CYPRO: The Influence of HIIT Versus MCT on Cardiorespiratory Fitness in PPMS

Sponsor

Klinik Valens (Other)

Overall Status

Recruiting

CT.gov ID

NCT05229861

Collaborator

Technische Universität Dortmund, Germany (Other)

Enrollment

Location

Arms

21.7

Anticipated Duration (Months)

2.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Primary Progressive Multiple Sclerosis Exercise Cardiorespiratory Fitness	Behavioral: HIIT Behavioral: MCT	N/A

Study Design

Study Type:

Interventional

Anticipated Enrollment :

61 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Single-centre Randomized Controlled Trial (RCT)Single-centre Randomized Controlled Trial (RCT)

Masking:

Double (Investigator, Outcomes Assessor)

Masking Description:

Blinding of the principal investigator and research assistant towards group allocation is ensured by a unique subject identification code given to each participant.

Primary Purpose:

Treatment

Official Title:

The Influence of High-Intensity Interval Training Compared to Moderate Continuous Training on Cardiorespiratory Fitness, Symptom Improvement, and Disease-specific Biomarkers in Primary Progressive Multiple Sclerosis

Actual Study Start Date :

May 10, 2022

Anticipated Primary Completion Date :

Feb 29, 2024

Anticipated Study Completion Date :

Feb 29, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: High-intensity Interval Training (HIIT) Participants will complete seven HR-controlled HIIT sessions within their 3-week inpatient stay, corresponding to 3 exercise bouts per week.	Behavioral: HIIT 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.
Active Comparator: Moderate Continuous Training (MCT) 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.	Behavioral: MCT 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.

Arm

Intervention/Treatment

Experimental: High-intensity Interval Training (HIIT)

Participants will complete seven HR-controlled HIIT sessions within their 3-week inpatient stay, corresponding to 3 exercise bouts per week.

Behavioral: HIIT

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.

Active Comparator: Moderate Continuous Training (MCT)

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.

Behavioral: MCT

Outcome Measures

Primary Outcome Measures

Cardiorespiratory fitness (peak oxygen consumption, VO2peak) [Three weeks (day 0 to day 21)]
Cardiorespiratory fitness will be measured by peak oxygen consumption achieved in the cardiopulmonary exercise test (CPET). Higher values indicate better cardiorespiratory fitness.

Secondary Outcome Measures

Peak power output (PPO) [Three weeks (day 0 to day 21)]
PPO is assessed during CPET and represents the maximum wattage achieved until exhaustion. Higher values reflect higher PPO.
Cognitive performance [Three weeks (day 0 to day 21)]
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.
Cognitive impairment at baseline [Baseline (day 0)]
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.
Walking capacity [Three weeks (day 0 to day 21)]
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.
Physical and psychological Impairment [Three weeks (day 0 to day 21)]
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.
Fatigue [Three weeks (day 0 to day 21)]
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.
Anxiety and depressive symptoms [Three weeks (day 0 to day 21)]
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.
Kynurenine pathway (KP) metabolites [Three weeks (day 0 to day 21)]
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).
Immune status (blood cells) [Time Frame: Three weeks (day 0 to day 21)]
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.
Immune status (pro-inflammatory cytokines) [Time Frame: Three weeks (day 0 to day 21)]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

adult age (≥ 18 years)
definite MS diagnosis according the 2017 revised McDonald criteria
disease course: PPMS according to the 2013 revised Lublin criteria
disease severity: Expanded Disability Status Scale (EDSS) score ≤ 6.0
Informed Consent as documented by signature of participants and PI

Exclusion Criteria:

Persons suffering from severe lower extremity spasticity or severe concomitant ´ disease states (i.e., orthopaedic, cardiovascular, metabolic, psychiatric (e.g., substance abuse), other neurological, other serious medical conditions) impairing their ability to participate.
Persons regularly performing HIIT (2-3 times per week)
Inability to follow the procedures of the study due to language problems (i.e., participant not fluent in oral and written German language)
Changes in disease-modifying drugs (≤ 6 weeks)
Immunosuppressive therapy (i.e., corticosteroids) (≤ 4 weeks)
Stem cell treatment (≤ 6 months)
Pregnant or breast-feeding women
Intention to become pregnant during the course of the study
Suspected non-compliance
Previous enrolment into the current study
Enrolment of the investigator, his/her family members, employees, and other dependent persons
occurrence of severe pulmonary or cardiovascular decompensations (i.e., blood pressure (Riva Rocci) > 240/120, HR ≥ HRmax (220-years of age) (e.g. due to renal failure, hepatic dysfunction, cardiovascular disease)
abnormalities in electrocardiography (ECG), pulse oximetry, or spirometry during initial CPET