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Enrolling by Invitation

NCT Number: NCT07343375

Effect of High-intensity Interval Training on the Lung in Patients With COPD Referred for Lung Volume Reduction Surgery: The PREGENERATE Trial

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.

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Key information

Conditions

COPD (Chronic Obstructive Pulmonary Disease) Chronic Disease Disease Attributes Lung Diseases Lung Diseases, Obstructive Pathologic Processes Pathological Conditions, Signs and Symptoms Pulmonary Disease, Chronic Obstructive Respiratory Tract Diseases

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Centre for Physical Activity Research, Copenhagen University Hospital

Copenhagen, Denmark

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Men and women
  • Referred for lung volume reduction surgery at Rigshospitalet because of emphysematous COPD.

Exclusion criteria

  • Symptoms of ischaemic heart disease
  • Known heart failure
  • Unable to complete or understand HIIT training
  • Claudication
  • Symptoms of acute disease within 2 weeks prior to the study
  • Known malignant disease
  • Pregnancy
  • Unstable cardiac arrhythmic disease
  • Renal or liver dysfunction
  • Known chronic kidney or liver disease
  • Elevated creatinine, urea, alanine transaminase (ALAT), aspartate transaminase (ASAT), bilirubin, basic phosphatases at blood test

Treatment and study plan

High Intensity Interval Training (HIIT)

Behavioral

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.

Primary outcomes

  1. Differential protein composition

    Time frame: At surgery

    Differences in change in differential protein composition in distal lung tissue between HIIT and control group post-intervention using spatial multimodal proteomics.

Secondary outcomes

  1. Differential protein composition

    Time frame: At surgery

    Differences in change in differential protein composition in distal lung tissue between HIIT and control group post-intervention using mass spectrometry.

  2. Lung tissue protein composition

    Time frame: At surgery

    Differences in change in distal lung tissue protein composition pre- and post-HIIT intervention via mass spectrometry.

  3. Serum protein profiles

    Time frame: At surgery

    Differences in change in serum protein profiles between HIIT and control groups after intervention using mass spectrometry.

  4. Tissue niche and cellular composition

    Time frame: At surgery

    Tissue niche and cellular composition in the lung will be determined

  5. Translational regions

    Time frame: At surgery

    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.

  6. Inflammatory and remodelling factors (blood samples)

    Time frame: From time of inclusion in the study and until surgery (up to 8 months)

    Difference in change from baseline to follow-up between groups in inflammatory and remodelling factor proteins in blood samples measured by mass spectrometry

  7. Protein markers

    Time frame: At surgery

    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.

  8. Lung cell population

    Time frame: At surgery

    Difference in change from baseline to follow-up between groups in lung cell populations by single cell-RNA sequencing.

  9. Lung tissue mass

    Time frame: From inclusion in the study and until surgery (up to 8 months)

    Difference in change from baseline to follow-up between groups in total LTM (g)

  10. Pulmonary blood volume at rest

    Time frame: From inclusion in the study and until surgery (up to 8 months)

    Difference in change from baseline to follow-up between groups in pulmonary blood volume (mL) at rest

  11. DLNO at rest and during exercise

    Time frame: From inclusion in the study and until surgery (up to 8 months)

    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)

  12. DLNO during exercise

    Time frame: From inclusion in the study and until surgery (up to 8 months)

    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)

  13. DLNO during exercise

    Time frame: From inclusion in the study and until surgery (up to 8 months)

    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)

  14. Pulmonary blood volume / total blood volume ratio

    Time frame: From inclusion in the study and until surgery (up to 8 months)

    Difference in change from baseline to follow-up between groups in pulmonary blood volume / total blood volume ratio

  15. Health related quality of life

    Time frame: From enrollment until 3 months post-surgery

    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)

  16. Extra cellular matrix structure

    Time frame: At surgery

    Extracellular matrix structure

  17. Inflammatory and remodelling factors (lung tissue)

    Time frame: At surgery

    Difference in change from baseline to follow-up between groups in inflammatory and remodelling factor proteins in lung tissue measured by mass spectrometry

Other outcomes

  1. Tissue morphology

    Time frame: At surgery

    Difference in change from baseline to follow-up between groups in tissue morphology

  2. Mechanotransduction pathways

    Time frame: At surgery

    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.

  3. Mesenchymal stromal cells

    Time frame: At surgery

    Difference in mesenchymal stromal cells from baseline until follow-up between the two groups

  4. Inflammatory patterns

    Time frame: At surgery

    Inflammatory patterns will be assessed understanding the difference in these inflammatory patterns from baseline until follow-up and the differences between the two groups

  5. Distal airspace dimensions

    Time frame: From enrollment to surgery

    Difference in change from baseline to follow-up between groups in distal airspace dimensions (rAiDA and R0) as measured by AiDA

  6. Neo-epitopes

    Time frame: At surgery

    Difference in change from baseline to follow-up between groups in neo-epitopes (degraded fragments of proteins) in lung tissue measured by mass spectrometry

  7. Changes in X-ray and electron-based imaging techniques

    Time frame: At surgery

    Difference in change from baseline to follow-up between groups in elemental and structural changes by X-Ray and electron-based imaging techniques

  8. Biophysical properties

    Time frame: At surgery

    Difference in change from baseline to follow-up between groups in biophysical properties (stiffness/elasticity) using tensile or atomic force microscopy (AFM

  9. Lung function

    Time frame: At surgery

    Differences in above measurements linked to lung function

  10. Cell activity

    Time frame: At surgery

    Differences in above measurements linked to cell activity

  11. Lobal lung tissue mass

    Time frame: From inclusion in the study until surgery (up to 8 months)

    Difference in change from baseline to follow-up between groups in lobar LTM (g)

  12. LTM/1.73 m2 BSA

    Time frame: From inclusion in the study until surgery (up to 8 months)

    Difference in change from baseline to follow-up between groups in LTM/1.73 m2 BSA (g/m2)

  13. Total blood volume

    Time frame: From inclusion in the study until surgery (up to 8 months)

    Difference in change from baseline to follow-up between groups in total blood volume

  14. DLNO during rest

    Time frame: From inclusion in the study and until surgery (up to 8 months)

    Difference in change from baseline to follow-up between groups in DL,NO (mmol/(min kPa)) during upright rest

  15. DLCOc during rest

    Time frame: From inclusion in the study until surgery (up to 8 months)

    Difference in change from baseline to follow-up between groups in DL,CO,5s (mmol/(min kPa)) during upright rest

  16. Pulmonary capillary blood volume

    Time frame: From inclusion in the study until surgery (up to 8 months)

    Difference in change from baseline to follow-up between groups in pulmonary capillary blood volume (VC, mL) during upright rest

  17. Membrane diffusing capacity

    Time frame: From inclusion in the study until surgery (up to 8 months)

    Difference in change from baseline to follow-up between groups in alveolar-capillary membrane diffusing capacity (DM, mmol/(min kPa)) during upright rest

  18. Cardiac hemodynamics during exercise

    Time frame: From inclusion in the study until surgery (up to 8 months)

    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

  19. VO2 during diffusing capacity measurements

    Time frame: From inclusion in the study until surgery (up to 8 months)

    DL,CO,NO-based V̇O2 during exercise at 60% of current maximal workload and 60% of baseline maximal workload, and during upright rest

  20. Cardiac pulmonary exercise test outcomes

    Time frame: From enrollment until 3 months post surgery

    Difference in change from baseline to follow-up between groups in relative (mL/kg/min) V̇O2peak

  21. Handgrip-strength

    Time frame: From enrollment until 3 months post surgery

    Difference in change from baseline to follow-up between groups in hand-grip strength (kg)

  22. Sit-to-stand

    Time frame: From enrollment until 3 months post surgery

    Difference in change from baseline to follow-up between groups in numbers of completed 60 seconds sit-to-stand test (n)

  23. Body composition

    Time frame: From inclusion in the study and until surgery (up to 8 months)

    Difference in change from baseline to follow-up between groups in body composition: total mass (kg)

  24. Lung function

    Time frame: From enrollment until 3 months post surgery

    Difference in change from baseline to follow-up between groups in lung function: FEV1 (L and %pred)

  25. 6-minutes walking distance

    Time frame: From enrollment until 3 months post surgery

    Difference in change in the distance (m) walked from baseline to follow-up between groups in a 6-minute walking test

  26. Exercise-induced cytokine response

    Time frame: From enrollment until 3 months post surgery

    Difference in change from baseline to follow-up between groups in exercise-induced cytokine responses (interleukin-6 (pg/mL)

  27. Mean bolus transit time - rest

    Time frame: From inclusion in the study until surgery (up to 8 months)

    Difference in change from baseline to follow-up between groups in mean bolus transit time (s) (supine rest)

  28. Mean bolus transit time exercise

    Time frame: From inclusion in the study until surgery (up to 8 months)

    Difference in change from baseline to follow-up between groups in mean bolus transit time (s) (adenosine infusion)

  29. Coronary flow reserve

    Time frame: From inclusion in the study until surgery (up to 8 months)

    Difference in change from baseline to follow-up between groups in global coronary flow reserve (mL/min)

  30. Pulmonary blood volume reserve

    Time frame: From inclusion in the study until surgery (up to 8 months)

    Difference in change from baseline to follow-up between groups in pulmonary blood volume reserve (mL)

  31. Ejection fraction

    Time frame: From inclusion in the study until surgery (up to 8 months)

    Difference in change from baseline to follow-up between groups in left ventricular ejection fraction (%)

  32. Cardiac dynamics - rest

    Time frame: From inclusion in the study until surgery (up to 8 months)

    Difference in change from baseline to follow-up between groups in cardiac output (L/min) (supine rest)

  33. Cardiac dynamics - exercise

    Time frame: From inclusion in the study until surgery (up to 8 months)

    Difference in change from baseline to follow-up between groups in cardiac output (L/min)

  34. Total plasma volume

    Time frame: From inclusion in the study until surgery (up to 8 months)

    Difference in change from baseline to follow-up between groups in total plasma volume

  35. Red blood cells

    Time frame: From inclusion in the study until surgery (up to 8 months)

    Difference in change from baseline to follow-up between groups in red blood cells

  36. Coronary calcium score

    Time frame: From inclusion in the study until surgery (up to 8 months)

    Difference in change from baseline to follow-up between groups in coronary calcium score

  37. Blood samples

    Time frame: From enrollment until 3 months post surgery

    Difference in change from baseline to follow-up between groups in blood samples: lipids (cholesterol (mmol/l)

  38. Lung resistance

    Time frame: From enrollment until 3 months post surgery

    Difference in change from baseline to follow-up between groups in resistance (Rrs, R5-R20) measured by IOS

  39. Lung reactance

    Time frame: From enrollment until 3 months post surgery

    Difference in change from baseline to follow-up between groups in reactance (Xrs, X5) measured by IOS

  40. Cardiac function and structure

    Time frame: From inclusion in the study until surgery (up to 8 months)

    Difference in change from baseline to follow-up between groups in cardiac structure and function including

  41. Progenitor cell changes

    Time frame: At surgery

    Difference in progenitor cells from baseline until follow-up between the two groups

  42. Cardio pulmonary test outcomes

    Time frame: From enrollment until 3 months post surgery

    Difference in change from baseline to follow-up between groups in absolute (mL/min) V̇O2peak

  43. Cardiac pulmonary exercise test outcomes

    Time frame: From enrollment until 3 months post surgery

    Difference in change from baseline to follow-up between group in ventilatory threshold (%)

  44. Cardiac pulmonary exercise test outcomes

    Time frame: From enrollment until 3 months post surgery

    Difference in change from baseline to follow-up between groups in ventilatory reserve (%)

  45. Body composition

    Time frame: From enrollment until 3 months post surgery

    Difference in change from baseline to follow-up between groups in body composition: total fat mass (kg and %)

  46. Body composition

    Time frame: From enrollment until 3 months post surgery

    Difference in change from baseline to follow-up between groups in body composition: lean body mass (kg)

  47. Body composition

    Time frame: From enrollment until 3 months post surgery

    Difference in change from baseline to follow-up between groups in body composition: fat percentage (%)

  48. Lung function

    Time frame: From enrollment until 3 months post surgery

    Difference in change from baseline to follow-up between groups in lung function: FVC (L and %pred)

  49. Lung function

    Time frame: From enrollment until 3 months post surgery

    Difference in change from baseline to follow-up between groups in lung function: RV (L and %pred)

  50. Lung function

    Time frame: From enrollment until 3 months post surgery

    Difference in change from baseline to follow-up between groups in lung function: , TLC (L and %pred)

  51. Lung function

    Time frame: From enrollment until 3 months post surgery

    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)

  52. Exercise-induced cytokine response

    Time frame: From enrollment until 3 months post surgery

    Difference in change from baseline to follow-up between groups in tumour necrosis factor-α (pg/mL)

  53. Exercise-induced cytokine response

    Time frame: From enrollment until 3 months post surgery

    Difference in change from baseline to follow-up between groups in C-reactive protein (μg/mL)

  54. Exercise-induced cytokine response

    Time frame: From enrollment until 3 months post surgery

    Difference in change from baseline to follow-up between groups in interleukin-8 (pg/mL)

  55. Exercise-induced cytokine response

    Time frame: From enrollment until 3 months post surgery

    Difference in change from baseline to follow-up between groups in interleukin-10 (pg/mL))

  56. Cardiac dynamics - rest

    Time frame: From inclusion in the study until surgery (up to 8 months)

    Difference in change from baseline to follow-up between groups in heart rate (bpm) (supine rest)

  57. Cardiac dynamics - rest

    Time frame: From inclusion in the study until surgery (up to 8 months)

    Difference in change from baseline to follow-up between groups in stroke volume (mL) (supine rest)

  58. Cardiac dynamics - exercise

    Time frame: From inclusion in the study until surgery (up to 8 months)

    Difference in change from baseline to follow-up between groups in cardiac output (L/min) (adenosine infusion)

  59. Cardiac dynamics - exercise

    Time frame: From inclusion in the study until surgery (up to 8 months)

    Difference in change from baseline to follow-up between groups in stroke volume (mL) (adenosine infusion)

  60. Blood samples

    Time frame: From enrollment until 3 months post surgery

    Difference in change from baseline to follow-up between groups in blood samples: LDL (mmol/l)

  61. Blood samples

    Time frame: From enrollment until 3 months post surgery

    Difference in change from baseline to follow-up between groups in blood samples: HDL (mmol/l))

  62. Blood samples

    Time frame: From enrollment until 3 months post surgery

    Difference in change from baseline to follow-up between groups in blood samples: HbA1C (mmol/l)

  63. Blood samples

    Time frame: From enrollment until 3 months post surgery

    Difference in change from baseline to follow-up between groups in blood samples: HsCRP (mg/L)

  64. Blood samples

    Time frame: From enrollment until 3 months post surgery

    Difference in change from baseline to follow-up between groups in blood samples: pro-BNP (pmol/L)

  65. Blood samples

    Time frame: From enrollment until 3 months post surgery

    Difference in change from baseline to follow-up between groups in blood samples: TSH (10-3 IU/L)

Sponsors and collaborators

Lead sponsor

Rigshospitalet, Denmark

Other

Collaborators

  • Lund University

Registry information

Acronym: PREGENERATE

Important dates

Study start
2026
Primary completion
2029
Study completion
2029
First posted
Jan 15, 2026
Registry last updated
Apr 2, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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