Developmental Clinical Studies - ACE inhibitors to augment the effects of pulmonary rehabilitation in COPD

Chronic obstructive pulmonary disease (COPD) is a combination of chronic bronchitis and destruction of lung tissue - "emphysema" usually caused by smoking. It is very common, affecting up to 2.4 million people in the UK. Because breathing capacity is reduced, patients get breathless with exercise and become less active. This in turn causes a loss of fitness which leads to worse breathlessness. This vicious spiral of inactivity can be helped by a supervised exercise program known as "pulmonary rehabilitation".
Muscle weakness occurs in about one third of people with COPD and is associated with a reduced ability to do daily activities and with a greater risk of death. Because COPD is so common it is only possible to provide short exercise programs and these are only available to a small proportion of patients. An additional problem is that the muscles of people with lung disease do not necessarily respond to exercise in the same way as healthy people. There is an excessive 'stress response' in the muscle and this blocks some of the beneficial effects of exercise. Researchers have been trying to find ways to increase the response to exercise training especially because of the limited resources available.
Laboratory experiments and some work in humans suggest that a class of medication called ACE inhibitors would provide a more 'oxidative' type of muscle which would have greater endurance properties, to enable people to do daily activities more easily. ACE inhibitors are commonly used as a treatment for high blood pressure.
To test our hypothesis we will enrol 80 patients with COPD who are limited in their daily activities to take part in an 8 week pulmonary rehabilitation study. Half of them will take an ACE inhibitor daily and half will take a placebo tablet. We will measure their exercise capacity on an exercise bike before and after the program to see if the ACE inhibitor group show more improvement. We will also take small samples of muscle and blood before and after so that we can study the molecular mechanisms involved and how these relate to changes in exercise capacity.
Because ACE inhibitors are an established (and relatively cheap) class of drug If the study is positive it would be possible to implement their use for this purpose into clinical practice quickly, potentially benefiting a large number of people.

Need addressed: COPD is a major worldwide public health problem characterised by breathlessness, reduced physical activity and significant skeletal muscle impairment. Pulmonary rehabilitation (PR) can improve the skeletal muscle impairment that occurs in COPD, but there is a need to develop therapies to enhance and sustain this effect.
Proposed solution: We propose to test the hypothesis that angiotensin converting enzyme inhibitors (ACE-I) will augment the improvements in exercise capacity seen following PR, enrolling 80 patients in a double-blind, placebo-controlled, parallel group study powered to demonstrate an increase in peak workload on cycle ergometry.
Rationale: PR is an effective therapy in COPD but the response may be suboptimal in some individuals because of oxidative and nitrosative stress. Biopsy evidence shows that pathways associated with muscle growth and fibre shift are attenuated in some patients. Angiotensin II is known to influence IGF-1, myostatin, the ubiquitin-proteasome proteolytic pathway, inflammatory pathways involving NFkB and angiogenesis. Hypertensive patients taking ACE-I are stronger than those on other therapies, ACE-gene polymorphism has been shown to influence the response to training and influence quadriceps strength in COPD. One trial has shown that ACE-I can improve exercise capacity in COPD. We will also take quadriceps muscle biopsies and will seek funding separately to analyse these so that the mechanisms underlying improvement can be best understood.
Development plan: ACE-I are already widely used for the treatment of hypertension and heart failure, have a good safety profile and are off patent. They could therefore be rapidly adopted if the treatment indication proposed here was found to be supported. Therefore if the results of the proposed trial were positive the next step would be to seek funding for a larger multicentre study powered according to patient relevant and health economic outcomes.

EXTENT OF TARGET POPULATION - Chronic obstructive pulmonary disease (COPD) is a common illness responsible for considerable morbidity and mortality and is predicted to become the third leading cause of death and the fifth leading cause of disability adjusted life years worldwide by 2020. It affects about 10% of the population over 50, an estimated 1.4 million people in England and is an NHS priority.
NATURE OF NEED COPD is characterised by a range of important systemic consequences. Skeletal muscle dysfunction is a common consequence of COPD and, since therapies intended to improve lung function have demonstrated only limited effectiveness and lung function alone determines only a proportion of the disease phenotype, there is a significant unmet need to improve strategies targeting systemic complications of COPD. The most effective therapy for alleviating the symptoms of COPD is pulmonary rehabilitation (PR). This approach involves a program of supervised exercise and education aimed at reversing the effects of skeletal muscle deconditioning. It has a grade A evidence base, with data demonstrating that PR is effective in improving exercise capacity, quality of life, muscle strength and reducing hospital admissions. In recognition of its importance the Department of Health in its National Clinical Strategy for COPD has highlighted the major role that PR has in managing the condition. Limited resources are available to provide PR programs - this includes access to a program at all, the duration of programs and the capacity to provide repeat programs to 'top up' the effect. This means that it is crucial that individual patients derive the maximum benefit from the program in which they are able to participate and that effective strategies are available to sustain this benefit for as long as possible. Importantly for this application the response to exercise training is variable in COPD and may be attenuated because of oxidative and nitrosative stress or because of other factors such as nutritional impairment. It is likely that pharmacologic adjuncts could have a role in overcoming this.
Therefore skeletal muscle weakness is a common, functionally relevant finding observed in patients with both early and advanced disease. There is a large potential target population who could benefit from improved exercise capacity, reduced functional limitation and better quality of life.
POTENTIAL FOR APPLICATION Angiotensin Converting enzyme (ACE) inhibitors are a well-established class of drugs with a good safety profile both acutely and for long term use. If we confirm that this novel indication, of using them as an adjunct to exercise training for an established class of drugs is effective, it could be rapidly translated to clinical benefit. The cost per QALY of PR in COPD is very low, so an intervention with a relatively cheap medication has a good chance to achieve a significant cost/benefit if it can augment the effect of PR.
An extension of the impact of this study is that there is considerable overlap between the mechanisms that drive muscle weakness in COPD and that occurring in other chronic medical conditions as well as the sarcopaenia of aging.