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

November 6, 2023 updated by: Dr. Anthony Feinstein, Sunnybrook Health Sciences Centre

Improving Cognition in People With Progressive Multiple Sclerosis: A Multi-Arm, Randomized, Blinded, Sham-Controlled Trial of Cognitive Rehabilitation and Aerobic Exercise.

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

309

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M4N3M5
        • Sunnybrook Health Science Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

25 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: Randomized
  • Interventional Model: Sequential Assignment
  • Masking: Double

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Baseline, 12 weeks, and 6 month

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Baseline, 12 weeks, & 6 month
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
Baseline, 12 weeks, & 6 month
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
Baseline, 12 weeks, and 6 month
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
Baseline, 12 weeks, and 6 month
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.
Baseline, 12 weeks, and 6 month
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.
Baseline, 12 weeks, and 6 month
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.
Baseline, 12 weeks, and 6 month
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.
Baseline, 12 weeks, and 6 month
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".
Baseline, 12 weeks, and 6 month
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.
Baseline, 12 weeks, and 6 month

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
Baseline, 12 weeks, 6 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sunnybrook Health Sciences Centre

Collaborators

Fondazione Italiana Sclerosi Multipla
University of Alabama at Birmingham
University College, London
Hasselt University
Unity Health Toronto
University of Southern Denmark
University of Plymouth
University of Florence
Ospedale San Raffaele
Kessler Foundation
Universita degli Studi di Genova

Investigators

  • Principal Investigator: Anthony Feinstein, MD, Sunnybrook Health Sciences Centre

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 18, 2019

Primary Completion (Actual)

October 30, 2022

Study Completion (Actual)

February 3, 2023

Study Registration Dates

First Submitted

August 23, 2018

First Submitted That Met QC Criteria

September 18, 2018

First Posted (Actual)

September 20, 2018

Study Record Updates

Last Update Posted (Estimated)

November 8, 2023

Last Update Submitted That Met QC Criteria

November 6, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 232-2018

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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