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

Primary Purpose

Primary Progressive Multiple Sclerosis, Exercise, Cardiorespiratory Fitness

Status

Recruiting

Phase

Not Applicable

Locations

Switzerland

Study Type

Interventional

Intervention

HIIT

MCT

About this trial

This is an interventional treatment trial for Primary Progressive Multiple Sclerosis focused on measuring Multiple Sclerosis, Primary Progressive Multiple Sclerosis, Exercise, High-intensity Interval Exercise, Rehabilitation, Cardiorespiratory Fitness, Cognition, Mobility limitation, Quality of Life, Fatigue, Depression, Immune signalling, Inflammation, Kynurenine pathway

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

Klinik Valens, Valens rehabilitation clinicRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

High-intensity Interval Training (HIIT)

Moderate Continuous Training (MCT)

Arm Description

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

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Peak power output (PPO)

PPO is assessed during CPET and represents the maximum wattage achieved until exhaustion. Higher values reflect higher PPO.

Cognitive performance

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

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

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

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

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

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

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)

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)

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.

Full Information

NCT ID

NCT05229861

First Posted

January 14, 2022

Last Updated

June 9, 2022

Sponsor

Klinik Valens

Collaborators

Technische Universität Dortmund, Germany

1. Study Identification

Unique Protocol Identification Number

NCT05229861

Brief Title

The Influence of HIIT Versus MCT on Cardiorespiratory Fitness in PPMS

Acronym

CYPRO

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

Study Type

Interventional

2. Study Status

Record Verification Date

June 2022

Overall Recruitment Status

Recruiting

Study Start Date

May 10, 2022 (Actual)

Primary Completion Date

February 29, 2024 (Anticipated)

Study Completion Date

February 29, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Klinik Valens

Collaborators

Technische Universität Dortmund, Germany

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Primary Progressive Multiple Sclerosis, Exercise, Cardiorespiratory Fitness

Keywords

Multiple Sclerosis, Primary Progressive Multiple Sclerosis, Exercise, High-intensity Interval Exercise, Rehabilitation, Cardiorespiratory Fitness, Cognition, Mobility limitation, Quality of Life, Fatigue, Depression, Immune signalling, Inflammation, Kynurenine pathway

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Model Description

Single-centre Randomized Controlled Trial (RCT)

Masking

InvestigatorOutcomes 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.

Allocation

Randomized

Enrollment

61 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

High-intensity Interval Training (HIIT)

Arm Type

Experimental

Arm Description

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

Arm Title

Moderate Continuous Training (MCT)

Arm Type

Active Comparator

Arm Description

Intervention Type

Behavioral

Intervention Name(s)

HIIT

Intervention Description

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.

Intervention Type

Behavioral

Intervention Name(s)

MCT

Intervention Description

Primary Outcome Measure Information:

Title

Cardiorespiratory fitness (peak oxygen consumption, VO2peak)

Description

Cardiorespiratory fitness will be measured by peak oxygen consumption achieved in the cardiopulmonary exercise test (CPET). Higher values indicate better cardiorespiratory fitness.

Time Frame

Three weeks (day 0 to day 21)

Secondary Outcome Measure Information:

Title

Peak power output (PPO)

Description

PPO is assessed during CPET and represents the maximum wattage achieved until exhaustion. Higher values reflect higher PPO.

Time Frame

Three weeks (day 0 to day 21)

Title

Cognitive performance

Description

Time Frame

Three weeks (day 0 to day 21)

Title

Cognitive impairment at baseline

Description

Time Frame

Baseline (day 0)

Title

Walking capacity

Description

Time Frame

Three weeks (day 0 to day 21)

Title

Physical and psychological Impairment

Description

Time Frame

Three weeks (day 0 to day 21)

Title

Fatigue

Description

Time Frame

Three weeks (day 0 to day 21)

Title

Anxiety and depressive symptoms

Description

Time Frame

Three weeks (day 0 to day 21)

Title

Kynurenine pathway (KP) metabolites

Description

Time Frame

Three weeks (day 0 to day 21)

Title

Immune status (blood cells)

Description

Time Frame

Time Frame: Three weeks (day 0 to day 21)

Title

Immune status (pro-inflammatory cytokines)

Description

Time Frame

Time Frame: Three weeks (day 0 to day 21)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Marie Kupjetz, cand. PhD

Phone

+41813031900.

Marie.Kupjetz@kliniken-valens.ch

First Name & Middle Initial & Last Name or Official Title & Degree

Jens Bansi, PhD

Phone

+41813031900.

Jens.Bansi@kliniken-valens.ch

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Roman Gonzenbach, MD

Organizational Affiliation

Klinik Valens

Official's Role

Study Director

First Name & Middle Initial & Last Name & Degree

Bansi Jens, PhD

Organizational Affiliation

Klinik Valens

Official's Role

Principal Investigator

Facility Information:

Facility Name

Klinik Valens, Valens rehabilitation clinic

City

Valens

State/Province

Sankt Gallen

ZIP/Postal Code

7317

Country

Switzerland

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Jens Bansi, PhD

Phone

+41813031900

Jens.Bansi@kliniken-valens.ch

First Name & Middle Initial & Last Name & Degree

Jens Bansi, PhD

First Name & Middle Initial & Last Name & Degree

Marie Kupjetz, cand. PhD

12. IPD Sharing Statement

Citations:

PubMed Identifier

29224960

Citation

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.

Results Reference

result

PubMed Identifier

28825348

Citation

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.

Results Reference

result

PubMed Identifier

32880214

Citation

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.

Results Reference

result

PubMed Identifier

33782190

Citation

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.

Results Reference

result

PubMed Identifier

34198345

Citation

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.

Results Reference

result

PubMed Identifier

33836459

Citation

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.

Results Reference

result

PubMed Identifier

33633658

Citation

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.

Results Reference

result

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The Influence of HIIT Versus MCT on Cardiorespiratory Fitness in PPMS

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