Personalised Exercise Training in COPD

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:

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

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.