When breathing, we inhale air into our lungs down the bronchial tubes that branch out into many smaller tubes called bronchioles. At the end of those are alveoli: the round elastic sacs that contain air and allow the capillaries to run through their walls and collect the vital oxygen that will then continue its journey in our bloodstream. The oxygen in the alveoli is exchanged against carbon dioxide, the organic gas waste to be exhaled out of our body via the same tract.
What is COPD?
Chronic Obstructive Pulmonary Disease (COPD) is a progressive lung disease characterised by increasing breathlessness, even at rest. The term covers several pulmonary pathologies such as chronic bronchitis, emphysema or non-reversible asthma. COPD impacts a patient’s everyday life and is the 3rd leading cause of death in both the U.S. and worldwide, according to the World Health Organisation (WHO). As no cure yet exists, it has become crucial for the healthcare industry to alleviate symptoms and control lung damage, in an attempt to stabilise and eventually improve COPD patients’ quality of life.
As COPD develops, it gradually limits the airflow – inhibiting the sufficient gas exchange that our metabolism needs to continue functioning. This is first caused by abnormalities or changes in the alveoli walls – they become more rigid or inflamed – which constrains the volume of air that can be contained in the lungs. The walls may also rupture, diminishing the number of air sacs, which significantly reduces the performance of the vital O2-CO2 gas exchange. This results in excess mucus formation, which eventually clogs the airways and triggers episodes of breathlessness. Such episodes are known as ‘exacerbations’, which are signs of worsening COPD symptoms.
What are the available treatments?
Usual care is prescribed by general clinicians and includes at least one of the following: a long-acting bronchodilator, an inhaled corticosteroid, and a LAMA (long-acting muscarinic antagonist) or a LABA (long-acting beta2-agonist). These are given usually in combination or as a dual or triple therapy.
In 2014, a new inhaler Relvar® Ellipta® was introduced into the market by GlaxoSmithKline (GSK). It delivers a fixed dose of fluticasone furoate and vilanterol (FF/VI). This new-generation dual bronchodilator is meant to replace usual care with a single dose per day, proving to be both efficacious as well as improving a patient’s daily experience.
What is the difference between asthma and COPD?
Although both conditions may have similar symptoms such as shortness of breath caused by inflammation and narrowing of the airways, the underlying mechanisms are very different. The pathophysiology of COPD exacerbations tends to be more infective, including bacterial infections. In asthma, they can be in relation to viruses, such as the rhinovirus which is also involved in common colds.
COPD occurs in older patients – typically above 50 – and its main cause is smoking. On the other hand, asthma usually occurs at a young age. However, a blurry line exists for a small part of the population that doesn’t fit into one of these two categories and as a result those cases are difficult to diagnose and prescribe treatment adequately. It is in fact possible for patients to suffer from both COPD and asthma.
The Salford Lung Study (SLS), sponsored by GlaxoSmithKline (GSK) was conducted to explore the effectiveness and safety of Relvar® Ellipta® when compared to other usual COPD treatments. Following GSK’s announcement of positive results published in the New England Journal of Medicine (NEJM) we were honoured to have an interview with Professor Norbert Berend, a Global Medical Expert at GSK, as well as the Head of Respiratory Research at the George Institute for Global Health. He helped the GSK team in the interrogation and interpretation of the SLS results, and provided expert clinician context for the study.
1. How did the Salford Lung Study (SLS) start?
The SLS is a pre-licensing study which was planned long before the drug was approved for use. The rationale for the study was based on the realisation that traditional clinical efficacy trials, designed to demonstrate the efficacy and safety profile of a drug, are conducted with a selected group of patients. Such trials do not include participants with co-morbidities and patients often fall within a certain age range along with other specific inclusion/exclusion criteria, which is not reflective of the patients that healthcare professionals see every day. In recent years, there has been an increasing recognition of the need for clinical effectiveness trials, which look at a broader group of patients in the community who reflect the different types of patient profiles the medical profession is confronted with in every day clinical practice. Compared with efficacy trials, effectiveness trial studies examine interventions under circumstances that more closely approach every day clinical practice, with more heterogeneous patient populations. Hence, these studies better mimic the everyday usage of the medicine in real patients regardless of disease severity or co-morbidities. Even health and medical regulators like the European Medicines Agency (EMA) requested for such studies to be conducted.
2. What was the focus of SLS?
The Salford Lung Study’s aim was to compare the effectiveness and safety profile of Relvar® Ellipta® with existing maintenance therapy for COPD in a patient population intended to represent that seen in everyday clinical practice. The hope is that generating these data will enable clinical decision makers to better evaluate a drug's effectiveness in the broader population in which it will be prescribed in clinical practice, and therefore determine its clinical value and impact on the healthcare system.
The primary endpoint was the mean annual rate of moderate or severe exacerbations in patients treated with Relvar® Ellipta® versus patients on usual care. The results showed that patients treated with Relvar® Ellipta® achieved a statistically significant 8.4% reduction in exacerbations compared with usual care. Exacerbations are the focal point of the study as some prove to be fatal and have a terrible effect on a patient’s quality of life. Every exacerbation can cause permanent lung damage and its repetition can accelerate disease progression. Repeated episodes of such incidents lead to breathlessness, where patients contract respiratory infections and make emergency trips to the hospital for a prescription of steroids.
3. Who was involved in the study and how was it conducted?
The Salford Lung Study was carried out over a 12-month period and was sponsored by GSK. Collaboration with external parties was key to the success of the study and GSK worked with multiple stakeholders including North West e-Health, The University of Manchester, NHS Salford and healthcare providers in Salford and surrounding areas of Greater Manchester. GPs, nurses, pharmacists and patients from the Salford and surrounding area all contributed to the success of the study. With the collective efforts of all these parties, the study successfully enrolled 2,802 COPD patients and evaluated the effectiveness and safety of Relvar® Ellipta® in everyday clinical practice.
The study utilised Salford’s sophisticated electronic health medical record (EMR) system, a clinical information system providing a single, integrated electronic patient record across GP surgeries and hospitals. The system enabled data on study endpoints and patient safety to be collected continuously and remotely, ensuring that patients are closely monitored with minimal intrusion into their everyday lives. This removes the need for the enforced interventions and controls required in traditional clinical trials, which are not representative of typical clinical practice and which may affect adherence and some study endpoints.
4. Can this study replace the necessity of other studies?
For regulatory purposes, clinical efficacy trials are still necessary to test drug efficacy for the targeted disease, and we therefore require a patient population with the isolated disease to avoid interference with the actual effect of the new drug being tested. Efficacy trials are also mandatory since they are done to establish the drug’s safety profile, though they don’t reflect actual clinical practice because of the highly selective nature of the patient population. This is why both efficacy and effectiveness studies are necessary to reveal the drug’s impact on a patient.
5. What did we learn from this clinical effectiveness trial?
While GSK already had the efficacy data showing the drug worked in COPD patients before it was launched, there are additional positive features of Relvar® Ellipta® that could only be revealed with effectiveness data. These include administering the medicine only once a day and a very easy to use inhaler design which has shown high patient acceptance. All these results were collected in the least intrusive manner that is without the strict monitoring seen in an efficacy trial that forces treatment adherence to test the effects of the drug on all subjects, and does not account for their compliance in real-life settings. We now know that Relvar® Ellipta® successfully treats patients, but also that it is in fact effective in a real life setting. This is very encouraging.
6. How do you define positive results?
While the SLS yielded an 8.4% reduction in the exacerbation’ rate, various other interventions in COPD yield differences up to 25% when tested against a placebo group. However, you don’t get this magnitude of change when you compare two effective regimens. What was stunning about the study was that we tested Relvar® Ellipta®’s effectiveness against a usual care group treated by GPs in a way that they thought was appropriate for majority of subjects who were already being treated. In fact, 88% of the patients were already on an inhaled steroid, and 52% were on three medications at the onset of the study, with an additional LAMA and a LABA. So the incremental benefit of 8.4% brought by Relvar® Ellipta® compared to usual and already efficient care is indeed significant for COPD patients. Another important number is the “Needed To Treat”, which indicates only seven patients have to be treated with Relvar® Ellipta® in order to reduce exacerbations by one per year. This is great in comparison to drugs such as aspirin, another secondary prevention to treat cardiovascular disease, where you need to treat about 30 patients for two and a half years to save one cardiac event.
7. How do you explain the number of adverse reactions that occurred in patients treated with Relvar® Ellipta® during the SLS?
Some of the adverse events are not necessarily related to this treatment, like nasal pharyngitis or bronchitis. These cases might simply occur in the population, which we had a much broader sample of in the SLS study. With regards to the incidence of side effects, there was no significant difference between the Relvar® Ellipta® group compared to participants given usual care. A particular focus was given to the pneumonia signal, because it had been previously shown that the use of inhaled corticosteroids confers an additional risk of developing pneumonia. As mentioned, 88% of the usual care group was already on an inhaler of steroid-containing regimen. There was a pneumonia signal in both groups, but no excessive risk was attributed to Relvar® Ellipta® over and above any other inhaled steroid medication. Side effects appear in every clinical trial and healthcare professionals are always on the lookout for these as any drug could have a range of side effects associated with it. What you try to do is find drugs with the lowest rate of side effects, and in this study, they were exactly the same for the two treatment groups.
8. What other treatment or lifestyle choice can complement the use of Relvar® Ellipta®?
Relvar® Ellipta® is not a solo drug, it’s already a combination of an inhaled steroid and a LABA. There isn’t a complement treatment in particular, but you can have people on triple therapy by adding a LAMA, which is more efficacious. In terms of nutrition, there’s no evidence that it significantly changes the exacerbations rate. Non-pharmacological treatment involves maintenance of ideal bodyweight and maintaining exercise capacity – which is difficult because the patients are usually breathless, but there is usually an exercise regimen within the pulmonary rehabilitation program to help them. Additionally, patients should be vaccinated against influenza and meningococcal disease to minimise risk of contracting infections or getting flu or pneumonia, given that their lungs are already weakened.
9. Could you explain why there are asthma-related death risks for COPD patients, when Relvar® Ellipta® is also used to treat asthma?
21% of the COPD patients were also diagnosed with asthma, and some patients are difficult to categorise and diagnose from each other. In fact, about 30% of patients with COPD are thought to have co-existing asthma. So while clinical efficacy trials looked at the effect of Relvar® Ellipta® on subjects with only isolated COPD, it is in fact a subgroup and there is yet to be an analysis of all the data of patients with or without co-morbidities, with or without additional asthma, different severities, and so on.
10. How do the treatments for asthma and COPD differ between countries?
Generally, we tend to use similar treatments for both, in other words bronchodilators and inhaled corticosteroids. We only use LAMAs to treat COPD, and we introduce inhaled corticosteroids at a later stage in COPD than we do in asthma. In the latter, it’s standard therapy because almost all the manifestations of asthma can be improved with the use of inhaled corticosteroids.
One of the issues is that a lot of the inhaled drugs are much more expensive than the oral drugs, because of the production cost of the inhaler. Additionally, in some countries, the use of inhalers is less socially accepted. In Australia too, there used to be a time when the use of an inhaler was associated with embarrassment, but not anymore because we recognise it as an effective treatment. In developing countries, they usually have a smaller range of drugs available, so there is lesser choice for the clinicians, and often there are social factors, about the acceptability of inhaled treatment and the additional cost incurred, which makes it more difficult to introduce inhaled drugs.
11. How do you think digital healthcare will change the way researchers design clinical trials?
I think there will be a huge clinical impact arising out of digitalisation of healthcare. We’ve already seen here the effect of an electronic health record, and the sort of information that can be gleaned by integrating information from a number of sources like hospital, pharmacies and other health institutes. You get a much better idea about what’s happening with patients. For example, at the moment we have inhalers with different characteristics and some are much harder to use than others, especially for COPD patients because they are elderly and have to synchronise pressing and inhaling correctly. The use of these medications among the majority of patients falls off drastically after 3 months, and by 12 months only 20% of them fill their prescriptions in a way that suggests they’re actually using their drugs. Digital devices could inform us on how often and how effectively patients use the inhaler, with electronic metering devices on the mouthpiece or elaborate acoustic technology. I think this will be very helpful in designing medical devices and drugs themselves, as well as managing the patients, analysing their bodily responses to drugs and monitoring real-life effectiveness of drugs on the market.
12. Do you feel that this kind of effectiveness study will end up being systematic since all the data will already be there?
This is looking into utopia. The Salford medical environment is sort of unique because it allowed us to conduct such a study, and there are very few places at the moment that have the infrastructure available to even contemplate doing this. Globalising electronic medical records is probably at least 20 years away. I think this is coming, but one of the major issues is the privacy aspect as well: everything we do is on an electronic record, with a chance that somebody can hack into it. However, most would argue that the good far outweighs the bad in the case of healthcare.
About the Interviewee
Professor Norbert Berend joined GSK as a Global Medical Expert in a part time capacity in 2015. Norbert is also Head of Respiratory Research at the George Institute for Global Health, Professor Emeritus at the University of Sydney and Member of the Physiology Group at the Woolcock Institute for Medical Research.
Norbert has been heavily involved in national and international respiratory societies having been President of the Thoracic Society of Australia and New Zealand and the Asian Pacific Society of Respirology. He has also served on the Council of the European Respiratory Society and has been a member of the Board of the American Thoracic Society. In 2011, Norbert was Chairman of the Forum of International Respiratory Societies.
He has a strong research background focusing on the pathophysiology of asthma and COPD and has a particular interest in small airways disease and function. Norbert’s awards include the Rhone-Poulenc Rorer Medal of the Thoracic Society of Australia and New Zealand (1997), the Asian Pacific Society of Respirology Medal (2011) and the TSANZ Medal (2012). In 2003, Norbert was made a Member of the Order of Australia for service to respiratory medicine as a researcher, administrator and educator.
This interview was conducted by APBN, Katya Guez and Carmen J.W. Loh.