Clinical trial NCT03679468: Improving Cognition in People With Progressive Multiple Sclerosis Using Aerobic Exercise and Cognitive Rehabilitation
Official title: Improving Cognition in People With Progressive Multiple Sclerosis: A Multi-Arm, Randomized, Blinded, Sham-Controlled Trial of Cognitive Rehabilitation and Aerobic Exercise.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Multiple Sclerosis, Primary Progressive
Cognitive Impairment
Lead sponsor: Sunnybrook Health Sciences Centre
Sponsor class: OTHER
Collaborators: name: University of Florence
name: Fondazione Italiana Sclerosi Multipla
name: University College, London
name: Kessler Foundation
name: University of Alabama at Birmingham
name: University of Southern Denmark
name: Hasselt University
name: University of Plymouth
name: Universita degli Studi di Genova
name: Unity Health Toronto
name: Ospedale San Raffaele
First posted: 2018-09-20
Enrollment: 309
Sex: ALL
Minimum age (years): 25
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
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.
Primary purpose: OTHER

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.

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.

Eligibility 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

Primary outcomes:
measure: Change from baseline cognitive Information processing speed at 12 weeks and 6 months
timeFrame: Baseline, 12 weeks, and 6 month
Secondary outcomes:
measure: Change from baseline cognitive verbal memory at 12 weeks and 6 months
timeFrame: Baseline, 12 weeks, & 6 month
measure: Change from baseline cognitive visual memory at 12 weeks and 6 months
timeFrame: Baseline, 12 weeks, & 6 month
measure: Change from baseline anxiety & depression, at 12 weeks and 6 months
timeFrame: Baseline, 12 weeks, and 6 month
measure: Change from baseline depression, at 12 weeks and 6 months
timeFrame: Baseline, 12 weeks, and 6 month
measure: Change from baseline fatigue, at 12 weeks and 6 months
timeFrame: Baseline, 12 weeks, and 6 month
measure: Change from baseline perceived deficits, at 12 weeks and 6 months
timeFrame: Baseline, 12 weeks, and 6 month
measure: Change from baseline subjective impact of walking, at 12 weeks and 6 months
timeFrame: Baseline, 12 weeks, and 6 month
measure: Change from baseline impact of Multiple Sclerosis, at 12 weeks and 6 months
timeFrame: Baseline, 12 weeks, and 6 month
measure: Change from baseline quality of life, at 12 weeks and 6 months
timeFrame: Baseline, 12 weeks, and 6 month
measure: Change from baseline global function, at 12 weeks and 6 months
timeFrame: Baseline, 12 weeks, and 6 month
Other outcomes:
measure: Change from baseline brain activity at 12 weeks and 6 months
timeFrame: Baseline, 12 weeks, 6 months
Locations:
city: Toronto
country: Canada
facility: Sunnybrook Health Science Center
state: Ontario
Study officials:
affiliation: Sunnybrook Health Sciences Centre
name: Anthony Feinstein, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Feinstein 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.
citation: Feinstein 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.
citation: Feinstein 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.
citation: Feinstein 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.
citation: Sandroff 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.
citation: Chiaravalloti 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.
citation: Veldkamp 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.
citation: Romano 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.
citation: Preziosa 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.