An interventional study of High Intensity interval training (HIIT) in COPD (Chronic Obstructive Pulmonary Disease), sponsored by Rigshospitalet, Denmark. Enrolling by invitation at 1 site in Denmark. Per ClinicalTrials.gov, last updated 2026-04-02.
Sponsored by Rigshospitalet, Denmark · Not applicable, Interventional, and Treatment
Patients with chronic obstructive lung disease (COPD) suffer from a progressive loss of lung function that leads to poor quality of life, and often invalidity and early death. Regular exercise can improve quality of life in these patients, but there is a lack in understanding the underlying mechanism of exercise-induced improvement in COPD and it is widely thought not to have any effect on the lung as such. In the present study, the investigators aim to investigate the impact of an extensive high-intensity interval training (HIIT)-based exercise scheme on the regenerative capacity of the lung in patients with COPD on waiting list for lung volume reduction surgery.
Design: Prospective randomized controlled clinical trial.
Intervention: 24 persons with COPD referred for lung volume reduction surgery will randomly be allocated (1:1) to prehabilitation with high intensity interval training (HIIT) or non-exercise control.
Outcomes: The primary outcome is differences in change in differential protein composition in distal lung tissue between HIIT and control groups post-intervention using spatial multimodal proteomics. Furthermore, lung tissue mass, protein composition (mass spectrometry and spatial omics e.g. MACSima), pulmonary blood volume, blood protein profile (biomarkers), diffusion capacity at rest and during exercise, oxygen consumption tests, body composition scan, distal airspace radii and physical functional tests will be measured before and after the intervention.
Perspective: This study may fundamentally change the view on the regenerative potential of the lungs in COPD.
Patients with chronic obstructive pulmonary disease (COPD) suffer from a progressive loss of lung function that leads to low physical performance, poor quality of life, and early death. Pulmonary rehabilitation, including exercise training, is considered the most effective non-pharmacological intervention for improving quality of life in patients with COPD. However, its use is halted by the lack of understanding of the mechanism of exercise-induced improvement in COPD, and is widely thought not to have any effect on lung function, at least as measured by dynamic spirometry and diffusion capacity measured at rest in the upright position. It is thus mainly considered a mean to alleviate symptoms, primarily by improving skeletal muscle function, but without the potential to reverse any structural changes within the pulmonary system which are seen in patients with COPD. The rationale for recommending exercise as a way to reduce symptom burden and increase quality of life, is based on the finding from the most recent Cochrane review. The authors stated that no additional studies comparing exercise with control were warranted, as exercise per se leads to improvements, regardless of the type of exercise.
The reasoning for not prescribing exercise more widely to patients with COPD is based on two assumptions: 1) new tissue cannot be formed in the adult lung, and 2) no consistent exercise training-induced changes in lung function have previously been documented.
However, de novo tissue formation has repeatedly been demonstrated in the adult lung, both in animals and humans, primarily in response to prolonged hypoxia and pneumonectomy. It has recently been reported that interval-based training counteracts the progressive loss of lung tissue in animal models of experimental COPD. The most likely stimulus is the mechanical strain, and if any measurable changes are to be induced by training, a high-intensity interval training (HIIT) scheme is preferable to be initiated in pulmonary rehabilitation.
An aspect of the progressive lung tissue loss in COPD that sets in from the very early stages of disease, seemingly before any ventilatory disturbance can be observed, is pulmonary vascular dysfunction and loss of pulmonary capillaries, driven by a seemingly disease-specific imbalance between angiogenetic and angiostatic processes in the pulmonary vasculature. Indeed, this is likely a mechanism that drives the concomitant loss of lung tissue, and also limits exercise capacity as the ability to expand the alveolar-capillary membrane though pulmonary capillary recruitment and distension becomes limited, thus critically attenuating oxygen uptake during exercise.
It is now well-established that the human lung conceals a diverse population of mechanosensitive progenitor and stem cells that appear to be dormant in COPD. Their reactivation by the stretch and strain as well as high vascular pressures associated with for example physical activity may likely explain why interval-based training has been found to counteract the progressive loss of lung tissue in animal models of experimental COPD. The investigators have developed in vitro protocols for assessing the regenerative capacity of the lung, and the next step will be to develop similar protocols for the human lung, both in the healthy state and from patients with COPD. In the present pilot study, the investigators will investigate the effects of an extensive high-intensity interval training (HIIT) on the regenerative capacity of the lung as determined by in vitro lung organoid culture and vascular tissue engineering 3D methods on patients with COPD on waiting list for lung volume reduction surgery.
Primary objective: To investigate whether prehabilitation with supervised HIIT while on waiting list for lung volume reduction surgery affects regenerative pathways in the lung. The investigators aim to determine if these effects can be detected non-invasively using blood biomarkers and spatial omics technologies to map region-specific molecular changes, cellular composition, and structural remodelling in lung tissue.
Secondary objectives: To determine whether an increase in blood volume is associated with an increased lung tissue mass (LTM), pulmonary blood volume (PBV), reduced symptom severity, and pulmonary diffusing capacity at rest and during exercise. To use explanted tissue to develop ex vivo models for disease and repair mechanisms.
Research hypotheses:
Primary: Prehabilitation while on waiting list for lung volume reduction surgery is superior to a non-exercise control group for increasing activating regenerative pathways in the lung with concomitant changes in LTM and PBV.
Secondary: Diffusing capacity during exercise and quality of life increases following prehabilitation with HIIT compared to a non-exercise control group. Finally, it is hypothesized that functional outcomes, V̇O2peak, body composition and cardiac output will be improved despite no/or limited changes in lung function in the HIIT group.
4,131 studies on the registry are indexed under Pulmonary Disease, Chronic Obstructive; 697 are open to participants now.
This study's planned enrollment of 24 is below the median of 70 across 2,926 interventional studies indexed under Pulmonary Disease, Chronic Obstructive.
Browse Pulmonary Disease, Chronic Obstructive studies →Rigshospitalet, Denmark is the lead sponsor of 1,017 studies on the registry; 183 are open to participants now.
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Exclusion criteria
Renal or liver dysfunction
The HIIT intervention group includes three supervised sessions per week over the period while on waitinglist for lung volumen reduction surgery. These will take place at either CFAS or at home and will be supervised
Behavioral: High Intensity interval training (HIIT)
Controls will be encouraged to maintain current exercise habits for the duration of the study.
The HIIT intervention consist of 4 intervals with each lasting 4 minutes (4x4min). If a participant reports discomfort related to the length of the intervals or start to feel unmotivated by performing the same exercise, we will use another HIIT protocol: 10x1min. The 4x4min HIIT consists of a warm-up period of 10 minutes with a target heart rate at 60-70% of HRmax, followed by 4 HIIT intervals with a target HR ≥85%. The intervals are separated by three minutes of active rest, in which the HR should drop to 60% of maximum. Following this, a cool down period of three minutes at warm up intensity is performed. The 10x1min HIIT consists of a 10-minute warm-up period.The warm-up is followed by 10 intervals, each lasting 1 min at 100% of maximal workload, separated by three minutes of active rest, in which the HR should drop to 60% of maximum. Following the intervals, a cool down period of three minutes at warm up intensity is performed.
Differential protein composition
Differences in change in differential protein composition in distal lung tissue between HIIT and control group post-intervention using spatial multimodal proteomics.
Time frame: At surgery
Differential protein composition
Differences in change in differential protein composition in distal lung tissue between HIIT and control group post-intervention using mass spectrometry.
Time frame: At surgery
Lung tissue protein composition
Differences in change in distal lung tissue protein composition pre- and post-HIIT intervention via mass spectrometry.
Time frame: At surgery
Serum protein profiles
Differences in change in serum protein profiles between HIIT and control groups after intervention using mass spectrometry.
Time frame: At surgery
Tissue niche and cellular composition
Tissue niche and cellular composition in the lung will be determined
Time frame: At surgery
Translational regions
Healthy, diseased and transitional (''border zones'') regions in the lung will be deliniated/identified by using spation omic analysis. This will be done both at a gene level, protein level and glycosaminoglycan level.
Time frame: At surgery
Inflammatory and remodelling factors (blood samples)
Difference in change from baseline to follow-up between groups in inflammatory and remodelling factor proteins in blood samples measured by mass spectrometry
Time frame: From time of inclusion in the study and until surgery (up to 8 months)
Protein markers
Protein markers will be identified by mass spectrometry and the difference in the spatial localisation of these will be identified between the groups after the intervention. This will be done using Pentachrome and/or multiplexed inmunofluorescence stainings.
Time frame: At surgery
Lung cell population
Difference in change from baseline to follow-up between groups in lung cell populations by single cell-RNA sequencing.
Time frame: At surgery
Lung tissue mass
Difference in change from baseline to follow-up between groups in total LTM (g)
Time frame: From inclusion in the study and until surgery (up to 8 months)
Pulmonary blood volume at rest
Difference in change from baseline to follow-up between groups in pulmonary blood volume (mL) at rest
Time frame: From inclusion in the study and until surgery (up to 8 months)
DLNO at rest and during exercise
Difference in change from baseline to follow-up between groups in DL,NO (mmol/(min kPa)) as a function of V̇O2 measured at rest, 60% of current maximal workload (relative), and at follow-up including 60% of maximal workload at baseline (absolute)
Time frame: From inclusion in the study and until surgery (up to 8 months)
DLNO during exercise
Difference in change from baseline to follow-up between groups in DL,NO (mmol/(min kPa)) during exercise at 60% of current maximal workload (relative)
Time frame: From inclusion in the study and until surgery (up to 8 months)
DLNO during exercise
Difference in change from baseline to follow-up between groups in DL,NO (mmol/(min kPa)) during exercise at 60% of the maximal workload measured at baseline (absolute)
Time frame: From inclusion in the study and until surgery (up to 8 months)
Pulmonary blood volume / total blood volume ratio
Difference in change from baseline to follow-up between groups in pulmonary blood volume / total blood volume ratio
Time frame: From inclusion in the study and until surgery (up to 8 months)
Health related quality of life
Difference in change from baseline to follow-up between groups in health-related quality of life - COPD Assessment Test (CAT) score, and St. George's Respiratory Questionnaire (SGRQ)
Time frame: From enrollment until 3 months post-surgery
Extra cellular matrix structure
Extracellular matrix structure
Time frame: At surgery
Inflammatory and remodelling factors (lung tissue)
Difference in change from baseline to follow-up between groups in inflammatory and remodelling factor proteins in lung tissue measured by mass spectrometry
Time frame: At surgery
Tissue morphology
Difference in change from baseline to follow-up between groups in tissue morphology
Time frame: At surgery
Mechanotransduction pathways
Detect increased activation of mechanotransduction pathways, marked by YAP/TAZ co-transcription factors, in lung tissue post-HIIT using spatial omics and advanced image analysis.
Time frame: At surgery
Mesenchymal stromal cells
Difference in mesenchymal stromal cells from baseline until follow-up between the two groups
Time frame: At surgery
Inflammatory patterns
Inflammatory patterns will be assessed understanding the difference in these inflammatory patterns from baseline until follow-up and the differences between the two groups
Time frame: At surgery
Distal airspace dimensions
Difference in change from baseline to follow-up between groups in distal airspace dimensions (rAiDA and R0) as measured by AiDA
Time frame: From enrollment to surgery
Neo-epitopes
Difference in change from baseline to follow-up between groups in neo-epitopes (degraded fragments of proteins) in lung tissue measured by mass spectrometry
Time frame: At surgery
Changes in X-ray and electron-based imaging techniques
Difference in change from baseline to follow-up between groups in elemental and structural changes by X-Ray and electron-based imaging techniques
Time frame: At surgery
Biophysical properties
Difference in change from baseline to follow-up between groups in biophysical properties (stiffness/elasticity) using tensile or atomic force microscopy (AFM
Time frame: At surgery
Lung function
Differences in above measurements linked to lung function
Time frame: At surgery
Cell activity
Differences in above measurements linked to cell activity
Time frame: At surgery
Lobal lung tissue mass
Difference in change from baseline to follow-up between groups in lobar LTM (g)
Time frame: From inclusion in the study until surgery (up to 8 months)
LTM/1.73 m2 BSA
Difference in change from baseline to follow-up between groups in LTM/1.73 m2 BSA (g/m2)
Time frame: From inclusion in the study until surgery (up to 8 months)
Total blood volume
Difference in change from baseline to follow-up between groups in total blood volume
Time frame: From inclusion in the study until surgery (up to 8 months)
DLNO during rest
Difference in change from baseline to follow-up between groups in DL,NO (mmol/(min kPa)) during upright rest
Time frame: From inclusion in the study and until surgery (up to 8 months)
DLCOc during rest
Difference in change from baseline to follow-up between groups in DL,CO,5s (mmol/(min kPa)) during upright rest
Time frame: From inclusion in the study until surgery (up to 8 months)
Pulmonary capillary blood volume
Difference in change from baseline to follow-up between groups in pulmonary capillary blood volume (VC, mL) during upright rest
Time frame: From inclusion in the study until surgery (up to 8 months)
Membrane diffusing capacity
Difference in change from baseline to follow-up between groups in alveolar-capillary membrane diffusing capacity (DM, mmol/(min kPa)) during upright rest
Time frame: From inclusion in the study until surgery (up to 8 months)
Cardiac hemodynamics during exercise
Difference in change from baseline to follow-up between groups in cardiac output (L/min) during exercise at 60% of current maximal workload and 60% of baseline maximal workload, and during upright rest
Time frame: From inclusion in the study until surgery (up to 8 months)
VO2 during diffusing capacity measurements
DL,CO,NO-based V̇O2 during exercise at 60% of current maximal workload and 60% of baseline maximal workload, and during upright rest
Time frame: From inclusion in the study until surgery (up to 8 months)
Cardiac pulmonary exercise test outcomes
Difference in change from baseline to follow-up between groups in relative (mL/kg/min) V̇O2peak
Time frame: From enrollment until 3 months post surgery
Handgrip-strength
Difference in change from baseline to follow-up between groups in hand-grip strength (kg)
Time frame: From enrollment until 3 months post surgery
Sit-to-stand
Difference in change from baseline to follow-up between groups in numbers of completed 60 seconds sit-to-stand test (n)
Time frame: From enrollment until 3 months post surgery
Body composition
Difference in change from baseline to follow-up between groups in body composition: total mass (kg)
Time frame: From inclusion in the study and until surgery (up to 8 months)
Lung function
Difference in change from baseline to follow-up between groups in lung function: FEV1 (L and %pred)
Time frame: From enrollment until 3 months post surgery
6-minutes walking distance
Difference in change in the distance (m) walked from baseline to follow-up between groups in a 6-minute walking test
Time frame: From enrollment until 3 months post surgery
Exercise-induced cytokine response
Difference in change from baseline to follow-up between groups in exercise-induced cytokine responses (interleukin-6 (pg/mL)
Time frame: From enrollment until 3 months post surgery
Mean bolus transit time - rest
Difference in change from baseline to follow-up between groups in mean bolus transit time (s) (supine rest)
Time frame: From inclusion in the study until surgery (up to 8 months)
Mean bolus transit time exercise
Difference in change from baseline to follow-up between groups in mean bolus transit time (s) (adenosine infusion)
Time frame: From inclusion in the study until surgery (up to 8 months)
Coronary flow reserve
Difference in change from baseline to follow-up between groups in global coronary flow reserve (mL/min)
Time frame: From inclusion in the study until surgery (up to 8 months)
Pulmonary blood volume reserve
Difference in change from baseline to follow-up between groups in pulmonary blood volume reserve (mL)
Time frame: From inclusion in the study until surgery (up to 8 months)
Ejection fraction
Difference in change from baseline to follow-up between groups in left ventricular ejection fraction (%)
Time frame: From inclusion in the study until surgery (up to 8 months)
Cardiac dynamics - rest
Difference in change from baseline to follow-up between groups in cardiac output (L/min) (supine rest)
Time frame: From inclusion in the study until surgery (up to 8 months)
Cardiac dynamics - exercise
Difference in change from baseline to follow-up between groups in cardiac output (L/min)
Time frame: From inclusion in the study until surgery (up to 8 months)
Total plasma volume
Difference in change from baseline to follow-up between groups in total plasma volume
Time frame: From inclusion in the study until surgery (up to 8 months)
Red blood cells
Difference in change from baseline to follow-up between groups in red blood cells
Time frame: From inclusion in the study until surgery (up to 8 months)
Coronary calcium score
Difference in change from baseline to follow-up between groups in coronary calcium score
Time frame: From inclusion in the study until surgery (up to 8 months)
Blood samples
Difference in change from baseline to follow-up between groups in blood samples: lipids (cholesterol (mmol/l)
Time frame: From enrollment until 3 months post surgery
Lung resistance
Difference in change from baseline to follow-up between groups in resistance (Rrs, R5-R20) measured by IOS
Time frame: From enrollment until 3 months post surgery
Lung reactance
Difference in change from baseline to follow-up between groups in reactance (Xrs, X5) measured by IOS
Time frame: From enrollment until 3 months post surgery
Cardiac function and structure
Difference in change from baseline to follow-up between groups in cardiac structure and function including
Time frame: From inclusion in the study until surgery (up to 8 months)
Progenitor cell changes
Difference in progenitor cells from baseline until follow-up between the two groups
Time frame: At surgery
Cardio pulmonary test outcomes
Difference in change from baseline to follow-up between groups in absolute (mL/min) V̇O2peak
Time frame: From enrollment until 3 months post surgery
Cardiac pulmonary exercise test outcomes
Difference in change from baseline to follow-up between group in ventilatory threshold (%)
Time frame: From enrollment until 3 months post surgery
Cardiac pulmonary exercise test outcomes
Difference in change from baseline to follow-up between groups in ventilatory reserve (%)
Time frame: From enrollment until 3 months post surgery
Body composition
Difference in change from baseline to follow-up between groups in body composition: total fat mass (kg and %)
Time frame: From enrollment until 3 months post surgery
Body composition
Difference in change from baseline to follow-up between groups in body composition: lean body mass (kg)
Time frame: From enrollment until 3 months post surgery
Body composition
Difference in change from baseline to follow-up between groups in body composition: fat percentage (%)
Time frame: From enrollment until 3 months post surgery
Lung function
Difference in change from baseline to follow-up between groups in lung function: FVC (L and %pred)
Time frame: From enrollment until 3 months post surgery
Lung function
Difference in change from baseline to follow-up between groups in lung function: RV (L and %pred)
Time frame: From enrollment until 3 months post surgery
Lung function
Difference in change from baseline to follow-up between groups in lung function: , TLC (L and %pred)
Time frame: From enrollment until 3 months post surgery
Lung function
Difference in change from baseline to follow-up between groups in lung function: single-breath diffusion capacity to carbon monoxide (mmol/(min kPa) and %pred)
Time frame: From enrollment until 3 months post surgery
Exercise-induced cytokine response
Difference in change from baseline to follow-up between groups in tumour necrosis factor-α (pg/mL)
Time frame: From enrollment until 3 months post surgery
Exercise-induced cytokine response
Difference in change from baseline to follow-up between groups in C-reactive protein (μg/mL)
Time frame: From enrollment until 3 months post surgery
Exercise-induced cytokine response
Difference in change from baseline to follow-up between groups in interleukin-8 (pg/mL)
Time frame: From enrollment until 3 months post surgery
Exercise-induced cytokine response
Difference in change from baseline to follow-up between groups in interleukin-10 (pg/mL))
Time frame: From enrollment until 3 months post surgery
Cardiac dynamics - rest
Difference in change from baseline to follow-up between groups in heart rate (bpm) (supine rest)
Time frame: From inclusion in the study until surgery (up to 8 months)
Cardiac dynamics - rest
Difference in change from baseline to follow-up between groups in stroke volume (mL) (supine rest)
Time frame: From inclusion in the study until surgery (up to 8 months)
Cardiac dynamics - exercise
Difference in change from baseline to follow-up between groups in cardiac output (L/min) (adenosine infusion)
Time frame: From inclusion in the study until surgery (up to 8 months)
Cardiac dynamics - exercise
Difference in change from baseline to follow-up between groups in stroke volume (mL) (adenosine infusion)
Time frame: From inclusion in the study until surgery (up to 8 months)
Blood samples
Difference in change from baseline to follow-up between groups in blood samples: LDL (mmol/l)
Time frame: From enrollment until 3 months post surgery
Blood samples
Difference in change from baseline to follow-up between groups in blood samples: HDL (mmol/l))
Time frame: From enrollment until 3 months post surgery
Blood samples
Difference in change from baseline to follow-up between groups in blood samples: HbA1C (mmol/l)
Time frame: From enrollment until 3 months post surgery
Blood samples
Difference in change from baseline to follow-up between groups in blood samples: HsCRP (mg/L)
Time frame: From enrollment until 3 months post surgery
Blood samples
Difference in change from baseline to follow-up between groups in blood samples: pro-BNP (pmol/L)
Time frame: From enrollment until 3 months post surgery
Blood samples
Difference in change from baseline to follow-up between groups in blood samples: TSH (10-3 IU/L)
Time frame: From enrollment until 3 months post surgery
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Pulmonary Disease, Chronic Obstructive→
Rigshospitalet, Denmark