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Improving Cognition in People With Progressive Multiple Sclerosis Using Aerobic Exercise and Cognitive Rehabilitation

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ClinicalTrials.gov Identifier: NCT03679468
Recruitment Status : Recruiting
First Posted : September 20, 2018
Last Update Posted : March 20, 2019
Sponsor:
Collaborators:
University of Florence
Fondazione Italiana Sclerosi Multipla
University College, London
Kessler Foundation
University of Alabama at Birmingham
University of Southern Denmark
Hasselt University
University of Plymouth
University of Genoa
St. Michael's Hospital, Toronto
Ospedale San Raffaele
Information provided by (Responsible Party):
Dr. Anthony Feinstein, Sunnybrook Health Sciences Centre

Brief Summary:
Given that up to 70% of people with secondary progressive MS are cognitively impaired, the search for effective treatments is considered a priority by people living with the disease. This proposal will address the effectiveness of cognitive rehabilitation (CR) and exercise, either alone, or in combination in this regard. A team of MS researchers has been assembled from the USA, Canada, the United Kingdom, Italy, Denmark, Germany and Belgium for this. A total of 360 people with progressive MS will make up the sample. Brain MRIs will be undertaken in a third of the sample before and after the 12 weeks of treatment to document the functional changes that are expected to occur with symptom improvement.

Condition or disease Intervention/treatment Phase
Multiple Sclerosis, Primary Progressive Cognitive Impairment Other: Cognitive Rehabilitation Other: Sham Exercise Other: Sham Cognitive Rehabilitation Other: Aerobic Exercise Not Applicable

Detailed Description:

Aim: The broad aim of this proposal is to evaluate a multidisciplinary and multi-modal approach to rehabilitation in people with progressive MS. Cognitive rehabilitation and aerobic exercise will be evaluated individually and in combinations to address cognitive dysfunction as the primary outcome variable.

Over 20 years have passed since the introduction of the first disease modifying treatment, interferon beta-1betaseron (b), for multiple sclerosis (MS).Since then 13 treatments have been approved and made it onto the market. All are for relapsing-remitting disease (RRMS), apart from mitoxantrone which is limited to progressive disease with relapses, Interferon-beta-1b, which is for secondary progressive disease (SPMS), but does not delay disability progression and Ocrelizumab for primary progressive MS only. Thus, for a sizeable proportion of people with MS there is no therapeutic option to slow progression. This raises the question, how are patients with primary and secondary progressive MS (PPMS and SPMS) to be helped? While research is underway to find a medication that holds promise of halting further deterioration in a disease that has already entered a progressive stage, patients and their clinicians are left with basically symptomatic treatments.

Hypothesis: The investigators hypothesize that CR and aerobic exercise are effective treatments for cognitive impairment (processing speed deficits) in people with progressive MS. In particular a combination of these two treatment given twice weekly over 12 weeks is more effective than each individual treatment given alone or as sham. The investigators further hypothesize that improvements in processing speed will be matched on functional MRI (fMRI) by enhanced neural activity in networks associated with information processing speed.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 360 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: We propose undertaking a randomized, blinded, sham controlled clinical trial investigating the effectiveness of CR and exercise, either singly or in combination, in treating cognitive dysfunction in people with progressive MS. Subjects will be randomly assigned to one of four groups: CR plus exercise; CR plus passive exercise; passive CR plus exercise and passive CR plus passive exercise. Subjects will receive one of these four treatments for 12 weeks, twice a week. One in three subjects will undergo structural and functional MRI to investigate how the brain responds to the two interventions.
Masking: Double (Participant, Investigator)
Masking Description: In order to prevent bias in our research results, we will employ a double-blind study design in which the examiner nor the research participant will know which group membership they were assigned to.
Primary Purpose: Other
Official Title: Improving Cognition in People With Progressive Multiple Sclerosis: A Multi-Arm, Randomized, Blinded, Sham-Controlled Trial of Cognitive Rehabilitation and Aerobic Exercise.
Actual Study Start Date : March 18, 2019
Estimated Primary Completion Date : November 2022
Estimated Study Completion Date : November 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Sham Comparator: Cognitive Rehab & Sham Exercise
Cognitive Rehabilitation by computer based brain tasks, and Sham exercises focusing primary on balance and stretching. Sessions will take place twice a week for 12 weeks.
Other: Cognitive Rehabilitation

RehaCom software

Information processing speed and attention modules


Other: Sham Exercise
Sets of balance and stretching exercises

Sham Comparator: Sham Cognitive Rehab & Sham Exercise
Sham cognitive Rehabilitation will consist of basic internet searches and learning to use a computer, and sham exercises focusing primary on balance and stretching. Sessions will take place twice a week for 12 weeks.
Other: Sham Exercise
Sets of balance and stretching exercises

Other: Sham Cognitive Rehabilitation

Kompozer software

24 session module consisting of basic internet searches


Sham Comparator: Sham Cognitive rehab & Aerobic Exercise
Sham cognitive rehabilitation will consist of basic internet searches and learning to use a computer, and aerobic exercises will focus primarily on improving cardio-respiratory fitness using a recumbent bike. Sessions will take place twice a week for 12 weeks.
Other: Sham Cognitive Rehabilitation

Kompozer software

24 session module consisting of basic internet searches


Other: Aerobic Exercise

Recumbent NuStep Bike

Aerobic cycling


Active Comparator: Cognitive Rehab & Aerobic Exercise
Cognitive Rehabilitation by computer based brain tasks and aerobic exercises will focus primarily on improving cardio-respiratory fitness using a recumbent bike. Sessions will take place twice a week for 12 weeks.
Other: Cognitive Rehabilitation

RehaCom software

Information processing speed and attention modules


Other: Aerobic Exercise

Recumbent NuStep Bike

Aerobic cycling





Primary Outcome Measures :
  1. Change from baseline cognitive Information processing speed at 12 weeks and 6 months [ Time Frame: Baseline, 12 weeks, and 6 month ]

    The Symbol Digit Modalities Test (SDMT) will be used to measure cognitive information processing speed

    The SDMT is a simple matching task that requires the participant to refer to a reference key, in order to correctly match a geometric symbol with the corresponding number. Participant will be under a 90 second time constraint to quickly and correctly match each pair.

    Test will be administered at index assessment, 12 weeks following cognitive rehab/ aerobic exercise, and at 6 months to examine cognitive retention



Secondary Outcome Measures :
  1. Change from baseline cognitive verbal memory at 12 weeks and 6 months [ Time Frame: Baseline, 12 weeks, & 6 month ]

    The California Verbal Learning Test (CVLT) will be used to measure verbal memory

    The CVLT test begins with the examiner reading a list of 16 words, participants are then instructed to report as many of the words as they can remember. After recall is recorded, the entire list is read again, altogether, there are five learning trials.

    Test will be administered at index assessment, 12 weeks following cognitive rehab/ aerobic exercise, and at 6 months to examine cognitive retention


  2. Change from baseline cognitive visual memory at 12 weeks and 6 months [ Time Frame: Baseline, 12 weeks, & 6 month ]

    The Brief Visuo-Spatial Memory Test (BVMT) will be used to measure visual memory

    Participants are presented with six abstract designs for 10 seconds, the display is then removed from view and participant are instructed to draw the designs from memory via pencil on paper. Each design is scored from 0 to 2 points representing accuracy and location. There are three learning trials.

    Test will be administered at index assessment, 12 weeks following cognitive rehab/ aerobic exercise, and at 6 months to examine cognitive retention


  3. Change from baseline anxiety & depression, at 12 weeks and 6 months [ Time Frame: Baseline, 12 weeks, and 6 month ]

    The following self report scale will be used to measure anxiety and depression:

    The Hospital Anxiety and Depression Scale (HADS) - The HADS is comprised of seven questions for anxiety and seven questions for depression, each reply has a likert scale ranging from 0-3.

    Total score will indicate:

    0-7 = normal 8-10 = borderline abnormal 11-21 = abnormal


  4. Change from baseline depression, at 12 weeks and 6 months [ Time Frame: Baseline, 12 weeks, and 6 month ]

    The following self report scale will be used to measure depression:

    Beck Depression Inventory-revised (BDI-II) - The BDI-II questionnaire is comprised of 21 questions, participant will circle a reply that closely matches their answer, each reply has a likert scale that ranges from 0-3.

    Total score indicate the following:

    1-10 = these ups and downs are considered normal 11-16 = Mild mood disturbance 17-20 = Borderline clinical depression 21-30 = Moderate depression 31-40 = Severe depression over 40 = Extreme depression


  5. Change from baseline fatigue, at 12 weeks and 6 months [ Time Frame: Baseline, 12 weeks, and 6 month ]

    Self report scale:

    The Modified Fatigue Impact Scale (MFIS), will evaluate the participants fatigue.

    The total score for the MFIS is the sum of the scores for the 21 items. Individual subscale scores for physical, cognitive, and psychosocial functioning can also be generated by calculating the sum of specific sets of items.


  6. Change from baseline perceived deficits, at 12 weeks and 6 months [ Time Frame: Baseline, 12 weeks, and 6 month ]

    Self report scale:

    The Perceived Deficits Questionnaire (PDQ), will evaluate the participants subjective cognitive difficulties.

    The total score for the PDQ is the sum of the scores for the 20 items. Individual subscale scores for attention/concentration, retrospective memory, prospective memory, and planning/organization will be generated by calculating the sum of specific sets of items.


  7. Change from baseline subjective impact of walking, at 12 weeks and 6 months [ Time Frame: Baseline, 12 weeks, and 6 month ]

    Self report scale:

    The Multiple Sclerosis Walking Scale (MSWS-12), will evaluate the participants subjective impact of walking.

    The MSWS-12 consist of 12 questions, each question ranges from 0-5. A high total score indicates greater impact on walking than lower scores.


  8. Change from baseline impact of Multiple Sclerosis, at 12 weeks and 6 months [ Time Frame: Baseline, 12 weeks, and 6 month ]

    Self report scale:

    Multiple Sclerosis Impact Scale (MSIS-29-V2) - will evaluate the participants impact of Multiple Sclerosis.

    The MSIS-29 is a 29 item scale measuring the physical (20 item) and psychological (9 item) impact of Multiple scleroses.


  9. Change from baseline quality of life, at 12 weeks and 6 months [ Time Frame: Baseline, 12 weeks, and 6 month ]

    Self report scale:

    European Quality of Life-5 Dimensions (EQ5D-5) - will be used to evaluate the participants quality of life.

    The EQ5D-5 comprises of five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions.

    The EQ5D-5 also records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled "The best health you can imagine" and "The worst health you can imagine".


  10. Change from baseline global function, at 12 weeks and 6 months [ Time Frame: Baseline, 12 weeks, and 6 month ]

    Self report scale:

    The Functional Assessment of Multiple Sclerosis (FAMS), will be used to asses the participants global function.

    The FAMS consist of 59 items, and domains that consist of questions on: mobility, symptoms, emotional well-being, general contentment, thinking/fatigue, family/social well-being, and additional concerns.

    FAMS total score range = 0 -176. Higher scores indicate better quality of life.



Other Outcome Measures:
  1. Change from baseline brain activity at 12 weeks and 6 months [ Time Frame: Baseline, 12 weeks, 6 months ]

    The participant will perform a modified Go no Go task while in the MRI. Changes in brain activity will indicate superiority of one of the four study groups.

    Go no Go task:

    Participants are required to either respond (i.e., pressing designated key) or withhold a response (not pressing designated key) depending on whether a go stimulus or a no-go stimulus is presented

    MRI Go no Go task will be administered at index assessment, 12 weeks following cognitive rehab/ aerobic exercise, and at 6 months to examine brain activity and anatomical changes




Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   25 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Have a confirmed diagnosis of progressive Multiple Sclerosis
  • Visual Acuity of 20/70
  • Language comprehension, to ensure subjects have the ability to understand instructions

Exclusion Criteria:

  • Wheelchair dependent (EDSS > 7.0)
  • History of central nervous system disease other than progressive MS
  • Steroids use within the past 3 months
  • Regular aerobic training (eg. bi-cycling, running, swimming or rowing)
  • Unwilling to travel to study sites for rehabilitation 2 times a week for 3 months

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03679468


Contacts
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Contact: Cecilia Meza 416 480 6100 ext 85382 cecilia.meza@sunnybrook.ca

Locations
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Canada, Ontario
Sunnybrook Health Science Center Recruiting
Toronto, Ontario, Canada, M4N3M5
Contact: Laura Kenton, PhD    416 480 6100 ext 7626    lauraekenton@gmail.com   
Sponsors and Collaborators
Sunnybrook Health Sciences Centre
University of Florence
Fondazione Italiana Sclerosi Multipla
University College, London
Kessler Foundation
University of Alabama at Birmingham
University of Southern Denmark
Hasselt University
University of Plymouth
University of Genoa
St. Michael's Hospital, Toronto
Ospedale San Raffaele
Investigators
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Principal Investigator: Anthony Feinstein, MD Sunnybrook Health Sciences Centre
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Dr. Anthony Feinstein, Professor, department of psychiatry, University of Toronto, Sunnybrook Health Sciences Centre
ClinicalTrials.gov Identifier: NCT03679468    
Other Study ID Numbers: 232-2018
First Posted: September 20, 2018    Key Record Dates
Last Update Posted: March 20, 2019
Last Verified: March 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Multiple Sclerosis
Multiple Sclerosis, Chronic Progressive
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases