Clinical trial NCT06068322: Supramaximal High-Intensity Interval Training in People With and Without Chronic Obstructive Pulmonary Disease
Official title: Effects and Mechanisms of Supramaximal High-Intensity Interval Training in People With and Without Chronic Obstructive Pulmonary Disease on Extrapulmonary Manifestations
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: COPD
Healthy Controls
Keywords: Chronic obstructive Pulmonary Disease
Pulmonary Disease, Chronic Obstructive
Chronic airway disease
COPD
physical activity
exercise
Lead sponsor: Umeå University
Sponsor class: OTHER
Collaborators: name: Hasselt University
name: Swedish Heart Lung Foundation
name: European Research Council
name: The Swedish Research Council
name: Ziekenhuis Oost-Limburg
name: Strategic Research Area - Health Care Science
First posted: 2023-10-05
Enrollment: 208
Sex: ALL
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: In Phase 1, participants will be randomised to either interventional arm or control arm with a 1:1 allocation ratio, using a computer-generated block randomisation schedule stratified for sex (male, female), age and centre with equal allocation to all study arms. For Phase 2 only the participants with COPD will continue the maintenance program in their allocated group. A usual of care group consisting of patients with COPD will also be recruited to serve as control in the maintenance part.
Primary purpose: TREATMENT

Brief summary: Beyond pulmonary complications, COPD presents with extrapulmonary manifestations including reduced cognitive, cardiovascular, and muscle function. While exercise training is the cornerstone in the non-pharmacological treatment of COPD, there is a need for new exercise training methods.

The COPD-HIIT trial intend to investigate the effects and mechanisms of 12 weeks supramaximal high-intensity interval-training (HIIT) compared to moderate intensive continous training (MICT) in people with COPD and matched healthy controls on important clinical outcomes.

The trial also intends to compare the effects of 24 months of exercise training (supramaximal HIIT or MICT) to usual care in people with COPD on brain health, cardiorespiratory fitness and muscle power; in people with COPD.

Detailed description: COPD-HIIT is a prospective, multi-centre, randomised, controlled, parallel-group superiority trial with assessor and data analyst blinding, featuring a 1:1 allocation ratio and two separate phases. In Phase 1, the trial will investigate the effects and mechanisms of a 12 week intervention with supramaximal HIIT compared to MICT in people with COPD and matched healthy controls. Upon completing the initial 12 week intervention and follow-up assessments, people with COPD, but not healthy controls, will enter Phase 2 of the trial. Phase 2 comprises a 21 month maintenance exercise program. Subsequently, exercise training (supramaximal HIIT or MICT) will be performed until a 24 month follow-up. A separate control group of people with COPD, receiving usual care only, will undergo assessments at baseline and 24-months, making Phase 2 a partially randomized controlled trial.

The primary objectives are:

1. to determine and compare the effect of 12-weeks of supramaximal HIIT and MICT on cognitive function, cardiorespiratory fitness, and muscle power in people with COPD compared to matched healthy controls (Phase 1).
2. to determine and compare the effect of 24-months of supramaximal HIIT, MICT and usual care on cognitive function, cardiorespiratory fitness and muscle power in people with COPD (Phase 2).

Phase 1 and 2 of the COPD-HIIT project will be performed at two recruiting centres. 1) Department of Community Medicine and Rehabilitation, Physiotherapy, Umeå University, Umeå, Sweden and Norrlands Universitetssjukhus, and 2) Faculty of Rehabilitation Sciences, Hasselt University, Diepenbeek, Belgium and Ziekenhuis Oost-Limburg (ZOL, Genk, Belgium).

In Phase 1, eligible participants will be randomized to either supramaximal HIIT (intervention arm) or MICT (active control arm) on a stationary bicycle (Smart ZBike, Zycle, Valencia, Spain). For both arms, training is performed two to three times per week for a total of 30 sessions (Table 1) using a group format with groups of 4-8 participants at the same time. Both protocols enable controlled and systematic adjustments of training intensity by means of standardized criteria to achieve a progressive overload

Regarding supramaximal HIIT, importantly, while the intensity is supramaximal, it is dosed and performed at a given fraction of the maximum capacity that the person can produce during the bout (6-seconds). In contrast to an all-out regimen, or sprint interval training (SIT), this allows for the introduction and titration of intensity to the highest acceptable level without the individual feeling unwell during the process.

In Phase 2, participants with COPD will enter a 21 month maintenance phase. They will continue to exercise using the same training modality (HIIT or MICT) as during the first 12-weeks but can select between three different settings to continue their training: "Home", "Outpatient", or "Mix" setting. Notably, the participant can, at any time during the maintenance period, change between the "Home", "Outpatient" or "Mix" settings when conducting their endurance training. Irrespective of the originally assigned group (supramaximal HIIT or MICT) or if the participant selects to continue in "Home", "Outpatient" or "Mix" setting, they will also perform a resistance training (RT) regime. The RT regime will consist of ten lower and upper-body exercises designed following American College of Sports Medicine guidelines and other relevant RT literature for increasing muscular strength, endurance, and power.

All exercise sessions will be held and supervised by an experienced health care professional, such as physiotherapists, exercise physiologists or other health professional with equivalent expertise. All intervention providers will receive training on exercise intervention protocols to ensure standardization among centres.

The between-group effects will be analyzed using analysis of covariance (ANCOVA). In the ANCOVA, baseline values, age, sex, center and VO2peak will be used as covariates. There will be one model for the COPD group and one for HC. To investigate any differential effects to the interventions between COPD and HC, an additional model including the Group (COPD/HC) × Intervention (HIIT/MICT) will be performed. Furthermore, pre-specified longitudinal mediation analyses will be performed on the entire MRI and PET/CT sample between changes in VO2peak, neurodegenerative measures, e.g., cognitive function and hippocampal volume, and inflammation levels between baseline and 24 months.

Analyses will employ the intention-to-treat when applicable. Meaning that all participants randomized, whether they receive their allocated intervention or withdrew from the trial, will be included in the analysis. The primary analyses are performed using Multiple Imputation by Chained Equations (MICE) for missing data. The imputation will be done separately for each intervention arm. In addition, a per-protocol analysis (defined as \> 75% attendance rate as well as no exacerbations during the last two weeks prior to follow-up assessment), and a complete-case analysis (including participants with complete outcome measurements independent on attendance rate) will be reported.

The full study protocol adheres to the SPIRIT guidelines and its outcomes extension, with intervention descriptions further guided by the TIDieR checklist the Consensus on Exercise Reporting Template (CERT). Publications from COPD-HIIT will follow the CONSORT statement, or relevant guidelines at the time of publication. Publications including qualitative outcomes will also be guided by the Consolidated Criteria for Reporting Qualitative Research (COREQ).

Eligibility criteria: The inclusion criteria are:

1. 60 years of age or older
2. Independent in activities of daily living
3. For people with COPD: Symptomatic (COPD assessment test \[CAT\] ≥10 or modified Medical Research Council dyspnea scale \[mMRC\] ≥2) or not being regularly physically active at a moderate or high intensity over the last year defined as not meeting WHO requirements for physical activity.
4. For people with COPD: Post-bronchodilator spirometry confirmed COPD diagnosis (forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) ratio \< 0.70).
5. For healthy controls: Normal lung function

The exclusion criteria are:

1. Movement related conditions, cardiovascular, neuromuscular, metabolic, skeletal and/or rheumatic conditions and diseases that are unstable and/or prohibits exercise or tests, based on screening by a physician. For example, but not limited to:

   I. Musculoskeletal pain prohibiting participation in tests and exercise II. Recent myocardial infarction, coronary artery bypass grafting, angioplasty, or other cardiac events III. Uncontrolled arterial hypertension IV. Pathological ECG-findings during CPET
2. Other lung conditions, including, but not limited to asthma, interstitial lung disease, lung cancer, pulmonary hypertension, pulmonary vascular disease, pulmonary fibrosis
3. Medical conditions and treatments with known effects on brain function and cognition, for example:

   I. Previous trauma to the head with lasting cognitive or symptom-related issues II. Physical or mental disabilities III. Neurological condition (dementia, multiple sclerosis, stroke) IV. Psychiatric illness, not including depression or general anxiety disorder V. Severe cognitive impairment VI. Recent or current cancer diagnosis and treatment
4. For those accepting MRI or PET/CT: metal implants, pacemakers, claustrophobia and other MRI incompatible factors.
5. Inability to read or speak Swedish (Umeå participants), Dutch, French (Hasselt participants) or English (Umeå and Hasselt participants).
6. For people with COPD:

I. Co-morbid conditions that limit exercise performance to a greater extent than the COPD diagnosis.

II. Currently participating in a pulmonary rehabilitation program or have been involved in pulmonary rehabilitation in the last 12 months.

III. Experienced a COPD exacerbation that led to a change in medication dosage or frequency in the preceding six weeks.

Primary outcomes:
measure: Change from baseline global cognitive function
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline cardiorespiratory fitness
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline quadriceps muscle power
timeFrame: Baseline, 12 weeks, 24 months
Secondary outcomes:
measure: Change from baseline brain structure
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline brain activity
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline cerebral perfusion
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline neuroinflammation
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline exercise tolerance
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from cardiorespiratory fitness
timeFrame: Baseline, 6 weeks
measure: Change from baseline lactate concentration during constant-workload cycle test (CWRT)
timeFrame: Baseline, 6 weeks, 12 weeks, 24 months
measure: Change from baseline cognitive function: Motor screening task
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline cognitive function: Reaction time
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline cognitive function: Visual information processing
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline cognitive function: Paired associates learning
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline cognitive function: Spatial working memory
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline cognitive function: Executive function
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline anaerobic exercise capacity
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline cognitive function: Verbal recognition memory
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline chronic inflammation
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline inflammatory markers
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline fibrinogen
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline blood cell count
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline neurotrophic factors
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline resting lactate
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline blood lipid profile
timeFrame: Baseline, 12 weeks, 24-months
measure: Change from baseline metabolic function: Glucose
timeFrame: Baseline, 12 weeks, 24-months
measure: Change from baseline metabolic function: Insulin
timeFrame: Baseline, 12 weeks, 24-months
measure: Change from baseline metabolic function: Insulin resistance
timeFrame: Baseline, 12 weeks, 24-months
measure: Change from baseline metabolic function: Glycated hemoglobin
timeFrame: Baseline, 12 weeks, 24-months
measure: Change from baseline quadriceps muscle strength
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline quadriceps muscle endurance
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline functional performance: Five time sit-to-stand test (5-STS)
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline functional performance: Stair climbing power test
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline muscle fibre size
timeFrame: Baseline, 12 weeks
measure: Change from baseline proportion of slow and fast subtypes of contractile myosin heavy chain isoforms
timeFrame: Baseline, 12 weeks
measure: Change from baseline capillary density
timeFrame: Baseline, 12 weeks
measure: Change from baseline capillaries per fiber
timeFrame: Baseline, 12 weeks
measure: Change from baseline capillaries to fiber area
timeFrame: Baseline, 12 weeks
measure: Change from baseline capillaries sharing factor
timeFrame: Baseline, 12 weeks
measure: Change from baseline myofiber and mitochondrial disruption/abnormalities (NADH-TR)
timeFrame: Baseline, 12 weeks
measure: Change from baseline mitochondrial biogenesis
timeFrame: Baseline, 12 weeks
measure: Change from baseline enzyme activity
timeFrame: Baseline, 12 weeks
measure: Change from baseline enzyme content
timeFrame: Baseline, 12 weeks
measure: Change from baseline angiogenesis
timeFrame: Baseline, 12 weeks
measure: Change from baseline proteins related to muscle-brain cross talk
timeFrame: Baseline, 12 weeks
measure: Change from baseline modulation of autonomic cardic function
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline blood pressure
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline epigenetic modifications in muscle samples
timeFrame: Baseline, 12 weeks
measure: Change from baseline epigenetic modifications in blood samples
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline body composition
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline impact of COPD in daily life
timeFrame: Baseline, 12 weeks, 6 months, 12 months, 15 months, 18 months, 21 months and 24 months
measure: Change from baseline disease specific quality of life
timeFrame: Baseline, 12 weeks, 6 months, 12 months, 15 months, 18 months, 21 months and 24 months
measure: Change from baseline Health related quality of life
timeFrame: Baseline, 12 weeks, 24 months
measure: Change from baseline state of depression and anxiety
timeFrame: Baseline, 12 weeks, 24 months
measure: Self-percieved change
timeFrame: 12 weeks, 24-months
measure: Number of responders
timeFrame: 12 weeks, 24-months
measure: Feasibility of interventions: Completion rate
timeFrame: 12-weeks and 24-months
measure: Feasibility of interventions: Attendance rate
timeFrame: 12-weeks and 24-months
measure: Feasibility of interventions: Exercise fidelity
timeFrame: Throughout the whole intervention period (24-months)
measure: Feasibility of interventions: Adherence to exercise duration and intensity
timeFrame: Throughout the whole intervention period (24-months)
measure: Feasibility of interventions: Satisfaction
timeFrame: Throughout the whole intervention period (24-months)
measure: Feasibility of interventions: Affective responses
timeFrame: Throughout the whole intervention period (24-months)
measure: Adverse events
timeFrame: Throughout the whole intervention period (24-months)
measure: Experiences of exercising and its effects
timeFrame: 12 weeks, 24-months
measure: Hospitalisations
timeFrame: 24 months
measure: Mortality
timeFrame: 24 months
measure: Exacerbations
timeFrame: 24 months
Other outcomes:
measure: Baseline global cognitive function
timeFrame: Baseline
measure: Baseline cardiorespiratory fitness
timeFrame: Baseline
measure: Baseline muscle power
timeFrame: Baseline
measure: Baseline brain structure
timeFrame: Baseline
measure: Baseline neuroinflammation
timeFrame: Baseline
measure: Baseline cognitive function: Montreal Cognitive Assessment (MoCA)
timeFrame: Baseline
measure: Baseline neurotrophic factors
timeFrame: Baseline
measure: Baseline inflammatory markers
timeFrame: Baseline
measure: Baseline chronic inflammation
timeFrame: Baseline
measure: Baseline fibrinogen
timeFrame: Baseline
measure: Baseline resting lactate
timeFrame: Baseline
measure: Baseline proportion of slow and fast subtypes of contractile myosin heavy chain isoforms
timeFrame: Baseline
measure: Baseline mitochondrial biogenesis
timeFrame: Baseline
measure: Baseline enzyme content
timeFrame: Baseline
Locations:
city: Hasselt
country: Belgium
facility: Hasselt University
state: Diepenbeek
city: Umeå
country: Sweden
facility: Umeå University
Study officials:
affiliation: Umeå University
name: André Nyberg, PhD
role: PRINCIPAL_INVESTIGATOR
References: