Background
Maintenance inhaled treatment of chronic obstructive pulmonary disease (COPD) is based on long-acting β
2-agonist (LABA) and/or long-acting muscarinic antagonists (LAMA) and LABA/inhaled corticosteroid (ICS) [
1]. Despite treatment, most of the patients remain symptomatic, requiring a change in therapy [
2].
A once-daily (q.d.) combination of indacaterol and glycopyrronium (IND/GLY) was effective and well tolerated in patients with moderate-to-severe COPD in several phase III trials [
3,
4]. Such pivotal trials are usually performed in selected patients and hospital settings [
5]. Patients with COPD treated in primary care settings often differ from those included in large randomised controlled trials (RCTs) [
6]. Moreover, in RCTs, prior to randomisation, patients typically go through a washout period, in contrast to clinical practice where treatment changes occur without any washout period [
5]. The effectiveness of a treatment in clinical practice can be evaluated more appropriately in a direct switch study in primary care settings, engaging a relevant patient pool with less stringent inclusion criteria [
6].
CRYSTAL (effect of glyCopyrronium or indacateRol maleate and glYcopyrronium bromide fixed-dose combination [FDC] on SympToms and heALth status in patients with moderate COPD) was a 12-week, prospective, multi-centre, open-label study carried out in clinical practice settings to evaluate the impact of a direct switch to GLY or IND/GLY from previous standard-of-care treatments on lung function and dyspnoea in symptomatic patients with moderate COPD.
In this manuscript, we focus on the fully recruited and adequately powered groups directly switched to IND/GLY; the results of the GLY groups are described in the Additional file
1: Section S6, Tables S1, S2, S3 and S4 and Figures S5 and S6.
Discussion
In the randomised, open-label CRYSTAL study in patients with moderate COPD, a direct switch to IND/GLY resulted in significant improvements in lung function and dyspnoea compared with continuation of LABA or LAMA monotherapies and LABA + ICS combinations. Patients on IND/GLY also achieved improvements in health status and presented reduced rescue medication use, with a safety profile similar to that reported in RCTs.
This is, to the best of our knowledge, the first study to evaluate the effectiveness of a step-up strategy from single long-acting bronchodilators to a dual bronchodilator. This is in accordance with the recent Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 strategy document that suggests escalation to dual bronchodilation in patients who have high level of symptoms and low risk of developing exacerbations (GOLD group B) and remain symptomatic on a LABA or LAMA [
1]. Existing evidence supports the de-escalation of appropriate stable COPD patients from triple therapy (LABA + LAMA + ICS) to dual bronchodilation [
11,
12], but data supporting treatment escalation are lacking. The CRYSTAL study supports the GOLD step-up recommendation from a single bronchodilator regimen to IND/GLY in symptomatic patients [
1].
Although the efficacy and safety of IND/GLY has been demonstrated in well-designed explanatory trials, real-world evidence is currently missing. In pragmatic trials conducted in clinical practice settings, outcome measures are typically clinically-relevant assessments that may support clinicians to decide between a new intervention and previously available treatments [
5]. The use of less stringent inclusion and exclusion criteria and direct switching between treatments without a washout period mimics the way treatment changes occur in clinical practice [
5]. The CRYSTAL study implemented a direct switch from various available treatments in symptomatic patients with moderate COPD, without a washout period. In the CRYSTAL study, patients were switched from a particular treatment to IND/GLY and patients continuing baseline therapy (LABA + ICS or LABA or LAMA) served as the control group. The study was conducted in 23 European countries and included approximately 50% non–hospital-based investigators (office-based pulmonologists and general practitioners), thus representing a wide range of clinical practice settings.
The efficacy and safety results of IND/GLY in this study were consistent with previous explanatory trials of the IGNITE programme, consisting of 11 trials conducted in >11,000 patients with moderate-to-very severe COPD [
3,
4,
13]. In the 26-week ILLUMINATE study, IND/GLY demonstrated superior improvements in the trough FEV
1 of 103 mL [
3], whereas in the 1-year FLAME study, the Δ was 62 mL compared with LABA/ICS [
4]. Similarly, in the 26-week SHINE study, IND/GLY showed greater improvements in lung function in trough FEV
1, with a Δ versus its monocomponents IND and GLY of 70 mL and 90 mL, respectively and 80 mL versus the open-label tiotropium [
14]. IND/GLY also demonstrated a significant improvement in TDI versus salmeterol-fluticasone in the ILLUMINATE study (Δ = 0.76 units) and versus LABA or LAMA (e.g. with a Δ of 0.51 units versus open-label tiotropium in the SHINE study [
3] and 0.49 units versus blinded tiotropium in the 6-week BLAZE study [
15]). Studies of other available LABA/LAMA FDCs (e.g. aclidinium/formoterol and umeclidinium/vilanterol) have reported significant improvements in dyspnoea in comparison with baseline or placebo, but in some of these studies, non-significant differences were also observed when compared with active comparators such as LAMA or LABA/ICS [
16‐
19].
In the CRYSTAL study, IND/GLY showed greater improvements in TDI total score versus the comparators than those observed in previous RCTs. The open-label comparison of a new and effective drug versus previous treatments may have resulted in a more pronounced effect on TDI total score. The inclusion of objective endpoints has been strongly recommended in open-label trials as they are less prone to bias [
20], and therefore FEV
1 was a pre-specified co-primary endpoint in this study. The improvements in dyspnoea (TDI) and lung function (trough FEV
1) in CRYSTAL were concurrent and the magnitude of the effect on lung function was similar to that shown in RCTs. Based on the above facts, we believe that the greater improvement in TDI total score, although higher than that observed in RCTs, is not a chance finding.
A higher numerical reduction in CAT total score with IND/GLY versus both LABA + ICS and LABA or LAMA monotherapy was observed that did not reach statistical significance. In contrast, there was a statistically significant improvement in the CCQ total score versus both comparators. A potential explanation for this discrepancy is that different scores have different sensitivities in the response to treatment. Moreover, CAT is a health status tool that was developed to help patients and their clinicians assess and quantify the symptoms and impacts of COPD [
21] and has been shown so far to be responsive to changes in health status following exacerbations and to pulmonary rehabilitation [
22]. Further studies are needed to evaluate the responsiveness of different health status tools to pharmacotherapy options.
The overall incidence of adverse events was similar in the investigational and comparator treatment groups, with a slightly higher percentage in IND/GLY groups. This difference may be attributed to a potential reporting bias of adverse events against the newly initiated treatment (IND/GLY) compared with previous treatments that have already been well tolerated by the patients. In open-label trials, there is a risk of increased adverse event reporting, both from patients who may research the ‘new’ drug and may be influenced in their reporting behaviour, as well as from the investigators who may be more susceptible to report adverse events related to the new drug [
23]. Importantly, the overall incidence of severe and fatal adverse events was similar in the IND/GLY and comparator treatments.
Improvements in lung function, symptoms, quality of life and exercise tolerance represent major needs for patients with COPD. Although we did not evaluate the exercise capacity of patients in the CRYSTAL study, the improvement in breathlessness and health status may resonate in improvement of exercise tolerance in certain patients [
24]. Long-acting bronchodilators also act as lung deflators, which may lead to the improvement in static and dynamic hyperinflation [
25]. IND/GLY has demonstrated significant improvements in inspiratory capacity, dyspnoea, exercise capacity and other patient-reported outcomes in RCTs [
3,
4,
24,
26,
27], and the consistent results of the CRYSTAL study support that these beneficial effects may be experienced also in routine clinical practice.
The CRYSTAL study was appropriately designed to complement previous RCTs by providing information on a direct switch to IND/GLY under routine clinical practice conditions, but, as other open-label studies, may have certain limitations. Firstly, some of the non-frequently exacerbating patients with moderate COPD recruited in the CRYSTAL study were appropriately treated with a single long-acting bronchodilator, whereas most of the patients on LABA + ICS were inappropriately treated according to the GOLD recommendations [
28], as it happens often in clinical practice. Importantly, the CRYSTAL study results show that even in these mildly symptomatic patients, the switch from a mono-bronchodilator regimen (with or without ICS) to a dual bronchodilator (IND/GLY) significantly improved their lung function, breathlessness and overall quality of life. Secondly, the duration of the study was only 12 weeks, and this short time frame does not allow for a clear understanding of the long-term effectiveness of IND/GLY and its potential effects on exacerbations and long-term safety. Nevertheless, the consistency of the CRYSTAL study results with those of previous RCTs indicates that the effectiveness of IND/GLY in clinical settings is likely to be similar to the efficacy observed in RCTs. Moreover, the direct switch from a LABA + ICS regimen may raise a question on carry-over effect of pre-treatments; however, given the short half-life of ICS, a period of 12 weeks is long enough to make any carry-over effects of ICS treatment unlikely. The third limitation is the fact that it was an open-label study with a potential reporting bias regarding patient-reported outcomes, e.g. measures of dyspnoea and health-related quality of life. However, in order to avoid a selection bias in this open-label study setting, patients were randomised at baseline. Finally, the short study duration does not allow for appropriate evaluation of exacerbation prevention in this setting. The results of the CRYSTAL study provide reassurance on the efficacy and safety of dual bronchodilation compared with mono-bronchodilators or LABA + ICS combinations.