Supramaximal High-Intensity Interval Training in People With and Without Chronic Obstructive Pulmonary Disease

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.

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.