment, using: 1) abducting/adducting eye ratio for saccadic peak velocity (pulse size ratio); 2) time difference in occurrence of peak acceleration in the adducting vs. the abducting eye (pulse time delay).
Change History Complete list of historical versions of study NCT02391961 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 22, 2016)
  • Visual function assessment [ Time Frame: baseline, after 4 weeks, after 6 weeks, after 10 weeks ]
    1) MNREAD acuity charts for reading acuity and speed; 2) King-Devick test for saccades performance.
  • Gait assessment [ Time Frame: baseline, after 4 weeks, after 6 weeks, after 10 weeks ]
    1) 25-foot Walk Test.
  • Visual disability assessment [ Time Frame: baseline, after 4 weeks, after 6 weeks, after 10 weeks ]
    NEI-VFQ-25 and NOS.
  • Quality of life assessment [ Time Frame: baseline, after 4 weeks, after 6 weeks, after 10 weeks ]
    MS Quality of Life Inventory.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 12, 2015)
  • Changes in visual function [ Time Frame: baseline, after 4 weeks, after 6 weeks, after 10 weeks ]
    1) MNREAD acuity charts for reading acuity and speed; 2) King-Devick test for saccades performance.
  • Visual function assessment [ Time Frame: baseline, after 4 weeks, after 6 weeks, after 10 weeks ]
    1) MNREAD acuity charts for reading acuity and speed; 2) King-Devick test for saccades performance.
  • Gait assessment [ Time Frame: baseline, after 4 weeks, after 6 weeks, after 10 weeks ]
    1) 25-foot Walk Test; 2) 6-minute Walk Test.
  • Visual disability and quality of life assessment [ Time Frame: baseline, after 4 weeks, after 6 weeks, after 10 weeks ]
    1) NEI-VFQ-25 and NOS; 2) MS Quality of Life Inventory.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study and Treatment of Visual Dysfunction and Motor Fatigue in Multiple Sclerosis
Official Title  ICMJE Study and Treatment of Visual Dysfunction and Motor Fatigue in Multiple Sclerosis
Brief Summary Primary fatigue represents a major cause of disability in patients with multiple sclerosis (MS), being reported in about 90% of cases. Fatigue interferes with everyday functioning but, unfortunately, little is known about its mechanisms. The investigators propose a characteristic eye movement abnormality (internuclear ophthalmoparesis, INO), commonly encountered in MS, as a simple model for primary motor fatigue. The investigators described worsening of ocular performance in MS patients with INO following visual tasks (ocular motor fatigue), which is likely due to decreased neural conduction along brain pathways injured by MS. This mechanism could represent a major component of MS-related primary motor fatigue. Relevant to Veterans' care, INO is a significant cause of visual disability, especially when complicated by ocular fatigue, and limits daily activities such as reading and driving. The investigators propose a medical treatment to improve ocular performance/fatigue in INO, which can reduce visual disability and improve quality of life in Veterans with MS.
Detailed Description

This project focuses on fatigue, an extremely common yet poorly understood complaint in patients affected by multiple sclerosis (MS). Primary fatigue, that is fatigue not secondary to other MS-associated symptoms (e.g., sleep disorder or depression), is a distinct clinical entity and a cause of severe disability in most patients. As fatigue limits everyday activities and interferes with exercise-based rehabilitation, understanding its mechanisms is crucial to improving function and quality of life of Veterans with MS. Primary fatigue is divided in two broad categories, mental (cognitive) and physical (motor) fatigue, the latter being the focus of this proposal. Evidence suggests that primary motor fatigue originates within the central nervous system (CNS) but, although several factors have been invoked (e.g., demyelination, axonal loss, inflammation), a neurophysiological model to explain its underlying mechanisms is still lacking.

First, with this project, the investigators propose a characteristic eye movement abnormality, internuclear ophthalmoparesis (INO), as a simple and accessible model for primary motor fatigue in MS. INO is a disorder of binocular coordination (conjugacy), in which fast eye movements (saccades) of the adducting eye (i.e., the eye moving towards the nose) are slow during horizontal gaze shifts, due to demyelination of a specific CNS pathway (the medial longitudinal fasciculus, MLF). Preliminary results in a small MS group of patients show that patients with INO exhibit changes in ocular conjugacy (i.e., ocular motor fatigue) during a 10-minute saccadic fatigue test, but normal subjects do not. The investigators hypothesize that ocular motor fatigue is representative of a major component of primary motor fatigue in MS, as it likely reflects deterioration of neural conduction fidelity along the demyelinated MLF axons. The investigators aim at showing that ocular motor fatigue occurs in a larger MS population with INO by measuring changes of binocular conjugacy on eye movement recordings using two main measures: 1) abducting/adducting eye ratio for saccadic peak velocity (pulse size ratio); 2) time difference in occurrence of peak acceleration in the adducting vs. the abducting eye (pulse time delay), during the 10-minute fatigue test. The investigators will determine whether ocular motor fatigue is associated with symptomatic subjective fatigue as assessed with standard fatigue questionnaires. Second, The investigators intend to test efficacy of dalfampridine, a potassium channel blocker that enhances neural conduction along demyelinated axons, in MS patients with INO with or without associated ocular motor fatigue. Visual dysfunction in MS patients with INO is a major cause of disability as they are severely limited in daily activities such as driving and can suffer further disability when developing ocular motor fatigue during a sustained visual task (e.g., reading). However, no medical therapy is available for INO/ocular motor fatigue. Preliminary results document improved binocular conjugacy in three MS patients taking dalfampridine for gait impairment (the FDA-approved indication for this medication). These data also showed improvement of ocular motor fatigue after dalfampridine in one patient. The investigators hypothesize that dalfampridine improves visual performance in MS patients with INO and counteracts ocular motor fatigue and, in turn, diminishes visual disability and improves quality of life. Thus, the investigators will conduct a randomized, placebo-controlled, double-blind, crossover trial of dalfampridine (10mg twice a day) of 10 weeks duration. Before and after treatment, the investigators will assess for changes in binocular conjugacy by eye movement measures as above, as well as changes in clinical measures, such as reading acuity and speed, saccades performance, gait performance, symptomatic fatigue, visual disability and quality of life. the investigators will determine whether improvement of visual performance has positive effects on overall disability and quality of life of MS patients with INO. The investigators will also determine whether there is an association between response of eye movement and gait performances to dalfampridine.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Condition  ICMJE
  • Multiple Sclerosis
  • Internuclear Ophthalmoplegia
  • Fatigue
Intervention  ICMJE
  • Drug: Dalfampridine
    10-week randomized, placebo controlled, double-blind, crossover trial, which includes a period of wash out of two weeks between treatment with dalfampridine and placebo.
  • Drug: Placebo
    10-week randomized, placebo controlled, double-blind, crossover trial, which includes a period of wash out of two weeks between treatment with dalfampridine and placebo.
Study Arms  ICMJE
  • Experimental: dalfampridine
    10-week randomized, placebo controlled, double-blind, crossover trial, which includes a period of wash out of two weeks between treatment with dalfampridine and placebo. Within the trial, each patient serves as his own control.
    Intervention: Drug: Dalfampridine
  • Placebo Comparator: placebo
    10-week randomized, placebo controlled, double-blind, crossover trial, which includes a period of wash out of two weeks between treatment with dalfampridine and placebo. Within the trial, each patient serves as his own control.
    Intervention: Drug: Placebo
Publications * Serra A, Chisari CG, Matta M. Eye Movement Abnormalities in Multiple Sclerosis: Pathogenesis, Modeling, and Treatment. Front Neurol. 2018 Feb 5;9:31. doi: 10.3389/fneur.2018.00031. eCollection 2018. Review.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 18, 2019)
20
Original Estimated Enrollment  ICMJE
 (submitted: March 12, 2015)
30
Actual Study Completion Date  ICMJE March 31, 2019
Actual Primary Completion Date January 31, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Diagnosis of MS of any course and duration
  • Evidence of mild to moderate internuclear ophthalmoparesis (INO), that is slowing of the adducting eye on physical examination of saccadic speed, whether INO is unilateral or bilateral, symmetrical or asymmetrical
  • Medically stable conditions, ability to give informed consent and understand and cooperate with the testing
  • Dalfampridine-naive as well as history of taking dalfampridine in the past, whether there was benefit in gait impairment or not, after a washout period of at least 2 weeks

Exclusion Criteria:

  • Lack of evidence of INO (slowing of the adducting eye) on physical examination of saccadic speed
  • Severe INO (i.e., exotropia in primary gaze) on physical examination
  • Medically unstable conditions, inability to give informed consent and understand and cooperate with the testing
  • History of side effects from dalfampridine
  • History of seizures
  • Moderate or severe renal failure, assessed by clearance of creatinine
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02391961
Other Study ID Numbers  ICMJE F1180-W
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Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party VA Office of Research and Development
Study Sponsor  ICMJE VA Office of Research and Development
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Alessandro Serra, MD PhD Louis Stokes VA Medical Center, Cleveland, OH
PRS Account VA Office of Research and Development
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP