Pulmonary Adaptive Responses to HIIT in COPD (COPDEX0)

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 the health care system lack the underlying mechanism of exercise-induced improvement in COPD and it is widely thought not to have any effect on lung function. The aim of the present study is to investigate to which extent lung tissue mass and rest-to-exercise diffusion capacity changes differ in COPD patients compared to the healthy state. In order to design prospective clinical trials on the putative impact of high-intensity interval training (HIIT) investigating these parameters, and a secondary aim is to assess the feasibility of such a study in terms of patient inclusion, adherence and methodology.

Study Overview

• Status: Recruiting
• Conditions: Chronic Obstructive Pulmonary Disease
• Intervention / Treatment: Other: High intensity interval training

Detailed Description

Patients with Chronic obstructive pulmonary 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 is considered the most effective non-pharmacological intervention for improving quality of life in these patients. 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 in the clinical setting. Exercise is thus mainly considered a way to alleviate symptoms, primarily by improving skeletal muscle function, but without the potential to reverse the disease. Therefore, relatively short and low-intensity exercise interventions are typically prescribed and are often not pursued in patients with the greatest symptom burden.

The reasoning for not prescribing exercise more widely in 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.

On this basis, this study aim to conduct a prospective randomised trial, in which the impact of HIIT on lung weight (assessed by CT), rest-to-exercise diffusion capacity, 3-dimensional distribution of pulmonary perfusion measured by single photon emission computed tomography (SPECT)-low dose CT are addressed. Indeed, the latter is an especially useful clinical tool for the pathophysiological classification of COPD patients, and rest-to-exercise SPECT has the potential as a diagnostic tool that 'pinpoints' the exact cause of dyspnoea in the individual COPD patient, but has not yet been validated for this purpose. While all the methods are established, there is a need for more information regarding COPD-associated changes in lung tissue mass ('lung weight') and rest-to-exercise pulmonary diffusion changes compared to the healthy state. An assessment of the feasibility of an extended HIIT-trial using these methods in COPD patients as well as estimates of the in-study changes in the resultant physiological estimates (for the purpose of sample size estimations) is warranted.

• Study Type: Interventional
• Enrollment (Anticipated): 24
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Ronan Martin Griffin Berg, MD; Phone Number: (+45) 3545 7641; Email: ronan.martin.griffin.berg@regionh.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Rigshospitalet
    • Principal Investigator: Jacob Hartmann, MD
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Centre for Physical Activity Research (CFAS)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion criteria -patients

• Men and women
• 45-80 years
• COPD (GOLD stage I to III)
• Forced expiratory volume in 1 sec (FEV1)/forced vital capacity ratio (FVC) < 0.8, FEV1 < 90% of predicted value
• Modified Medical Research Council score (mMRC 0 - 3)
• Resting arterial oxygenation > 90%
• Do not fulfil the physical activity recommendations by the Danish Health Authority

Inclusion criteria - controls

• Men and women
• 45-80 years
• Normal FEV1, FVC, FEV1/FVC, and single-breath diffusion capacity
• Same sex, age (± 3 years) and BMI (± 10%)
• Do not fulfil the physical activity recommendations by the Danish Health Authority (19)
• BMI 18-35

Exclusion criteria - patients

• Symptoms of ischaemic heart disease
• Known heart failure
• Previous severe or current COVID-19
• Unable to complete or understand HIIT training
• Claudication
• Symptoms of disease within 2 weeks prior to the study
• Participation in pulmonary rehabilitation within 6 months
• Known malignant disease
• Pregnancy
• Unstable cardiac arrhythmic disease
• Renal or liver dysfunction

Exclusion criteria - controls

• COPD
• Asthma
• Known ischaemic heart disease
• Known heart failure
• Previous severe or current COVID-19
• Unable to complete or understand HIIT training
• Symptoms of disease within 2 weeks prior to the study
• Known malignant disease
• Claudication
• Pregnancy
• Unstable cardiac arrhythmic disease
• Renal or liver dysfunction

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: COPD patients; This arm will consist of only COPD patients.	Other: High intensity interval training; Participants will undergo 12 weeks of supervised HIIT training (3 times per week). The HIIT protocol will consist of 4x4 min.
EXPERIMENTAL: Healthy controls; This arm will consist of age and BMI matched healthy controls.	Other: High intensity interval training; Participants will undergo 12 weeks of supervised HIIT training (3 times per week). The HIIT protocol will consist of 4x4 min.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lung tissue mass	Change in lung weight in COPD patients compared to matched controls using CT-scans.	CT-scans at baseline and at 12 week follow up.
Rest-to-exercise diffusion capacity	Change in rest-to-exercise pulmonary diffusion capacity between COPD patients and matched healthy controls measured by DLNO/CO.	DLNO/CO measured at baseline and at 12 week follow up.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rest-to-exercise pulmonary perfusion ratio change	Rest-to-exercise pulmonary perfusion ratio change in COPD patients compared to matched controls measured by single photon emission computed tomography (SPECT).	At baseline and at 12 week follow up
Rest-to-exercise leg blood flow change in COPD	Rest-to-exercise leg blood flow change in COPD patients compared to matched controls measured by ultrasound doppler in a single leg knee extensor model.	At baseline and at 12 week follow up

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rest-to-exercise cardiac output change	Cardiac output measured by oxygen pulse.	At baseline and at 12 week follow up
VO2peak (and estimated VO2max)	Incremental exercise test on bike ergometer with COSMED system using breath by breath analysis.	At baseline and at 12 week follow up
VO2 verification bout	Confirmation of maximum oxygen consumption measured 20 minutes after intitial VO2 peak test at a 110 % of maximum workload.	At baseline and at 12 week follow up
The maximal workload (knee extension)	Incremental exercise test on one leg knee extensor chair.	At baseline and at 12 week follow up.
Hand-grip strength	Measured with a dynamometer.	At baseline and at 12 week follow up.
Body composition	total fat mass, lean body mass measured with dual energy x-ray absorption.	At baseline and at 12 week follow up.
Lung function: FEV1	Change in Forced expiratory volume in 1 second (FEV1) (ml)	At baseline and at 12 week follow up.
Lung function: TLC	Change in total lung capacity (TLC)(ml)	Measured during the 12 week intervention.
Lung function: FVC	Change in forced vital capacity (FVC)(ml)	Measured during the 12 week intervention.
Lung function: RV	Change in residual volume (RV) (ml)	Measured during the 12 week intervention.
Lung function: VA	Change in alveolar volume (VA) (ml)	Measured during the 12 week intervention.
Lung function: DLCOc	Single-breath diffusion capacity to carbon monoxide corrected for hemoglobin (ml/min/mmHg)	Measured during the 12 week intervention.
6-minute walking test	Distance transversed during 6 minutes of maximum effort walking.	At baseline and at 12 week follow up.
Chronic obstructive pulmonary disease Assessment Test (CAT-score)	Health-related quality of life - COPD Assessment Test, (CAT) score. Higher values meaning a smaller burden of symptoms.	At baseline and at 12 week follow up.
Oxygen extraction in lower limb musculature during small mass exercise	Calculated from paired arterial and venous blood gases obtained from intraarterial and venous catheters.	At baseline and at 12 week follow up.
Intima media thickness in the carotid artery	Measured with ultrasound.	At baseline and at 12 week follow up.
Exercise feasibility: exercise sessions attendance rate.	Exercise attendance rate (%) defined as number of attended exercise sessions / by number of prescribed sessions x 100.	Measured during the 12 week intervention.
Exercise feasibility: Relative dose intensity (RDI)	RDI (%) of exercise, defined as prescribed exercise dose / performed exercise dose x 100	Measured during the 12 week intervention.
Exercise feasibility: early exercise termination	Incidence of early termination of attended exercise sessions, defined as termination of an exercise session before the prescribed exercises have been performed	Measured during the 12 week intervention.
Withdrawal rate	Incidence of permanent discontinuations of the exercise intervention, defined as participants that withdraw entirely from the exercise intervention.	Measured during the 12 week intervention.
Exercise feasibility: Patient-reported symptomatic adverse events (paint, dizziness, nausea, fatigue, other)	Changes in patient-reported symptomatic adverse events (pain, dyspnea, fatigue, cough, sore muscles)	Measured during the 12 week intervention.
Glucose	Exercise induced changes in plasma levels of glucose	At baseline and at 12 week follow up.
IL-1	Exercise induced changes in plasma levels of interleukin 1	At baseline and at 12 week follow up.
IL-1RA	Exercise induced changes in plasma levels of interleukin-1 receptor antagonist	At baseline and at 12 week follow up.
TNF-alfa	Exercise induced changes in plasma levels of tumor necrosis factor alfa	At baseline and at 12 week follow up.
IL-6	Exercise induced changes in plasma levels of interleukin-6	At baseline and at 12 week follow up.
IL-10	Exercise induced changes in plasma levels of interleukin 10	At baseline and at 12 week follow up.
Adiponectin	Exercise induced changes in plasma levels of adiponectin	At baseline and at 12 week follow up.
IL-15	Exercise induced changes in plasma levels of interleukin 15	At baseline and at 12 week follow up.
HS-CRP	Exercise induced changes in plasma levels of high sensitive c-reactive protein	At baseline and at 12 week follow up.
HDL	Exercise induced changes in plasma levels of High density lipoprotein	At baseline and at 12 week follow up.
LDL	Exercise induced changes in plasma levels of low density lipoprotein	At baseline and at 12 week follow up.
Insulin	Exercise induced changes in plasma levels of insulin	At baseline and at 12 week follow up.
Creatinine	Exercise induced changes in plasma levels of creatinine	At baseline and at 12 week follow up.
Leptin	Exercise induced changes in plasma levels of leptin	At baseline and at 12 week follow up.
Carbamide	Exercise induced changes in plasma levels of carbamide	At baseline and at 12 week follow up.
ALAT	Exercise induced changes in plasma levels of alanine-aminotransferase	At baseline and at 12 week follow up.
Leucocytes	Exercise induced changes in plasma levels of leucocytes	At baseline and at 12 week follow up.

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 5, 2022
• Primary Completion (ANTICIPATED): August 1, 2024
• Study Completion (ANTICIPATED): August 1, 2024

Study Registration Dates

• First Submitted: September 13, 2022
• First Submitted That Met QC Criteria: September 20, 2022
• First Posted (ACTUAL): September 23, 2022

Study Record Updates

• Last Update Posted (ACTUAL): October 17, 2022
• Last Update Submitted That Met QC Criteria: October 13, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Blood flow; Diffusion capacity; High intensity interval training (HIIT); Lung growth; Lung tissue mass; Oxygen extraction
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
• Other Study ID Numbers: COPDEX0

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Can be retrieved upon request from primary investigator.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No