Clinical trial NCT03817294: Personalised Exercise Training in COPD
Official title: Personalised Exercise Training in COPD - Exploring the Interaction Between Exercise Physiology, Exercise Perception and Training Progression
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: COPD
Lead sponsor: Loughborough University
Sponsor class: OTHER
First posted: 2019-01-25
Enrollment: 25
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This a pilot/feasibility study, aiming to characterise exercise limitation at baseline and then conducting an abridged RCT with 4 training arms. The main outcomes are related to training progression and perception
Primary purpose: TREATMENT

Brief summary: Exercise training as part of Pulmonary Rehabilitation (PR) has been shown conclusively to improve breathlessness,quality of life and exercise capacity for people with COPD. However generally PR is delivered in a 'one size fits all' approach without considering different aspects of an individual's disease. It is hypothesised that a more personalised approach to PR may yield even better results. However to design a personalised programme of PR we need a better understanding of how different people with COPD respond to different possible exercise training modalities. This study will therefore comprehensively characterise a group of patients and then ask them to complete 3 weeks of exercise training in one of four modalities; conventional cycling, eccentric cycling, one-legged cycling and resistance training. The aim is not to prove which type of training is more effective but to develop an idea of which groups of patients would benefit from which type of training.

Baseline measures would be designed to fully understand how an individual responds to exercise and would therefore be comprised of a variety of endurance tests, strength tests, questionnaires, and measurements of lung capacity and body composition. This is to give as much information as possible to identify different responses to exercise.

Detailed description: Chronic obstructive pulmonary disease (COPD) is a highly prevalent condition affecting an estimated 1.2 million people in the UK and is the second most common lung disease after asthma. COPD not only affect the lungs, but is a systemic disease with muscle dysfunction being a significant feature. Exercise, as part of a programme of pulmonary rehabilitation (PR), has been shown to improve exercise capacity and quality of life of patients with COPD. However, despite the effectiveness of PR at a population level, there remains room for improvement. The individual treatment response is heterogeneous with some patients failing to achieve clinically significant improvements, whilst others struggle to adhere to the exercise component or drop out altogether. Currently, whilst exercise intensities (the "dose") are individualised during PR, the character and content of PR is generally provided in a "one size fits all" manner. There is therefore scope to modify the content of PR to meet individual needs and underlying physiology thereby enhancing adherence and benefits.

Precision medicine, tailoring therapy to specific "treatable traits" of an individual's condition, holds the potential to maximise treatment effect whilst minimising adverse effects. The investigators propose the same principles of precision medicine can be used to improve the delivery of PR by identifying an individual's exercise response at enrolment to PR and using this information to personalise exercise training. There are a growing number of diverse, novel training modalities that have been shown to be feasible and potentially efficacious in COPD, offering opportunities for delivering a personalised training programme. A key step in the development of this personalised/precision approach in exercise medicine is the understanding and measurement of the individual exercise pathophysiology that predicts preferential benefits to a particular exercise training modality. However, the relationship between baseline exercise pathophysiology (and indeed other disease and demographic variables) and such a response is currently unknown.

Eccentric exercise, contraction of a muscle as it lengthens, and one-legged cycling are two options for diversifying PR. For a given muscle workload, eccentric exercise results in lower energy demand and oxygen consumption and therefore puts less strain on the cardiopulmonary system. Consequently, this type of exercise may be ideally suited for patients with lung disease, particularly for those who stop exercise due to ventilatory limitations. It may be more tolerable for patients as it causes less breathlessness, whilst allowing greater muscle specific work. Eccentric cycling involves use of a bike with an attached motor which drives the pedals in reverse. The subject must resist the rotation of the pedals to maintain a constant pedal speed, thereby performing eccentric work with their legs. Using eccentric exercise as a training modality had historically been avoided due to the fear of causing muscle damage. High intensity eccentric resistance exercise leads to delayed onset muscle soreness (DOMS) and has been used for many years as a model of inducing muscle damage. However over the last 30 years there have been an increasing number of studies showing comprehensively that if load is gradually increased, muscle damage and soreness is minimal and acceptable. In patient populations, because loads achieved are particularly low, the occurrence of significant muscle damage is even more infrequent and previous work, has demonstrated that eccentric cycling is well tolerated in patients with COPD.

Whole body exercise, such as walking or cycling, requires recruitment of a large muscle mass generating a high oxygen demand. However, there is a disparity between whole body maximal oxygen uptake and muscle maximum aerobic capacity, even in a healthy population, and consequently significant variation in the muscle training stimuli achieved. This is emphasised in patients with COPD with a ventilatory limit to exercise. By exercising a smaller muscle mass, this ventilatory limitation can be bypassed and the individual muscle can be worked at significantly higher intensity. One method to reduce the exercising muscle mass is one-legged cycling. Two randomised controlled trials have demonstrated a greater improvement in V̇O2peak following one-legged cycling compared with two legged cycling in patients with COPD. One-legged cycling has been demonstrated to be a feasible addition to a PR programme and well received by patients and physiotherapists.

This study aims to determine how disease, demographic and exercise physiological variables recorded at baseline relate to subsequent perception and progression of novel training modalities compared to conventional training. The investigators will perform a comprehensive assessment of physiological response to exercise at baseline in terms of exercise capacity, exercise limitation, muscle volume and strength, physical activity, frailty and muscle composition. Participants will then be randomly allocated to one of 4 training modalities; eccentric cycling, one-legged cycling, concentric (traditional 2-legged cycling), or lower limb resistance training.

This is a pilot/feasibility study with the broad aim of identifying potential subphenotypes of patients with COPD that might respond preferentially to particular modalities of training. This knowledge is crucial to the development of definitive clinical trials of such exercise medicine interventions that could be delivered in routine clinical practice. The specific aims are:

1. To characterise in detail the underlying pulmonary and systemic pathophysiological characteristics of patients with COPD who are disabled by exercise limitation.
2. To measure progression of training loads during each training intervention relative to baseline values.
3. To determine how baseline characteristics and pathophysiology relate to training progression and exercise experience.

Eligibility criteria: Inclusion Criteria:

* Male or Female, aged 40 years or above
* Diagnosis of COPD
* FEV1/FVC \<0.7 and FEV1 \< 80% predicted
* Medical Research Council (MRC) dyspnoea scale ≥3
* Participant is willing and able to give informed consent for participation in the study.
* Stable dose of current regular medication for at least 4 weeks prior to study entry.
* Participant has clinically acceptable ECG at enrolment.
* Able (in the Investigators opinion) and willing to comply with all study requirements.
* English speaking

Exclusion Criteria:

* Any other significant disease or disorder which, in the opinion of the Investigator, may either put the participants at risk because of participation in the study, or may influence the result of the study, or the participant's ability to participate in the study.
* Any major or uncontrolled comorbidity that would impair the participant's ability to exercise or would mean exercise was unsafe.
* Participants who have participated in another research study involving an investigational product in the past 12 weeks
* Participation in pulmonary rehabilitation in the preceding 6 months
* Participation in another research study involving exercise training in the preceding 6 months
* Acute exacerbation in the preceding 4 weeks (would become eligible 4 weeks following recovery)
* Scheduled elective surgery or other procedures requiring general anaesthesia during the study.

Primary outcomes:
measure: Training Progression (Total work during training relative to baseline)
timeFrame: 3 weeks
measure: Training adherence
timeFrame: 3 weeks
measure: Subjective exercise experience scale during each exercise modality
timeFrame: Week 2
Secondary outcomes:
measure: Experience of different exercise modalities - Qualitative questionnaire
timeFrame: 3 weeks
measure: Exercise capacity - peak V̇O2 during a maximal incremental 2 leg cycle test
timeFrame: Baseline
measure: Exercise capacity - peak V̇O2 during a maximal incremental 1 leg cycle test
timeFrame: Baseline
measure: Inspiratory capacity during maximal 2 leg cycling
timeFrame: Baseline
measure: Functional capacity - constant work rate cycling test
timeFrame: Baseline
measure: Functional capacity - measured by Timed up-and-go test
timeFrame: Baseline
measure: Muscle strength - maximal concentric quadriceps strength
timeFrame: Baseline
measure: Muscle strength - maximal eccentric quadriceps strength
timeFrame: Baseline
measure: Muscle strength - 10 rep max Leg extension
timeFrame: Baseline
measure: Health related quality of life - St George's respiratory questionnaire
timeFrame: Baseline
measure: Frailty - Groningen Frailty Index
timeFrame: Baseline
measure: Balance - Activities specific balance scale (ABC scale)
timeFrame: Baseline
measure: Physical activity - 7-day activity monitor
timeFrame: Baseline
measure: Muscle architectural measures seen on muscle biopsy
timeFrame: Baseline
measure: Muscle architectural measures seen on muscle biopsy
timeFrame: Baseline
measure: Capillary density on muscle biopsy
timeFrame: Baseline
measure: Body composition - bioelectrical impedance
timeFrame: Baseline
measure: Breathlessness during exercise - Multidimensional dyspnoea profile
timeFrame: Baseline
Other outcomes:
Locations:
city: Loughborough
country: United Kingdom
facility: Loughborough University
Study officials:
References:
citation: Maltais F, Decramer M, Casaburi R, Barreiro E, Burelle Y, Debigare R, Dekhuijzen PN, Franssen F, Gayan-Ramirez G, Gea J, Gosker HR, Gosselink R, Hayot M, Hussain SN, Janssens W, Polkey MI, Roca J, Saey D, Schols AM, Spruit MA, Steiner M, Taivassalo T, Troosters T, Vogiatzis I, Wagner PD; ATS/ERS Ad Hoc Committee on Limb Muscle Dysfunction in COPD. An official American Thoracic Society/European Respiratory Society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2014 May 1;189(9):e15-62. doi: 10.1164/rccm.201402-0373ST.
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citation: Bjorgen S, Helgerud J, Husby V, Steinshamn S, Richadson RR, Hoff J. Aerobic high intensity one-legged interval cycling improves peak oxygen uptake in chronic obstructive pulmonary disease patients; no additional effect from hyperoxia. Int J Sports Med. 2009 Dec;30(12):872-8. doi: 10.1055/s-0029-1238292.
citation: Evans RA, Dolmage TE, Mangovski-Alzamora S, Romano J, O'Brien L, Brooks D, Goldstein RS. One-Legged Cycle Training for Chronic Obstructive Pulmonary Disease. A Pragmatic Study of Implementation to Pulmonary Rehabilitation. Ann Am Thorac Soc. 2015 Oct;12(10):1490-7. doi: 10.1513/AnnalsATS.201504-231OC.