Multiple Sclerosis, Primary ProgressiveNCT03679468
Improving Cognition in People With Progressive Multiple Sclerosis Using Aerobic Exercise and Cognitive Rehabilitation
A study testing Cognitive Rehabilitation and Aerobic Exercise in people with Multiple Sclerosis, Primary Progressive and Cognitive Impairment, run by Sunnybrook Health Sciences Centre at 1 site in Canada.
Trial 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. Read more about this study
- Who is it for?
- Ages 25 to 65 years
- Conditions the study is for
- Multiple Sclerosis, Primary Progressive, Cognitive Impairment
- What is being tested?
- Cognitive Rehabilitation and Aerobic Exercise
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 309 participants
- Where
- 1 siteCanada
- Study dates
- 18 Mar 2019to 3 Feb 2023
- Phase
- Interventional
- Are there results?
- None posted in the registry
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 25 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Have a confirmed diagnosis of progressive Multiple Sclerosis
- Visual Acuity of 20/70
- Language comprehension, to ensure subjects have the ability to understand instructions
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: 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.
Read the 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.
- Being tested
- Cognitive Rehabilitation, Sham Exercise, Sham Cognitive Rehabilitation, Aerobic Exercise
- Medical subject headings
- Multiple Sclerosis, Chronic Progressive, Cognitive Dysfunction
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Cognitive RehabilitationOther
RehaCom software
Information processing speed and attention modules
Sham ExerciseOther
Sets of balance and stretching exercises
Sham Cognitive RehabilitationOther
Kompozer software
24 session module consisting of basic internet searches
Aerobic ExerciseOther
Recumbent NuStep Bike
Aerobic cycling
| Study group | Role | What they receive |
|---|---|---|
| Cognitive Rehab & Sham Exercise | Sham comparator | 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. Receives: Other: Cognitive Rehabilitation; Other: Sham Exercise |
| Sham Cognitive Rehab & Sham Exercise | Sham comparator | 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. Receives: Other: Sham Exercise; Other: Sham Cognitive Rehabilitation |
| Sham Cognitive rehab & Aerobic Exercise | Sham comparator | 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. Receives: Other: Sham Cognitive Rehabilitation; Other: Aerobic Exercise |
| Cognitive Rehab & Aerobic Exercise | Active comparator | 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. Receives: Other: Cognitive Rehabilitation; Other: Aerobic Exercise |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change from baseline cognitive Information processing speed at 12 weeks and 6 months
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
Measured: Baseline, 12 weeks, and 6 month
Secondary outcomes (10)
Change from baseline cognitive verbal memory at 12 weeks and 6 months
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
Measured: Baseline, 12 weeks, & 6 month
Change from baseline cognitive visual memory at 12 weeks and 6 months
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
Measured: Baseline, 12 weeks, & 6 month
Change from baseline anxiety & depression, at 12 weeks and 6 months
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
Measured: Baseline, 12 weeks, and 6 month
Change from baseline depression, at 12 weeks and 6 months
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
Measured: Baseline, 12 weeks, and 6 month
Change from baseline fatigue, at 12 weeks and 6 months
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.
Measured: Baseline, 12 weeks, and 6 month
Change from baseline perceived deficits, at 12 weeks and 6 months
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.
Measured: Baseline, 12 weeks, and 6 month
Change from baseline subjective impact of walking, at 12 weeks and 6 months
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.
Measured: Baseline, 12 weeks, and 6 month
Change from baseline impact of Multiple Sclerosis, at 12 weeks and 6 months
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.
Measured: Baseline, 12 weeks, and 6 month
Change from baseline quality of life, at 12 weeks and 6 months
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".
Measured: Baseline, 12 weeks, and 6 month
Change from baseline global function, at 12 weeks and 6 months
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.
Measured: Baseline, 12 weeks, and 6 month
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Sep 2018
- Study start18 Mar 2019
- Primary completion30 Oct 2022
- Study completion3 Feb 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (14)Papers the sponsor has linked to this study.
- Other trials for Multiple Sclerosis, Primary ProgressiveStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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 N/A
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Sequential
- 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 blind
- Who is masked
- Participant, Investigator
- Enrolment
- 309 participants (actual)
Sponsor and investigators
- Lead sponsor
- Sunnybrook Health Sciences Centre
- Sponsor type
- University, hospital or other
- 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, Universita degli Studi di Genova, Unity Health Toronto, Ospedale San Raffaele
- Responsible party
- Principal investigator, Dr. Anthony Feinstein, Sunnybrook Health Sciences Centre
- Investigators
- Anthony Feinstein, MD, Principal investigator, Sunnybrook Health Sciences Centre
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03679468
- Sponsor's protocol ID
- 232-2018
- Status last verified
- Nov 2023
- First submitted
- 23 Aug 2018
- Last updated
- 8 Nov 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Feinstein A, Amato MP, Brichetto G, Chataway J, Chiaravalloti N, Dalgas U, DeLuca J, Feys P, Filippi M, Freeman J, Meza C, Inglese M, Motl RW, Rocca MA, Sandroff BM, Salter A, Cutter G; CogEx Research Team. Study protocol: improving cognition in people with progressive multiple sclerosis: a multi-arm, randomized, blinded, sham-controlled trial of cognitive rehabilitation and aerobic exercise (COGEx). BMC Neurol. 2020 May 22;20(1):204. doi: 10.1186/s12883-020-01772-7.
PubMed 32443981Feinstein A, Amato MP, Brichetto G, Chataway J, Chiaravalloti ND, Cutter G, Dalgas U, DeLuca J, Farrell R, Feys P, Filippi M, Freeman J, Inglese M, Meza C, Motl RW, Rocca MA, Sandroff BM, Salter A; CogEx Research Team. Cognitive rehabilitation and aerobic exercise for cognitive impairment in people with progressive multiple sclerosis (CogEx): a randomised, blinded, sham-controlled trial. Lancet Neurol. 2023 Oct;22(10):912-924. doi: 10.1016/S1474-4422(23)00280-6.
PubMed 37739574Feinstein A, Amato MP, Brichetto G, Chataway J, Chiaravalloti ND, Cutter G, Dalgas U, DeLuca J, Farrell R, Feys P, Filippi M, Freeman J, Inglese M, Meza C, Motl R, Rocca MA, Sandroff BM, Salter A; CogEx Research Team. The impact of the COVID-19 pandemic on an international rehabilitation study in MS: the CogEx experience. J Neurol. 2022 Apr;269(4):1758-1763. doi: 10.1007/s00415-021-10881-3. Epub 2021 Nov 5.
PubMed 34741240Feinstein A, Amato MP, Brichetto G, Chataway J, Chiaravalloti ND, Cutter G, Dalgas U, DeLuca J, Farrell R, Feys P, Filippi M, Freeman J, Inglese M, Meza C, Motl RW, Rocca MA, Sandroff BM, Salter A; CogEx Research Team. The late onset of emotional distress in people with progressive multiple sclerosis during the Covid-19 pandemic: longitudinal findings from the CogEx study. J Neurol. 2022 Dec;269(12):6202-6210. doi: 10.1007/s00415-022-11295-5. Epub 2022 Aug 8.
PubMed 35939096Feinstein A. The CogEx trial - Cognitive rehabilitation and aerobic exercise for cognitive impairment in people with progressive multiple sclerosis: A randomised, blinded, sham-controlled trial. Mult Scler. 2023 Nov;29(13):1523-1525. doi: 10.1177/13524585231210178. Epub 2023 Nov 2. No abstract available.
PubMed 37916484Sandroff BM, Motl RW, Amato MP, Brichetto G, Chataway J, Chiaravalloti ND, Cutter GR, Dalgas U, DeLuca J, Farrell R, Feys P, Filippi M, Freeman J, Inglese M, Meza C, Rocca MA, Salter A, Feinstein A. Cardiorespiratory fitness and free-living physical activity are not associated with cognition in persons with progressive multiple sclerosis: Baseline analyses from the CogEx study. Mult Scler. 2022 Jun;28(7):1091-1100. doi: 10.1177/13524585211048397. Epub 2021 Oct 1.
PubMed 34595972Chiaravalloti ND, Amato MP, Brichetto G, Chataway J, Dalgas U, DeLuca J, Meza C, Moore NB, Feys P, Filippi M, Freeman J, Inglese M, Motl R, Rocca MA, Sandroff BM, Salter A, Cutter G, Feinstein A; CogEx Research Team. The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis. J Neurol. 2021 May;268(5):1598-1607. doi: 10.1007/s00415-020-10160-7. Epub 2020 Aug 19.
PubMed 32813051Veldkamp R, D'hooge M, Sandroff BM, DeLuca J, Kos D, Salter A, Feinstein A, Amato MP, Brichetto G, Chataway J, Farrell R, Chiaravalloti ND, Dalgas U, Filippi M, Freeman J, Motl RW, Meza C, Inglese M, Rocca MA, Cutter G, Feys P; CogEx Research Team. Profiling cognitive-motor interference in a large sample of persons with progressive multiple sclerosis and impaired processing speed: results from the CogEx study. J Neurol. 2023 Jun;270(6):3120-3128. doi: 10.1007/s00415-023-11636-y. Epub 2023 Mar 7.
PubMed 36881147Romano F, Motl RW, Valsasina P, Amato MP, Brichetto G, Bruschi N, Chataway J, Chiaravalloti ND, Cutter G, Dalgas U, DeLuca J, Farrell R, Feys P, Freeman J, Inglese M, Meza C, Salter A, Sandroff BM, Feinstein A, Rocca MA, Filippi M; CogEx Research Team. Abnormal thalamic functional connectivity correlates with cardiorespiratory fitness and physical activity in progressive multiple sclerosis. J Neurol. 2023 Jun;270(6):3213-3224. doi: 10.1007/s00415-023-11664-8. Epub 2023 Mar 18.
PubMed 36933030Preziosa P, Rocca MA, Pagani E, Valsasina P, Amato MP, Brichetto G, Bruschi N, Chataway J, Chiaravalloti ND, Cutter G, Dalgas U, DeLuca J, Farrell R, Feys P, Freeman J, Inglese M, Meani A, Meza C, Motl RW, Salter A, Sandroff BM, Feinstein A, Filippi M; the CogEx Research Team. Structural and functional magnetic resonance imaging correlates of fatigue and dual-task performance in progressive multiple sclerosis. J Neurol. 2023 Mar;270(3):1543-1563. doi: 10.1007/s00415-022-11486-0. Epub 2022 Nov 27.
PubMed 36436069Meza C, Hernandez RS, Costa SL, Salter A, Chiaravalloti ND, Amato MP, Brichetto G, Chataway J, Cutter G, Dalgas U, DeLuca J, Farrell R, Feys P, Filippi M, Freeman J, Inglese M, Motl RW, Rocca MA, Sandroff BM, Feinstein A; CogEx Research Team. Looking Beyond Dose: Identifying Responders and Non-Responders to RehaCom Computerized Cognitive Rehabilitation in Progressive MS-The CogEx Study. Neurorehabil Neural Repair. 2026 Jul;40(7):575-586. doi: 10.1177/15459683261432556. Epub 2026 Apr 25.
PubMed 42033185Romano F, Rocca MA, Pagani E, Amato MP, Brichetto G, Chataway J, Chiaravalloti ND, Cutter G, Dalgas U, DeLuca J, Farrell R, Feys P, Freeman J, Inglese M, Cipriano E, Meza C, Motl RW, Salter A, Sandroff BM, Feinstein A, Filippi M; CogEx Research Team. Effects of cognitive rehabilitation and exercise on brain structure in progressive multiple sclerosis: results from the CogEx trial. J Neurol. 2025 Sep 23;272(10):645. doi: 10.1007/s00415-025-13382-9.
PubMed 40986118Rocca MA, Valsasina P, Romano F, Tedone N, Amato MP, Brichetto G, Boccia VD, Chataway J, Chiaravalloti ND, Cutter G, Dalgas U, DeLuca J, Farrell RA, Feys P, Freeman J, Inglese M, Meza C, Motl RW, Salter A, Sandroff BM, Feinstein A, Filippi M; Cogex Research Team. Cognitive rehabilitation effects on grey matter volume and Go-NoGo activity in progressive multiple sclerosis: results from the CogEx trial. J Neurol Neurosurg Psychiatry. 2024 Nov 18;95(12):1139-1149. doi: 10.1136/jnnp-2024-333460.
PubMed 38754979Ramari C, D'hooge M, Dalgas U, Feinstein A, Amato MP, Brichetto G, Chataway J, Chiaravalloti ND, Cutter GR, DeLuca J, Farrell R, Filippi M, Freeman J, Inglese M, Meza C, Motl RW, Rocca MA, Sandroff BM, Salter A, Kos D, Feys P. Prevalence and Associated Clinical Characteristics of Walking-Related Motor, Cognitive, and Fatigability in Progressive Multiple Sclerosis: Baseline Results From the CogEx Study. Neurorehabil Neural Repair. 2024 May;38(5):327-338. doi: 10.1177/15459683241236161. Epub 2024 Mar 1.
PubMed 38426484
Study at a glance
From the registry record, last updated by the sponsor on 8 Nov 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Improving Cognition in People With Progressive Multiple Sclerosis: A Multi-Arm, Randomized, Blinded, Sham-Controlled Trial of Cognitive Rehabilitation and Aerobic Exercise.
- ClinicalTrials.gov ID
- NCT03679468
- Acronym / sponsor ID
- 232-2018
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 309 participants (actual)
- Lead sponsor
- Sunnybrook Health Sciences CentreUniversity, hospital or other
- 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, Universita degli Studi di Genova, Unity Health Toronto, Ospedale San Raffaele
- Study start
- 18 Mar 2019 (actual)
- Primary completion
- 30 Oct 2022 (actual)
- Study completion
- 3 Feb 2023 (actual)
- First posted
- 20 Sep 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- Double blind (participant, investigator)
- Number of arms
- 4
- 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.
| Arm | Type | Receives |
|---|---|---|
| Cognitive Rehab & Sham Exercise | Sham comparator | Other: Cognitive Rehabilitation, Other: Sham ExerciseCognitive 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. |
| Sham Cognitive Rehab & Sham Exercise | Sham comparator | Other: Sham Exercise, Other: Sham Cognitive RehabilitationSham 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. |
| Sham Cognitive rehab & Aerobic Exercise | Sham comparator | Other: Sham Cognitive Rehabilitation, Other: Aerobic ExerciseSham 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. |
| Cognitive Rehab & Aerobic Exercise | Active comparator | Other: Cognitive Rehabilitation, Other: Aerobic ExerciseCognitive 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. |
Who may qualify
- Ages
- 25 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Have a confirmed diagnosis of progressive Multiple Sclerosis
- Visual Acuity of 20/70
- Language comprehension, to ensure subjects have the ability to understand instructions
Key exclusion criteria (5 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Cognitive RehabilitationRehaCom software Information processing speed and attention modules | Other | Cognitive Rehab & Aerobic Exercise, Cognitive Rehab & Sham Exercise |
| Sham ExerciseSets of balance and stretching exercises | Other | Cognitive Rehab & Sham Exercise, Sham Cognitive Rehab & Sham Exercise |
| Sham Cognitive RehabilitationKompozer software 24 session module consisting of basic internet searches | Other | Sham Cognitive Rehab & Sham Exercise, Sham Cognitive rehab & Aerobic Exercise |
| Aerobic ExerciseRecumbent NuStep Bike Aerobic cycling | Other | Cognitive Rehab & Aerobic Exercise, Sham Cognitive rehab & Aerobic Exercise |
Primary outcome
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
10 secondary outcomes
Change from baseline cognitive verbal memory at 12 weeks and 6 months
Time frame: Baseline, 12 weeks, & 6 month
Change from baseline cognitive visual memory at 12 weeks and 6 months
Time frame: Baseline, 12 weeks, & 6 month
Change from baseline anxiety & depression, at 12 weeks and 6 months
Time frame: Baseline, 12 weeks, and 6 month
Change from baseline depression, at 12 weeks and 6 months
Time frame: Baseline, 12 weeks, and 6 month
Change from baseline fatigue, at 12 weeks and 6 months
Time frame: 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
Change from baseline subjective impact of walking, at 12 weeks and 6 months
Time frame: 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
Change from baseline quality of life, at 12 weeks and 6 months
Time frame: 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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Nov 2023.
- Results publication: PubMed 32443981Feinstein A, Amato MP, Brichetto G, Chataway J, Chiaravalloti N, Dalgas U, DeLuca J, Feys P, Filippi M, Freeman J, Meza C, Inglese M, Motl RW, Rocca MA, Sandroff BM, Salter A, Cutter G; CogEx Research Team. Study protocol: improving cognition in people with progressive multiple sclerosis: a multi-arm, randomized, blinded, sham-controlled trial of cognitive rehabilitation and aerobic exercise (COGEx). BMC Neurol. 2020 May 22;20(1):204. doi: 10.1186/s12883-020-01772-7.
- Results publication: PubMed 37739574Feinstein A, Amato MP, Brichetto G, Chataway J, Chiaravalloti ND, Cutter G, Dalgas U, DeLuca J, Farrell R, Feys P, Filippi M, Freeman J, Inglese M, Meza C, Motl RW, Rocca MA, Sandroff BM, Salter A; CogEx Research Team. Cognitive rehabilitation and aerobic exercise for cognitive impairment in people with progressive multiple sclerosis (CogEx): a randomised, blinded, sham-controlled trial. Lancet Neurol. 2023 Oct;22(10):912-924. doi: 10.1016/S1474-4422(23)00280-6.
- Results publication: PubMed 34741240Feinstein A, Amato MP, Brichetto G, Chataway J, Chiaravalloti ND, Cutter G, Dalgas U, DeLuca J, Farrell R, Feys P, Filippi M, Freeman J, Inglese M, Meza C, Motl R, Rocca MA, Sandroff BM, Salter A; CogEx Research Team. The impact of the COVID-19 pandemic on an international rehabilitation study in MS: the CogEx experience. J Neurol. 2022 Apr;269(4):1758-1763. doi: 10.1007/s00415-021-10881-3. Epub 2021 Nov 5.
- Results publication: PubMed 35939096Feinstein A, Amato MP, Brichetto G, Chataway J, Chiaravalloti ND, Cutter G, Dalgas U, DeLuca J, Farrell R, Feys P, Filippi M, Freeman J, Inglese M, Meza C, Motl RW, Rocca MA, Sandroff BM, Salter A; CogEx Research Team. The late onset of emotional distress in people with progressive multiple sclerosis during the Covid-19 pandemic: longitudinal findings from the CogEx study. J Neurol. 2022 Dec;269(12):6202-6210. doi: 10.1007/s00415-022-11295-5. Epub 2022 Aug 8.
- Results publication: PubMed 37916484Feinstein A. The CogEx trial - Cognitive rehabilitation and aerobic exercise for cognitive impairment in people with progressive multiple sclerosis: A randomised, blinded, sham-controlled trial. Mult Scler. 2023 Nov;29(13):1523-1525. doi: 10.1177/13524585231210178. Epub 2023 Nov 2. No abstract available.
- Results publication: PubMed 34595972Sandroff BM, Motl RW, Amato MP, Brichetto G, Chataway J, Chiaravalloti ND, Cutter GR, Dalgas U, DeLuca J, Farrell R, Feys P, Filippi M, Freeman J, Inglese M, Meza C, Rocca MA, Salter A, Feinstein A. Cardiorespiratory fitness and free-living physical activity are not associated with cognition in persons with progressive multiple sclerosis: Baseline analyses from the CogEx study. Mult Scler. 2022 Jun;28(7):1091-1100. doi: 10.1177/13524585211048397. Epub 2021 Oct 1.
- Results publication: PubMed 32813051Chiaravalloti ND, Amato MP, Brichetto G, Chataway J, Dalgas U, DeLuca J, Meza C, Moore NB, Feys P, Filippi M, Freeman J, Inglese M, Motl R, Rocca MA, Sandroff BM, Salter A, Cutter G, Feinstein A; CogEx Research Team. The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis. J Neurol. 2021 May;268(5):1598-1607. doi: 10.1007/s00415-020-10160-7. Epub 2020 Aug 19.
- Results publication: PubMed 36881147Veldkamp R, D'hooge M, Sandroff BM, DeLuca J, Kos D, Salter A, Feinstein A, Amato MP, Brichetto G, Chataway J, Farrell R, Chiaravalloti ND, Dalgas U, Filippi M, Freeman J, Motl RW, Meza C, Inglese M, Rocca MA, Cutter G, Feys P; CogEx Research Team. Profiling cognitive-motor interference in a large sample of persons with progressive multiple sclerosis and impaired processing speed: results from the CogEx study. J Neurol. 2023 Jun;270(6):3120-3128. doi: 10.1007/s00415-023-11636-y. Epub 2023 Mar 7.
- Results publication: PubMed 36933030Romano F, Motl RW, Valsasina P, Amato MP, Brichetto G, Bruschi N, Chataway J, Chiaravalloti ND, Cutter G, Dalgas U, DeLuca J, Farrell R, Feys P, Freeman J, Inglese M, Meza C, Salter A, Sandroff BM, Feinstein A, Rocca MA, Filippi M; CogEx Research Team. Abnormal thalamic functional connectivity correlates with cardiorespiratory fitness and physical activity in progressive multiple sclerosis. J Neurol. 2023 Jun;270(6):3213-3224. doi: 10.1007/s00415-023-11664-8. Epub 2023 Mar 18.
- Results publication: PubMed 36436069Preziosa P, Rocca MA, Pagani E, Valsasina P, Amato MP, Brichetto G, Bruschi N, Chataway J, Chiaravalloti ND, Cutter G, Dalgas U, DeLuca J, Farrell R, Feys P, Freeman J, Inglese M, Meani A, Meza C, Motl RW, Salter A, Sandroff BM, Feinstein A, Filippi M; the CogEx Research Team. Structural and functional magnetic resonance imaging correlates of fatigue and dual-task performance in progressive multiple sclerosis. J Neurol. 2023 Mar;270(3):1543-1563. doi: 10.1007/s00415-022-11486-0. Epub 2022 Nov 27.
- Derived from this study: PubMed 42033185Meza C, Hernandez RS, Costa SL, Salter A, Chiaravalloti ND, Amato MP, Brichetto G, Chataway J, Cutter G, Dalgas U, DeLuca J, Farrell R, Feys P, Filippi M, Freeman J, Inglese M, Motl RW, Rocca MA, Sandroff BM, Feinstein A; CogEx Research Team. Looking Beyond Dose: Identifying Responders and Non-Responders to RehaCom Computerized Cognitive Rehabilitation in Progressive MS-The CogEx Study. Neurorehabil Neural Repair. 2026 Jul;40(7):575-586. doi: 10.1177/15459683261432556. Epub 2026 Apr 25.
- Derived from this study: PubMed 40986118Romano F, Rocca MA, Pagani E, Amato MP, Brichetto G, Chataway J, Chiaravalloti ND, Cutter G, Dalgas U, DeLuca J, Farrell R, Feys P, Freeman J, Inglese M, Cipriano E, Meza C, Motl RW, Salter A, Sandroff BM, Feinstein A, Filippi M; CogEx Research Team. Effects of cognitive rehabilitation and exercise on brain structure in progressive multiple sclerosis: results from the CogEx trial. J Neurol. 2025 Sep 23;272(10):645. doi: 10.1007/s00415-025-13382-9.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Anthony Feinstein, MD principal investigator
Sunnybrook Health Sciences Centre
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Cognitive Rehabilitation and Aerobic Exercise in people with Multiple Sclerosis, Primary Progressive and Cognitive Impairment, run by Sunnybrook Health Sciences Centre at 1 site in Canada.
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 3 inclusion and 5 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 8 Nov 2023. 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 Canada. 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. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Change from baseline cognitive Information processing speed at 12 weeks and 6 months (time frame: Baseline, 12 weeks, and 6 month). 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 NCT03679468, which also lists 14 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 8 Nov 2023.