COPD exacerbations trial design

Exacerbation trials design in chronic obstructive pulmonary disease – time to reflect

Jørgen Vestbo1,2andAshley Woodcock1,2

  1. Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, The University of Manchester, Manchester, UK.
  2. North West Lung Centre, University Hospital South Manchester NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.

Correspondence:Professor Jørgen Vestbo

ERC Building

University Hospital South Manchester

Southmoor Road

M23 9LT Manchester

UK

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Phone: +44 (0)161 291 5869

Running title: COPD exacerbations trial design

Word count: 1243

Chronic obstructive pulmonary disease (COPD) in a common chronic condition responsible for more than 2.3 million deaths globally. Early studies of the efficacy of inhaled therapies were powered on small changes in forced expiratory volume in 1 second (FEV1), without much consideration of patient benefit. Things have moved on!

Exacerbations of respiratory symptoms occur frequently and are responsible for much of the morbidity associated with COPD (1).Not all COPD patients suffer from exacerbations, but some patients experience frequent exacerbations of their disease (2). One of the main goals of COPD management is to reduce exacerbations and several drugs have been shown to reduce the number of exacerbations in patients at risk (1). Most of the evidence base for reducing the risk of exacerbations comes from carefully conducted efficacy trials in narrowly defined populationswith the recent effectiveness trial, The Salford Lung Study, a notable exception (3). A closer understanding of the evidence base for risk reduction may be required as recent exacerbation trials have been very carefully designed to maximize the odds of a successful outcome for the drug or drug combination under study, be itan anti-inflammatory agent ora regimen of combined bronchodilators. The full impact of these tweaks of design may not be obvious, fully acknowledged or understood. We believe that most clinicians are unaware of how trials may have been engineered to deliver their aims, and that the evidence base in guidelines on which clinicians make decisions, may not be relevant to the patients they are caring for.

Trials in COPDdid not focus on exacerbations as an outcome until the Inhaled Steroids in Obstructive Lung Disease in Europe (ISOLDE) study (4). In this trial the primary outcome was not met as patients receiving the inhaled corticosteroid fluticasone propionate had a rate of decline in forced expiratory volume in 1 second (FEV1) that did not differ from that seen in the placebo group. However, a change in severity of exacerbations was seen and this was the starting gun for a number of large studies with exacerbations as primary outcome, examining both inhaled corticosteroids and long-acting bronchodilators.In virtually all subsequent trials the exacerbations have been defined on the basis of health-care utilization, with moderate exacerbations being defined as those events managed with systemic corticosteroids,or antibiotics or both, and severe exacerbations defined as events requiring hospital admission.

In several trials, inhaled corticosteroids (ICS) tendedto showgreater efficacy in preventing exacerbations that patients’ clinicians would have treated with systemic corticosteroids, compared to all exacerbations independent of treatment (i.e., including an antibiotic alone)(5). This may not be surprising as exacerbations without signs of bacterial infection are often regarded as “inflammatory” in contrast to “infectious” and it seems likely that an inhaled anti-inflammatory agent would reduce the number of these events. Supportive data for this idea came from the Investigating New Standards for Prophylaxis in Reducing Exacerbations (INSPIRE) study in which exacerbation rates were similar overall in patients treated with a long-acting anti-muscarinic agent (LAMA) when compared to patients treated with a combination of an ICS and a long-acting beta-agonist (LABA) (6).However, in this study the combination of an ICS and a LABA had superior efficacy on preventing exacerbations requiring treatment with oral corticosteroids, but inferior efficacy on preventing exacerbations treated with antibiotics.

Since these insights,most trials of anti-inflammatory agents have used subtly different ways of defining exacerbations, compared to those designed to show the efficacy of bronchodilators, potentially with significant impact on the conclusions drawn, and more important, the applicability of the results to clinical practice. Recent efficacy trials aiming to show an effect of an anti-inflammatory agent have used moderate exacerbation defined as events requiring treatment with systemic corticosteroids with or without an antibiotic (i.e., excluding exacerbations treated with antibiotics alone). This was the case in a study examining the impact of adding combined budesonide/formoterol to tiotropium (7) and in the trials leading to the registration of roflumilast. By leaving out exacerbations treated with antibiotics only, this will likely lead to more favorable efficacy of an anti-inflammatory agent (since it will not be diluted by “infectious” exacerbations, in which the effect is believed to be minimal). The latter was nicely demonstrated in a recent secondary analysis of the Study to Understand Mortality and MorbidITy (SUMMIT) study (8).

Fixed combinations of two long-acting bronchodilators - a LAMA combined with a LABA - have recently been launched and not surprisingly, these combinations have better efficacy symptoms than a combination of an ICS and a LABA.The two exacerbation trials to test the new dual long-acting bronchodilators have used theold definition of exacerbations defining moderate exacerbations as those events managed with systemic corticosteroids and/or antibiotics (i.e. including those with antibiotics alone) and severe exacerbations being defined as events requiring hospital admission. However, in addition, both studies used daily electronic symptom diary card registration, which included notification of the patient when symptoms were compatible with a possible exacerbation. It is likely that using symptom diary cards to prompt patients will trigger recognition of more events, and lead to symptom variation being registered as exacerbations more often than in trials not using a symptom triggering diarycard, thus potentially favouring a dual bronchodilator using symptom triggering diaries to emphasise symptomatic benefit (9).

It is also notable, that the frequency of exacerbations in the trial period varies approximately four-fold from 0.5 per year to 2 per year and this likely reflects patient selection as a result of varying in- and exclusion criteria (3, 10). However, it is not only in efficacy, but also in safety aspects where it is crucial to know the trials in detail. In studies to datethere has not been a safety signal for dual bronchodilators in COPD patients. However, in all trials a variable proportion of patients with any cardiac risk factors were excluded (often only described in the on-line supplement). The importance of data on safetyshould be considered in the context of routine clinical practice where more than half of patients have concomitant cardiac or vascular disease (3).

It is important to stress that it is notwrong to design efficacy trials for the purpose of increasing the likelihood of a conclusive outcome. Given the large investments in a new therapyby the time it has reached large later phase trials with COPD exacerbations as an outcome, there is undoubtedly a wish to ensure a positive outcome in order to reach registration. There is only a problem if these important but subtle considerations are not made specifically clear to the reader of the study papers.

There is currently a large push towards using dual long-acting bronchodilators early in COPD as several pharmaceutical companies have recently launched such combinations.In the recent strategy document from the Global Initiative for Obstructive Lung Diseases (GOLD) (1), the dual bronchodilator combination is the preferred option for symptomatic patients at risk for exacerbations. However, this new approach is based on only two studies, and these two studies differ from the majority of exacerbation trials by prompting exacerbations based on diary cards. Based on the differences in outcomes depending on study design described above, we may need more trials before feeling assured that this strategy is correct.

Finally, we need to consider if carefully designed efficacy studies are at all relevant to routine clinical practice, and if indeed they should be replaced or at least supplemented by effectiveness studies for determining treatment guidelines. Actually, this applies to all diseases.

References:

  1. Vogelmeier CF, Criner GJ, Martinez FJ, et al. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease 2017 Report: GOLD Executive Summary. Eur Respir J 2017; DOI: 10.1183/13993003.00214-2017.
  2. Hurst JR, Vestbo J, Anzueto A, et al, for the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) investigators. Susceptibility to Exacerbation in Chronic Obstructive Pulmonary Disease. N Engl J Med 2010; 363: 1128-38.
  3. Vestbo J, Leather D, Diar Bakerly N, et al, for the Salford Lung Study Investigators. Effectiveness of Fluticasone Furoate–Vilanterol for COPD in Clinical Practice. N Engl J Med 2016; 375: 1253-60.
  4. Burge PS, Calverley PMA, Jones PW, Spencer S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000; 320: 1297-1303.
  5. Calverley PMA, Anderson JA, Celli B, et al, on behalf of the TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med 2007; 356: 775-89.
  6. Wedzicha JA, Calverley PM, Seemungal TA, Hagan G, Ansari Z, Stockley RA; INSPIRE Investigators. The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Am J Respir Crit Care Med 2008; 177: 19-26.
  7. Welte T, Miravitlles M, Hernandez P, et al. Efficacy and tolerability of budesonide/formoterol added to tiotropium in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2009; 180: 741-50.
  8. Martinez FJ, Vestbo J, Anderson JA, et al; SUMMIT Investigators. Effect of Fluticasone Furoate and Vilanterol on exacerbations of COPD in patients with moderate airflow obstruction. Am J Respir Crit Care Med 2016; Oct 21: [Epub ahead of print], PMID: 27767328.
  9. Wedzicha JA, Banerji D, Chapman KR, et al, for the FLAME Investigators. Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD. N Engl J Med 2016; 374: 2222-34. 299.
  10. Singh D, Papi A, Corradi M, et al. Single inhaler triple therapy versus inhaled corticosteroid plus long-acting β2-agonist therapy for chronic obstructive pulmonary disease (TRILOGY): a double-blind, parallel group, randomised controlled trial. Lancet 2016; 388: 963-73.

Box

Key points:

  1. Several drugs and combination of drugs have in efficacy trials been shown to reduce the risk of exacerbations in COPD patients at risk of exacerbations.
  2. Capture and definition of moderate exacerbations have varied in studies to date, likely affecting the chance of showing beneficial effect of either anti-inflammatory drugs or long-acting bronchodilators.
  3. Summarising evidence on exacerbation reduction using these trials may not result in an unbiased evaluation.
  4. In the future, it must be more clear how exacerbations were defined and captured in trials aimed at reducing exacerbations in COPD.
  5. There is a urgent need for effectiveness trials with subjects much more representative of the patients who will subsequently be treated and with exacerbation end-points easily interpreted by clinicians.

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