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| Name | Class |
|---|---|
| Technische Universität Dortmund, Germany | UNKNOWN |
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Endurance training revealed to be an effective means to increase cardiorespiratory fitness in persons with Multiple Sclerosis (MS), considered relevant to health-related quality of life in this population. Moreover, endurance training improves MS-related symptoms, such as reduced walking capacity, fatigue, depression, and cognitive impairment. Owing to these benefits, endurance training has evolved as an integral part of MS rehabilitation, anchored in current treatment guidelines.
In recent years, High-Intensity Interval training (HIIT) evolved as a time-efficient and safe alternative to standard care in MS rehabilitation that is Moderate Continuous Training (MCT). Indeed, HIIT has already been proven superior to MCT in improving cardiorespiratory fitness, MS-related symptoms (e.g. cognitive impairment) and, beyond, seems to elicit disease-modifying effects on MS-pathophysiology (i.e. alleviated neuroinflammation and neurodegeneration).
However, current evidence is restricted to clinical trials that include samples with mixed MS disease courses, in which persons with primary progressive MS (PPMS) are underrepresented due to comparatively low prevalence rates.
Distinct pathophysiological mechanisms and symptom constellations prohibit the generalisation of previous findings to persons with PPMS. In this population, however, evidence-based rehabilitative strategies are urgently needed, as disability progression in PPMS is poorly responsive to pharmacotherapy.
This study, aims to validate previous findings on the superior effect of HIIT compared to MCT on improving cardiorespiratory fitness, MS-related symptoms and MS pathophysiology in persons with PPMS, contributing to the development of specific recommendations to maximize the effects of exercise as a potent non-pharmacological treatment adjuvant.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| High-intensity Interval Training (HIIT) | Experimental | Participants will complete seven HR-controlled HIIT sessions within their 3-week inpatient stay, corresponding to 3 exercise bouts per week. |
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| Moderate Continuous Training (MCT) | Active Comparator | MCT represents the standard treatment at Valens rehabilitation clinic. Participants will complete seven HR-controlled MCT sessions within their 3-week inpatient stay, corresponding to 3 exercise bouts per week. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| HIIT | Behavioral | Exercise intensity will be regulated and heart rate controlled based on the achieved maximum heart rate (HRmax) assessed during the initial Cardiopulmonary Exercise Testing. Participants will perform five high-intensity intervals (95% HRpeak) at high pedalling rates of 80-100 rpm for 90 seconds each. Intervals are interspersed by active breaks of unloaded pedalling (20W, 60-70rpm) aimed to return to 60% HRpeak (approximately 1-1.5 min). The duration of a HIIT sessions is approximately 25 minutes. |
| Measure | Description | Time Frame |
|---|---|---|
| Cardiorespiratory fitness (peak oxygen consumption, VO2peak) | Cardiorespiratory fitness will be measured by peak oxygen consumption achieved in the cardiopulmonary exercise test (CPET). Higher values indicate better cardiorespiratory fitness. | Three weeks (day 0 to day 21) |
| Measure | Description | Time Frame |
|---|---|---|
| Peak power output (PPO) | PPO is assessed during CPET and represents the maximum wattage achieved until exhaustion. Higher values reflect higher PPO. | Three weeks (day 0 to day 21) |
| Cognitive performance |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Marie Kupjetz, cand. PhD | Contact | +41813031900. | Marie.Kupjetz@kliniken-valens.ch | |
| Jens Bansi, PhD | Contact | +41813031900. | Jens.Bansi@kliniken-valens.ch |
| Name | Affiliation | Role |
|---|---|---|
| Roman Gonzenbach, MD | Klinik Valens | Study Director |
| Bansi Jens, PhD | Klinik Valens | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Klinik Valens, Valens rehabilitation clinic | Recruiting | Valens | Canton of St. Gallen | 7317 | Switzerland |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 29224960 | Result | Bansi J, Koliamitra C, Bloch W, Joisten N, Schenk A, Watson M, Kool J, Langdon D, Dalgas U, Kesselring J, Zimmer P. Persons with secondary progressive and relapsing remitting multiple sclerosis reveal different responses of tryptophan metabolism to acute endurance exercise and training. J Neuroimmunol. 2018 Jan 15;314:101-105. doi: 10.1016/j.jneuroim.2017.12.001. Epub 2017 Dec 6. | |
| 28825348 |
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| ID | Term |
|---|---|
| D020528 | Multiple Sclerosis, Chronic Progressive |
| D009043 | Motor Activity |
| D009103 | Multiple Sclerosis |
| D051346 | Mobility Limitation |
| D005221 | Fatigue |
| D003863 | Depression |
| D007249 | Inflammation |
| ID | Term |
|---|---|
| D020278 | Demyelinating Autoimmune Diseases, CNS |
| D020274 | Autoimmune Diseases of the Nervous System |
| D009422 | Nervous System Diseases |
| D003711 | Demyelinating Diseases |
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Single-centre Randomized Controlled Trial (RCT)
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Blinding of the principal investigator and research assistant towards group allocation is ensured by a unique subject identification code given to each participant.
|
| MCT | Behavioral | Exercise intensity will be regulated and heart rate controlled based on the achieved maximum heart rate (HRmax) assessed during the initial Cardiopulmonary Exercise Testing. Participants perform continuous bicycle ergometry at moderate intensity (60% HRpeak) and 60-70 rpm for the duration of 30 minutes. |
|
Cognitive performance is assessed with the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS). This test battery involves three tests to assess the main cognitive domains vulnerable to MS: information processing speed, verbal and visual memory. The battery includes the Symbol Digit modalities Test (SDMT), Californian Verbal Learning Test-II (CVLT-II) and the Brief Visuospatial Memory Test revised (BVMT-R). Processing speed is the most relevant test and is assessed by the SDMT where the patients have 90s to voice numbers as rapidly as possible that were associated with target symbols within a grid printed at the top of a Stimulus page. The final score is the correct number of substitutions in 90 s, and scores ranges between 0 and 110. Higher scores indicating better cognition.
| Three weeks (day 0 to day 21) |
| Cognitive impairment at baseline | Screening of cognitive impairment is performed using the Montreal Cognitive Assessment (MoCA). The MoCA is a 30-point paper-pencil test that can be easily completed within 10 minutes. Items of the MoCA query short-term memory recall, visuospatial abilities, executive functions, attention, concentration, working memory, language, and orientation to time and place, all of which are summed up to a total score. A MoCa total score of < 26 is a sensitive measure of cognitive impairment in otherwise healthy subjects and in persons with MS. | Baseline (day 0) |
| Walking capacity | Walking capacity is assessed via the six-minute walk test (6-MWT). The 6-MWT is used to determine the total distance in meters covered within six minutes when walking back and forth on a 30 metres hallway, as a measure of endurance walking capacity. Longer distance covered in metres reflects higher walking capacity. | Three weeks (day 0 to day 21) |
| Physical and psychological Impairment | Physical and psychological Impairment is queried using the Multiple Sclerosis Impact Scale-29 (MSIS-29).The MSIS-29 contains a total of 29 items, split into two subscales, that adress physical impairment (20 items) and psychological impairment (9 items). Each item is ranked on a 5-point Likert scale with higher scores indicating higher physical and psychological impairment. | Three weeks (day 0 to day 21) |
| Fatigue | Fatigue is assessed by means of the Fatigue Motor and Cognitive Scale (FSMC), that allows separate rating of motor and cognitive fatigue, based on a 5-point Likert scale (range 1-5). Scores range from 20-100 for the total, and from 10-50 for each subscale. Higher scores indicate a higher level of fatigue. | Three weeks (day 0 to day 21) |
| Anxiety and depressive symptoms | Anxiety and depressive symptoms are assessed with the Hospital Anxiety and Depression Scale (HADS). The HADS was created as a 14-item scale for adults with physical ailments. On a 4-point Likert scale (range 0-3), patients rate anxiety (7 items) and depressive symptoms (7 items), respectively. Higher scores indicate a higher level of anxiety or depressive symptoms. | Three weeks (day 0 to day 21) |
| Kynurenine pathway (KP) metabolites | Changes in KP metabolites are assessed to investigate the biological mechanisms that may underpin clinical improvement in persons with PPMS. The KP is dysregulated in persons with MS and is sensitive to exercise-related changes. KP metabolites include tryptophan, kynurenine, kynurenic acid, quinolinic acid, indolamine 2,3-dioxygenase, and tryptophan 2,3-dioxygenase. Higher levels of kynurenic acid and tryptophan, and lower levels of kynurenine, kynurenic acid, quinolinic acid, indolamine 2,3-dioxygenase, and tryptophan 2,3-dioxygenase indicate a beneficial effect of KP regulation. KP metabolites are analyzed via targeted metabolomics (HPLC MS/MS). | Three weeks (day 0 to day 21) |
| Immune status (blood cells) | Numbers and proportions of circulating immune cells associated with MS and exercise (Th17 cell, cytotoxic T-cells, naïve T-cells, memory T-cells, NK-cells, Monocytes) are assessed, with higher values indicating higher levels of inflammation. Number and proportion of circulating regulatory T cells with higher values indicating lower levels of inflammation. Numbers of proportions of these circulating immune cells are determined by flow cytometric characterization of Th17 cell, cytotoxic T-cells, naïve T-cells, memory T-cells, NK-cells, and Monocytes. | Time Frame: Three weeks (day 0 to day 21) |
| Immune status (pro-inflammatory cytokines) | The pro-inflammatory cytokines IL-6, IFN-γ, TNF-α are known to be produced or secreted in response to chronic exercise and modify immune homeostasis. Higher values indicate higher levels of inflammation. Serum concentrations of IL-6, IFN-γ, and TNF-α are determined using commercial enzyme-linked immunosorbent assays (ELISAs) according to the manufacturer's instructions. | Time Frame: Three weeks (day 0 to day 21) |
| Result |
| Zimmer P, Bloch W, Schenk A, Oberste M, Riedel S, Kool J, Langdon D, Dalgas U, Kesselring J, Bansi J. High-intensity interval exercise improves cognitive performance and reduces matrix metalloproteinases-2 serum levels in persons with multiple sclerosis: A randomized controlled trial. Mult Scler. 2018 Oct;24(12):1635-1644. doi: 10.1177/1352458517728342. Epub 2017 Aug 21. |
| 32880214 | Result | Joisten N, Proschinger S, Rademacher A, Schenk A, Bloch W, Warnke C, Gonzenbach R, Kool J, Bansi J, Zimmer P. High-intensity interval training reduces neutrophil-to-lymphocyte ratio in persons with multiple sclerosis during inpatient rehabilitation. Mult Scler. 2021 Jun;27(7):1136-1139. doi: 10.1177/1352458520951382. Epub 2020 Sep 3. |
| 33782190 | Result | Joisten N, Rademacher A, Warnke C, Proschinger S, Schenk A, Walzik D, Knoop A, Thevis M, Steffen F, Bittner S, Gonzenbach R, Kool J, Bloch W, Bansi J, Zimmer P. Exercise Diminishes Plasma Neurofilament Light Chain and Reroutes the Kynurenine Pathway in Multiple Sclerosis. Neurol Neuroimmunol Neuroinflamm. 2021 Mar 29;8(3):e982. doi: 10.1212/NXI.0000000000000982. Print 2021 May. |
| 34198345 | Result | Lea Schlagheck M, Wucherer A, Rademacher A, Joisten N, Proschinger S, Walzik D, Bloch W, Kool J, Gonzenbach R, Bansi J, Zimmer P. VO2peak Response Heterogeneity in Persons with Multiple Sclerosis: To HIIT or Not to HIIT? Int J Sports Med. 2021 Dec;42(14):1319-1328. doi: 10.1055/a-1481-8639. Epub 2021 Jul 1. |
| 33836459 | Result | Rademacher A, Joisten N, Proschinger S, Hebchen J, Schlagheck ML, Bloch W, Gonzenbach R, Kool J, Bansi J, Zimmer P. Do baseline cognitive status, participant specific characteristics and EDSS impact changes of cognitive performance following aerobic exercise intervention in multiple sclerosis? Mult Scler Relat Disord. 2021 Jun;51:102905. doi: 10.1016/j.msard.2021.102905. Epub 2021 Mar 18. |
| 33633658 | Result | Rademacher A, Joisten N, Proschinger S, Bloch W, Gonzenbach R, Kool J, Langdon D, Bansi J, Zimmer P. Cognitive Impairment Impacts Exercise Effects on Cognition in Multiple Sclerosis. Front Neurol. 2021 Jan 28;11:619500. doi: 10.3389/fneur.2020.619500. eCollection 2020. |
| 37087424 | Derived | Kupjetz M, Joisten N, Rademacher A, Gonzenbach R, Bansi J, Zimmer P. Cycling in primary progressive multiple sclerosis (CYPRO): study protocol for a randomized controlled superiority trial evaluating the effects of high-intensity interval training in persons with primary progressive multiple sclerosis. BMC Neurol. 2023 Apr 22;23(1):162. doi: 10.1186/s12883-023-03187-6. |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D001519 | Behavior |
| D012816 | Signs and Symptoms |
| D001526 | Behavioral Symptoms |