Supramaximal High-Intensity Interval Training in People With and Without Chronic Obstructive Pulmonary Disease (COPD-HIIT)

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

Effects and Mechanisms of Supramaximal High-Intensity Interval Training in People With and Without Chronic Obstructive Pulmonary Disease on Extrapulmonary Manifestations

Hasselt University, Swedish Heart Lung Foundation, European Research Council, The Swedish Research Council, Strategic Research Area Health Care Science (SFO-V), Ziekenhuis Oost-Limburg

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 statistician 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: 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). 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 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. 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 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).

Chronic obstructive Pulmonary Disease, Pulmonary Disease, Chronic Obstructive, Chronic airway disease, COPD, physical activity, exercise

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.

The outcome assessors and data analysts will be masked to group allocation. The participants will be given repeated instructions not to reveal their group allocation to the outcome assessors. The dataset will be blinded regarding group allocation when performing analyses.

Each HIIT session consists of 10 repeated 6-seconds regulated high intensity cycling sprints against an individualized load set to reach a supramaximal exercise intensity (i.e. power output is higher than power output at maximum oxygen uptake). Session duration for HIIT is initially 20 min, including warm-up (5 min) and cool-down (5 min). The protocol enables controlled and systematic adjustments of training intensity by means of standardized criteria.

Each MICT session will consist of aerobic training regulated against an individualized load set to reach a moderate submaximal exercise intensity (i.e. power output is lower than power output at maximum oxygen uptake). Session duration for MICT is initially 30 min, including warm-up (5 min) and cool-down (5 min). The protocol enables controlled and systematic adjustments of training intensity by means of standardized criteria.

The passive control group will receive usual care alone and a standardized phone call every three months including assessments of health status (CAT), disease specific quality of life (CRQ) and questions on symptoms of exacerbations. We will match the participants in the standard care group to those randomized to HIIT or MICT by age, sex, disease severity, educational level, and physical activity.

Training is performed two to three times per week for a total of 30 sessions using a group format. Both regimens start with a five-minute warm-up and ends with a five-minute cool-down, performed at an intensity corresponding to 30% of the maximal work rate achieved during a CPET (i.e., max aerobic power [MAP]) with a self-selected pedalling cadence of 50-70 revolutions per minute (RPM). All exercise sessions will be held and supervised by an experienced health care professional, i.e. physiotherapists or other health professional. The different types of exercise training is described under the specific arm. Following the first 12-week training period, 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.

Global cognitive function will be assessed as the Z-score determined by the combined performances on six tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) and the trail making test (TMT-A, TMT-B). The following tests from the CANTAB will be used: Motor screening task, reaction time, visual information processing, paired associates learning, spatial working memory, verbal recognition memory. The test battery takes around 60 minutes to complete. The test scores from the seven tests will be combined into a composite Z-score. The Z-score describes how much a point deviates from a mean or specific point. The Z-score represents how many standard deviations an individual's score is from the mean score of the reference population, which is represented as zero.

Measured as maximum oxygen uptake (VO2peak [ml O2/min/kg]) during a standardized ramp-protocol cardiopulmonary exercise test (CPET) on a cycle ergometer. The CPET will start with a 3-minute resting phase before a 3-minute unloaded (or lowest wattage possible) warm-up phase. The aim is to have a ramp-phase of 8-12 minutes, until the participant stops due to voluntarily exhaustion, symptom-limitation or failure to maintain a cadence of 50-70 RPM.

Peak power (Nm/s) assessed during a seated leg extension in a dymanometer (Biodex System 4). Participants will be instructed to extend their leg as fast and as hard as possible and then passively return the leg to the starting position.

Assessed using standard MRI-sequences including in a 3 Tesla MRI-scanner. T1-weighted images will be used to determine volumes of grey matter, white matter and lateral ventricle size. T2-weighted, fluid-attenuated inversion recovery (FLAIR), and susceptibility weighted (SW) images are collected to assess perivascular spaces, lacunes, white-matter lesions and microbleeds. For structural MRI data volume (mm3), area (mm2) and cortical thickness (mm) will be the unit of measure.

Task-based functional MRI will be performed to evaluate brain activity in the hippocampus and prefrontal cortex, measured as BOLD signal change.The face-name association task will be used.

In vivo neuroinflammation is measured as uptake rate (ki) of 11C-deprenyl in the brain assessed with PET/CT (General Electric, WI, USA) under resting-state conditions after intravenous injection of 314 MBq of 11C-Deprenyl. . Uptake rate of 11C-deprenyl in the brain is modeled with Patlak analyses, where higher uptake is representative of higher levels of inflammation.

Test duration (mm:ss) on a constant-workload cycle test (CWRT) set at 75% of maximal power achieved during a CPET. After a 3-minute resting phase and a 3-minute warm-up phase at 30% of MAP, participants will cycle at a constant workload corresponding to 75% of MAP with a self-selected pedaling cadence of 50-70 RPM. Participants will be instructed to exercise for as long as possible.

Capillary blood lactate (mmol/L) will be measured during and immediately after the CWRT to assess the metabolic demand.

Test score in the CANTAB Motor screen task. During the test, colored crosses appear in different locations on the screen. The participant must select the cross as quickly and accurately as possible.

Test score in the CANTAB reaction time test. During the test, participants must select a button on the screen. Circles are presented above the button and the participant is asked to react as soon as possible once a yellow dot appears in one of the circles by clicking the corresponding circle.

Test score in the CANTAB Visual information processing test. During the test, a white box is shown in the center of the screen where digits from 2 to 9 appear in a pseudo-random order at the rate of 100 digits per minute. Participants are requested to detect target sequences of digits (e.g., 2-4-6, 3-5-7, 4-6-8). When the participant sees the target sequence, they must respond by selecting the button in the center of the screen as quickly as possible.

Test score in the CANTAB Paired associates learning test. In the test, boxes are displayed on the screen and are opened in a randomized order. One or more of them will contain a pattern. The patterns are then displayed in the middle of the screen, one at a time and the participant must select the box in which the pattern was originally located.

Test score in the CANTAB spatial working memory test. During the test, several colored boxes are shown on the screen. The aim of this test is that, by selecting the boxes and using a process of elimination, the participant should find one yellow 'token' in each of several boxes and use them to fill up an empty column on the right-hand side of the screen

Test score in the trail making test. The TMT consists of two parts, A and B and is performed with paper and pencil. During part A, the participant needs to connect 25 digits in ascending order as fast as possible by drawing lines between the digits. During part B, the participants need to connect 13 digits in ascending order and 12 letters in alphabetical order, alternating digits, and letters (i.e., 1 - A - 2 - B - 3 - C, etcetera) as fast as possible by drawing lines between the digits and letters.

Intensity (produced power, in watts) at the final stage during a Borg cycle strength test (BCST). The BCST is a submaximal cycle ergometer test that is used to estimate maximum mean power output for 30 seconds (MPO30) without an all-out effort. The BCST consists of 30-second efforts with increasing intensity, interspersed with 30-seconds passive recovery between each effort. With a target pedaling cadence of 80-90 RPM, participants cycle until they score an RPE of ≥17, or when they cannot keep the target cadence (<75 RPM for five seconds).

Test score in the CANTAB verbal recognition memory test. During the test, the participant is shown a list of words to remember. During the recognition phase, the participant is asked to say whether they remember seeing the word on the screen before. The word can be one of the originals, or a new word (distractor) which they have not yet seen before.

Levels of BDNF, irisin, IGF-1, Cathepsin B and clusterin in venous blood samples. Unit of measure is pq/ml.

Levels of glucose and insulin levels will be used to calculate the HOMA-IR (Homeostatic Model Assessment of Insulin Resistance). The unit of measure is arbitrary units where values above 1.9 indicates early insulin resistance, and above 2.9 indicates significant insulin resistance.

Muscle strength will be determined as the one-repetition maximum (1-RM) defined as the maximum torque (Nm/s) able to be lifted through the full range of motion during seated leg extension in the dominant leg, using a dymanometer (Biodex System 4)

Defined as the maximum number of repetitions able to be lifted with a good technique through the full ROM at an intensity corresponding to 45% of 1-RM, during seated leg extension in the dominant leg, using a dymanometer (Biodex System 4).

The tissue sample obtained from the vastus lateralis muscle will be examined with morphometric analyses to determine cross-sectional fiber area of all fibres and per subtype. Unit of measurement is square micrometers.

The tissue sample obtained from the vastus lateralis muscle will be examined with immunohistochemistry techniques to categorize fiber types. Expressed as relative distribution in percent and relative area of the muscle in percent.

The tissue sample obtained from the vastus lateralis muscle will be examined with morphometric analysis to determine capillary density, estimated as the total number of capillaries per millimeter squared muscle cross-section.

The tissue sample obtained from the vastus lateralis muscle will be examined with morphometric analysis to determine the number of capillaries in close contact with each muscle fiber. Unit of measure is number of capillaries in close contact with fibre.

The tissue sample obtained from the vastus lateralis muscle will be examined with morphometric analysis to determine the number of capillaries around each fiber relative to its cross-sectional area.

The tissue sample obtained from the vastus lateralis muscle will be examined with morphometric analysis to determine the capillary-to-fiber ratio

Staining of reduced nicotinamide adenine dinucleotide-tetrazolium reductase, succinate dehydrogenase, and cytochrome c oxidase. Measured as % of fibers with abnormal staining pattern and fiber area in µm2 of fibers with abnormal staining pattern.

mRNA and protein levels of peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) alpha and PGC-1beta. Unit of measure is fold-change or arbitrary units.

Enzyme activities of phosphofructokinase (PFK; glycolysis), lactate dehydrogenase (LDH; anaerobic glycolysis), citrate synthase (CSM Krebs cycle), succinate dehydrogenase (SDH; Krebs cycle), 3-hydroxyacyl Coenzyme A dehydrogenase (HADH; beta-oxidation) and mitochondrial complex I-V. Unit of measure is micromol/min/g tissue.

Enzyme content of phosphofructokinase (PFK; glycolysis), lactate dehydrogenase (LDH; anaerobic glycolysis), citrate synthase (CS; Krebs cycle), succinate dehydrogenase (SDH; Krebs cycle), 3-hydroxyacyl Coenzyme A dehydrogenase (HADH; beta-oxidation) and mitochondrial complex I-V. Unit of measure is micromol/min/g tissue.

mRNA and protein level of BDNF, fibronectin type III domain-containing protein 5 (FNDC5) and kynurenine aminotransferase (KAT1-4). Unit of measure is fold change and arbitrary units.

Resting heart rate variability measured in the time domain as the root mean square of the successive differences (RMSSD, in milliseconds), and time domain (LH:HF ratio) using a chest strap heart rate monitor.

Whole blood EDTA samples will be analysed for genome-wide DNA methylation, via the EPICarray technology.

Body composition measures include body mass index, waist and hip circumference (cm), percentage of body fat, fat-free mass (kg), and fat-free mass index (kg/m2). Fatmass and fatfree mass is measured with bioelectrical impedance.

Measured with the chronic respiratory disease questionnaire (COPD group only). The CRQ measures the impact of chronic respiratory disease on HRQoL and covers four key domains of HRQoL, including: dyspnea, fatigue, emotional function, and mastery. Each item is scored on a 7-point Likert scale; scores within each domain are summated for a total score per domain.

Measured with the EQ-5D-5L questionnaire.It assesses an individual's HRQoL in five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression91. Each dimension has five response levels, ranging from level 1 (no problems) to level 5 (extreme problems). By combining one level from each dimension, a health state ranging from 11111 (the best health state) to 55555 (the worst health state) is defined and converted into an index score using a scoring algorithm.

The Hospital Anxiety and Depression Scale (HADS) will be used to assess states of depression and anxiety. The HADS is a reliable 14-item questionnaire regarding feeling of depression and anxiety in the past week which can be answered within 2 - 5 minutes. A separate score is given for depression and anxiety. where a higher score means higher severity.

Self-perceived change in outcomes will be measured via the Global Rate of Change scale with the purpose to quantify the extent to which a participant's outcomes have improved or deteriorated over time. Participants will provide an answer via a 11-point Likert scale (-5 = "Much worse"; 0 = "Unchanged"; 5 = "Much better").

Total amount of responders, defined as a response over the known minimal detectable change or minimal important difference for included tests, will be determined, and compared between HIIT and MICT.

Completion rate is determined by the total number of participants still performing the exercise training intervention at 12-week and 24-month follow-up. Reasons for non-completion are also obtained.

Attendance rate is determined by the total number of attended sessions divided by total number of sessions prescribed, presented as a percentage. Reasons for non-attendance are also obtained.

Exercise fidelity is determined as the incidence of exercise sessions requiring modifications, defined as any deviation from the prescribed exercise.

Adherence to exercise duration is determined as the adherence to the predefined intervals/minutes of the exercise training. Reasons for non-adherence are also obtained. Adherence to exercise intensity is determined as the adherence to the prescribed intensity of the exercise training. Reasons for non-adherence are also obtained. Exercise intensity (absolute workload [W], relative intensity [% of MAP, % of MPO6], the level of dyspnoea and leg fatigue [0-10, arbitrary units] on the Borg CR10 scale and perceived exertion [6-20, arbitrary units] on the Borg Rating of RPE scale.

Participant satisfaction with the performed exercise training (supramaximal HIIT / MICT) will be recorded by adaptation of an existing patient satisfaction questionnaire previously used cycling exercises in COPD. (Evans et. al. Ann Am Thorac Soc 2015)

Affective response/mood will be measured using the Feeling scale, during and after exercise sessions. The Feeling scale ranges from -5 to +5, where a higher score indicates a better feeling.

Adverse events are rated into four different categories: 1) minor and temporary, 2) serious symptoms (potential risk of severe injury or life threatening, 3) manifest injury or disease, and 4) death, as previously described. An adverse event rate will be calculated for each participant as the total number of sessions during which any adverse events occurred divided by the total number of attended sessions.

Face-to-face interviews will explore the participants' experiences and perceptions of participating in the program.

Number of hospitalisations per participant during the study period. Time, cause, length of stay, and emergency room visits (with no hospitalization afterwards) and their cause will also be extracted. Hospitalizations and emergency room visits will be classified as respiratory or non-respiratory. In Phase 2, data on hospitalizations will be extracted from the participant's medical record and cross-checked with the participant's diary.

Number of deaths during the study period will be extracted from the participant's medical record. Time and cause of each death will also be extracted.

In the COPD groups, number of exacerbations during the whole study period will be recorded during the whole study period. In Phase 2, data on exacerbations will be extracted from the participant's medical record and cross-checked with the participant's diary.

Baseline global cognitive function, as determined by the Z-score derived from CANTAB and TMT-test battery (primary outcome) will be compared between the groups at baseline to compare the different cohorts (COPD versus healthy controls).

Baseline cardiorespiratory fitness will be compared between the groups at baseline to compare the different cohorts (COPD versus healthy controls). Measured as maximum oxygen uptake (VO2peak [ml O2/min/kg]) during a standardized ramp-protocol cardiopulmonary exercise test (CPET) on a cycle ergometer.

Baseline cardiorespiratory fitness will be compared between the groups at baseline to compare the different cohorts (COPD versus healthy controls). Peak power (Nm/s) assessed during a seated leg extension in a dymanometer (Biodex System 4).

Baseline brain structured assessed in MRI will be compared between the groups to compare the different cohorts (COPD versus healthy controls). Volume (mm3), area (mm2) and cortical thickness (mm) will be the unit of measure.

Baseline neuroinflammation assessed in PET/CT will be compared between the groups to compare the different cohorts (COPD versus healthy controls). Neuroinflammation is measured as uptake rate (ki) of 11C-deprenyl in the brain assessed

Baseline cognitive function assessed with the MoCA will be investigated at baseline to compare the different cohorts (COPD vs healthy controls) and any differences in cognitive impairment at baseline. The MoCA evaluates multiple domains of cognitive function and yields a score, 0-30 points, where higher is better.

Neurotrophic factors will be investigated at baseline to compare the different cohorts (COPD versus healhy controls). Levels of BDNF, irisin, IGF-1, Cathepsin B and clusterin in venous blood samples. Unit of measure is pq/ml

Markers of systemic inflammation at baseline will be investigated to compare the different cohorts (COPD versus healthy controls). Levels of interleukin-6, interleukin-8 and TNF-alpha in venous blood, measured in pq/mL, will be assessed.

Baseline chronic inflammation, assessed as hs-CRP (mg/L) will be investigated at baseline to compare the different cohorts (COPD versus healthy controls)

Baseline fibrinogen levels (g/L) will be investigated at baseline to compare the different cohorts (COPD versus healthy controls).

Proportion of slow and fast subtypes of contractile myosin heavy chain isoforms will be assessed at baseline to compare the different cohorts (COPD versus healthy controls). The tissue sample obtained from the vastus lateralis muscle will be examined with immunohistochemistry techniques to categorize fiber types. Expressed as relative distribution in percent and relative area of the muscle in percent.

mRNA and protein levels of peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1) alpha and PGC-1beta will be investigated at baseline to compare the different cohorts (COPD versus healthy controls). Unit of measure is fold-change or arbitrary units.

Enzyme content will be investigated at baseline to compare the different cohorts (COPD versus healthy controls). Including phosphofructokinase (PFK; glycolysis), lactate dehydrogenase (LDH; anaerobic glycolysis), citrate synthase (CS; Krebs cycle), succinate dehydrogenase (SDH; Krebs cycle), 3-hydroxyacyl Coenzyme A dehydrogenase (HADH; beta-oxidation) and mitochondrial complex I-V. Unit of measure is micromol/min/g tissue.

The inclusion criteria are: 60 years of age or older Independent in activities of daily living 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. 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). The exclusion criteria are: 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 Other lung conditions, including, but not limited to asthma, interstitial lung disease, lung cancer, pulmonary hypertension, pulmonary vascular disease, pulmonary fibrosis Medical conditions and treatments with known effects on brain function and cognition, for example: I. Previous trauma to the head 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 For those accepting MRI or PET/CT: metal implants, pacemakers, claustrophobia and other MRI incompatible factors. Inability to read or speak Swedish (Umeå participants), Dutch, French (Hasselt participants) or English (Umeå and Hasselt participants). 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.

We strive to share all the IPD that underlie results in a publication in a open data repository, if this will be possible given regulations and agreements at that time.

IPD will become available 6 months after publication. The full study protocol including the analysis plan will be submitted for publication during 2023. Informed consent forms and other supporting material will be available on a reasonable request to the principal investigator.

The principal investigator will review requests for supporting material. IPD will be open access in a data repository.