Stefano Vezzoli

Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomised controlled trial

BACKGROUND Limited data are available for the efficacy of triple therapy with two long-acting bronchodilators and an inhaled corticosteroid in chronic obstructive pulmonary disease (COPD). We compared treatment with extrafine beclometasone dipropionate, formoterol fumarate, and glycopyrronium bromide (BDP/FF/GB; fixed triple) with tiotropium, and BDP/FF plus tiotropium (open triple). METHODS For this double-blind, parallel-group, randomised, controlled trial, eligible patients had COPD, post-bronchodilator forced expiratory volume in 1 s (FEV1) of less than 50%, at least one moderate-to-severe COPD exacerbation in the previous 12 months, and a COPD Assessment Test total score of at least 10. After a 2-week run-in period receiving one inhalation per day via single-dose dry-powder inhaler of open-label 18 μg tiotropium, patients were randomised (2:2:1) using a interactive response technology system to 52 weeks treatment with tiotropium, fixed triple, or open triple. Randomisation was stratified by country and severity of airflow limitation. The primary endpoint was moderate-to-severe COPD exacerbation rate. The key secondary endpoint was change from baseline in pre-dose FEV1 at week 52. The trial is registered with ClinicalTrials.gov, number NCT01911364. FINDINGS Between Jan 21, 2014, and March 18, 2016, 2691 patients received fixed triple (n=1078), tiotropium (n=1075), or open triple (n=538). Moderate-to-severe exacerbation rates were 0·46 (95% CI 0·41-0·51) for fixed triple, 0·57 (0·52-0·63) for tiotropium, and 0·45 (0·39-0·52) for open triple; fixed triple was superior to tiotropium (rate ratio 0·80 [95% CI 0·69-0·92]; p=0·0025). For week 52 pre-dose FEV1, fixed triple was superior to tiotropium (mean difference 0·061 L [0·037 to 0·086]; p<0·0001) and non-inferior to open triple (-0·003L [-0·033 to 0·027]; p=0·85). Adverse events were reported by 594 (55%) patients with fixed triple, 622 (58%) with tiotropium, and 309 (58%) with open triple. INTERPRETATION In our TRINITY study, treatment with extrafine fixed triple therapy had clinical benefits compared with tiotropium in patients with symptomatic COPD, FEV1 of less than 50%, and a history of exacerbations. FUNDING Chiesi Farmaceutici SpA.

Extrafine beclomethasone/formoterol in severe COPD patients with history of exacerbations

The FORWARD study is a randomised, double-blind trial that compares the efficacy and safety of 48 weeks treatment with extrafine beclomethasone dipropionate/formoterol fumarate (BDP/FOR), 100/6 μg pMDI, 2 inhalations BID, vs. FOR 12 μg pMDI, 1 inhalation BID, in severe COPD patients with a history of exacerbations. Co-primary endpoints were exacerbation rate over 48 weeks and pre-dose morning FEV(1) at 12 weeks. The ITT population included 1186 patients (69% males, mean age 64 years) with severe airflow limitation (mean post-bronchodilator FEV(1) 42% predicted). Salbutamol as rescue therapy, theophylline and tiotropium (if stable regimen prior to screening) were allowed. Compared to FOR, BDP/FOR: (1) reduced the exacerbation rate (rate ratio: 0.72 [95% confidence interval 0.62-0.84], p < 0.001); (2) improved pre-dose morning FEV(1) (mean difference: 0.069 L [0.043-0.095] p < 0.001); (3) prolonged the time to first exacerbation; (4) improved the SGRQ total score. The percentage of patients with adverse events was similar (52.1% with BDP/FOR and 49.2% with FOR). Pneumonia incidence was low, slightly higher with BDP/FOR (3.8%) than with FOR (1.8%). No difference for laboratory values, ECG or vital signs. Extrafine BDP/FOR significantly reduces the exacerbation rate and improves lung function of patients with severe COPD and history of exacerbations as compared to FOR alone.

Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial

BACKGROUND Evidence is scarce on the relative risk-benefit of inhaled triple therapy, consisting of inhaled corticosteroid, long-acting muscarinic antagonist, and long-acting β2-agonist, versus dual bronchodilation for chronic obstructive pulmonary disease (COPD). We aimed to compare a single-inhaler triple combination of beclometasone dipropionate, formoterol fumarate, and glycopyrronium (BDP/FF/G) versus a single-inhaler dual bronchodilator combination of indacaterol plus glycopyrronium (IND/GLY) in terms of the rate of moderate-to-severe COPD exacerbations over 52 weeks of treatment. METHODS This randomised, parallel-group, double-blind, double-dummy study was done at 187 sites across 17 countries. Eligible patients had symptomatic COPD, severe or very severe airflow limitation, at least one moderate or severe exacerbation in the previous year, and were receiving inhaled maintenance medication. After a 2 week run-in period with one inhalation per day of IND/GLY (85 μg/43 μg), patients were randomly assigned (1:1), via an interactive response technology system, to receive 52 weeks of treatment with two inhalations of extrafine BDP/FF/G (87 μg/5 μg/9 μg) twice per day or one inhalation of IND/GLY (85 μg/43 μg) per day. Randomisation was stratified by country and severity of airflow limitation. The primary endpoint was the rate of moderate-to-severe COPD exacerbations across 52 weeks of treatment in all randomised patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02579850. FINDINGS Between May, 29 2015, and July 10, 2017, 1532 patients received BDP/FF/G (n=764) or IND/GLY (n=768). Moderate-to-severe exacerbation rates were 0·50 per patient per year (95% CI 0·45-0·57) for BDP/FF/G and 0·59 per patient per year (0·53-0·67) for IND/GLY, giving a rate ratio of 0·848 (0·723-0·995, p=0·043) in favour of BDP/FF/G. Adverse events were reported by 490 (64%) of 764 patients receiving BDP/FF/G and 516 (67%) of 768 patients receiving IND/GLY. Pneumonia occurred in 28 (4%) patients receiving BDP/FF/G versus 27 (4%) patients receiving IND/GLY. One treatment-related serious adverse event occurred in each group: dysuria in a patient receiving BDP/FF/G and atrial fibrillation in a patient receiving IND/GLY. INTERPRETATION In patients with symptomatic COPD, severe or very severe airflow limitation, and an exacerbation history despite maintenance therapy, extrafine BDP/FF/G significantly reduced the rate of moderate-to-severe exacerbations compared with IND/GLY, without increasing the risk of pneumonia. FUNDING Chiesi Farmaceutici.

Bronchodilator efficacy of extrafine glycopyrronium bromide: the Glyco 2 study

An extrafine formulation of the long-acting muscarinic antagonist glycopyrronium bromide (GB) is in development for chronic obstructive pulmonary disease (COPD), in combination with beclometasone dipropionate and formoterol fumarate – a “fixed triple”. This two-part study was randomized, double blind, placebo controlled in patients with moderate-to-severe COPD: Part 1: single-dose escalation, GB 12.5, 25, 50, 100 or 200 μg versus placebo; Part 2: repeat-dose (7-day), four-period crossover, GB 12.5, 25 or 50 μg twice daily (BID) versus placebo, with an open-label extension in which all patients received tiotropium 18 μg once daily. On the morning of Day 8 in all five periods, patients also received formoterol 12 μg. In study Part 1, 27 patients were recruited. All GB doses significantly increased from baseline forced expiratory volume in 1 second (FEV1) area under the curve (AUC0–12h) and peak FEV1, with a trend toward greater efficacy with higher GB dose. All adverse events were mild–moderate in severity, with a lower incidence with GB than placebo and no evidence of a dose–response relationship. In study Part 2, of 38 patients recruited, 34 completed the study. Adjusted mean differences from placebo in 12 h trough FEV1 on Day 7 (primary) were 115, 142 and 136 mL for GB 12.5, 25 and 50 μg BID, respectively (all P<0.001). GB 25 and 50 μg BID were superior (P<0.05) to GB 12.5 μg BID for pre-dose morning FEV1 on Day 8. For this endpoint, GB 25 and 50 μg BID were also superior to tiotropium. Compared with Day 7, addition of formoterol significantly increased Day 8 FEV1 peak and AUC0–12h with all GB doses and placebo (all P<0.001). All adverse events were mild–moderate in severity and there was no indication of a dose-related relationship. This study provides initial evidence on bronchodilation, safety and pharmacokinetics of extrafine GB BID. Overall, the results suggest that GB 25 μg BID is the optimal dose in patients with COPD.

Inhaled corticosteroid containing combinations and mortality in COPD

There is no solid evidence that any pharmacological treatment reduces mortality in chronic obstructive pulmonary disease (COPD). Two large trials with mortality as an efficacy outcome have been carried out testing a combination of a long-acting beta-agonist (LABA) and an inhaled corticosteroid (ICS) and in both, the reduction in mortality failed to reach statistical significance [1, 2]. This could be seen as proof of absence of effect, but given that the TORCH trial [1] resulted in a hazard ratio (HR) of 0.825 (95% CI 0.681–1.002; p=0.052) for the comparison of combined fluticasone propionate and salmeterol with placebo, the interpretation may not be that simple. The other negative trial, the SUMMIT trial [2], only included patients with moderate COPD and increased risk of cardiovascular comorbidity. Combinations containing inhaled corticosteroids may reduce mortality in patients with COPD http://ow.ly/6UCy30lpwEi

P271 Effect of extrafine single inhaler triple therapy on lung function and use of rescue medication: results from the trinity study

Rationale Treatment with extrafine triple therapy in a single inhaler has beneficial effects compared to LAMA monotherapy on lung function and symptoms. This analysis focuses on rescue medication use (as this is associated with symptoms) and lung function responder analysis identifying clinically relevant effects. Methods In this 52 week multicentre, randomised, double-blind, active-controlled study, 2691 patients with severe to very severe COPD, exacerbations history, and CAT total score ≥10 were randomised (2:2:1) to tiotropium, fixed triple (beclometasone/formoterol/glycopyrronium), or free triple (beclometasone/formoterol+tiotropium). Secondary endpoints included FEV1 responders at week 26 and 52 using different thresholds for response and change from baseline in average use of rescue medication. Results Both fixed and free triple FEV1 responder percentages were significantly greater than tiotropium at weeks 26 and 52 regardless of the threshold used to define the response (p<0.001 for all analyses). At 26 weeks the proportion of responders were 48.0% (fixed triple) and 48.1% (free triple) for the 50 ml threshold, and 36.7% and 34.8% at the higher 120 mL threshold, with similar Results at week 52. Corresponding FEV1 responder percentages for tiotropium were lower at the 50 mL threshold (35.7% and 34.8%, at weeks 26 and 52 respectively) and 120 mL threshold (25.3% and 24.8%, respectively). In terms of average percentage of days without rescue medication use over 52 weeks, all treatments showed statistically significant increases from baseline which were more marked with fixed and free triple (13.9 [95%CI: 12;15.8] and 14.8% [95%CI: 12.1;17.4] respectively) compared to 5.2% [95%CI: 3.3;7.1] for tiotropium alone (p<0.001) and no difference observed between fixed and free triple with an adjusted mean difference of −0.8% [95% CI: −4.1;2.4] (p=0.616). Average use of rescue medication with both fixed and free triple treatments over 52 weeks compared to tiotropium alone was reduced by 0.6 [95%CI: 0.4;0.7] and 0.6 [95%CI: 0.5;0.8] puffs/day, respectively (p<0.001). Conclusions Extrafine triple therapy in a single inhaler provides superior clinical benefits in severe to very severe COPD patients in terms of lung function (by individual responder analysis) and rescue medication use compared with tiotropium alone. Please refer to page A260 for declarations of interest in relation to abstract P271.

P273 Association of incident pneumonia and exacerbations with extrafine triple therapy in one single inhaler in copd patients: a post-hoc analysis from trilogy and trinity studies

Rationale Efficacy and safety of extrafine fixed triple combination of beclometasone dipropionate, formoterol fumarate, and glycopyrronium bromide (BDP/FF/GB; 100/6/12.5 mcg, two actuations BID via pMDI; ‘fixed triple’) has been recently demonstrated in two phase III trials. Fixed triple has shown superiority in improving lung function and reducing moderate/severe exacerbations versus BDP/FF (Fostair 100/6 mcg, two actuations BID via pMD; TRILOGY – Singh et al. Lancet 2016; 388: 963–73) and versus tiotropium (18 mcg one inhalation OD via DPI; TRINITY – Vestbo et al. Lancet 2017; 389: 1919–29). Increase in pneumonia risk associated with ICS containing medications is a known class effect. The risk/benefit balance of extrafine fixed triple was evaluated by comparing variations in pneumonia and exacerbation events. Methods Information on moderate/severe exacerbations and confirmed pneumonia was extracted from TRINITY and TRILOGY. A frequency plot was generated considering days in the study versus cumulative number of events. Results In TRILOGY study, the number of recorded events was 288 exacerbations (rate: 0.448 exacerbations per patient per year) versus 25 pneumonias (rate: 0.039 events per patient per year) with fixed triple and 353 exacerbations (0.565) versus 18 pneumonias (0.029) with Fostair (figure 1A). In TRINITY study, the number of events was 485 exacerbations (0.472) versus 30 pneumonias (0.029) with fixed triple and 569 exacerbations (0.583) versus 20 pneumonias (0.020) with tiotropium (figure 1B). Overall, treatment with fixed triple therapy reduced exacerbations by 65 events compared to Fostair (adjusted rate ratio: 0.773, p=0.005) and by 84 events compared to tiotropium (0.801, p=0.003). No fatal pneumonias occurred in TRILOGY while 5 pneumonias led to death in TRINITY (1 with fixed triple versus 4 with tiotropium). All pneumonias were classified as non-related to treatment. Conclusions This analysis confirms that, in two independent populations of COPD patients treated with an ICS containing extrafine fixed triple combination, the number of incident pneumonia remains very small compared to that of moderate/severe exacerbations. The benefit observed in reducing the absolute number of exacerbations outweighs the increase observed in absolute number of pneumonias, thus confirming the positive risk benefit balance of extrafine fixed triple in severe/very severe COPD patients. Please refer to page A260 for declarations of interest in relation to abstract P273.

P276 Cardiovascular safety of extrafine single inhaler triple combination of beclometasone dipropionate, formoterol fumarate, and glycopyrronium bromide in copd: results of safety analysis from the trilogy and trinity studies

Rationale COPD often co-exists with other chronic diseases that can contribute to patients’ health status and prognosis. In particular, patients with COPD are at greater risk of cardiovascular disease compared with age and sex-matched controls. Methods Two 52 week multi-centre, randomised, double-blind, active-controlled studies recruited patients with symptomatic COPD, severe to very severe airflow limitation, and an exacerbation history. In TRILOGY, patients were randomised (1:1) to an extrafine fixed triple combination of beclometasone dipropionate, formoterol fumarate, and glycopyrronium bromide (BDP/FF/GB; 100/6/12.5 mcg, two actuations twice daily [BID] via pressurised metered dose inhaler [pMDI]; ‘fixed triple’) or an extrafine fixed combination of BDP/FF (100/6 mcg, two actuations BID via pMDI; Fostair) (Singh et al. Lancet 2016; 388: 963–73). In TRINITY patients were randomised 2:2:1 to BDP/FF/GB, tiotropium (18 mcg once daily via single-dose dry powder inhaler [SDDPI]), or BDP/FF+tiotropium: free triple (Vestbo et al. Lancet 2017; 389: 1919–29). In this analysis, we evaluated the occurrence of Major Adverse Cardiovascular Events (MACEs). MACEs included acute myocardial infarction, stroke, cardiovascular death, arrhythmias, and heart failure. Results MACE incidence and rate in the two BDP/FF/GB groups was similar to the BDP/FF and tiotropium groups (Table 1). The majority of reported MACEs were severe in intensity, with a slightly higher percentage of fatal events in the Tiotropium only group. Importantly, in patients with relevant concomitant cardiovascular diseases, the trend was similar to that seen in the overall populations. None of the other subgroup analyses (by age, spacer use and gender) highlighted relevant differences in the safety profiles compared with the overall population. Conclusions These Results provide further reassurance that the additional clinical benefits of this extrafine fixed triple compared to standard treatment are not associated with a greater impact on the cardiovascular safety in severe to very severe COPD patients, further supporting its positive benefit/risk ratio. Importantly, the presence of concomitant cardiac comorbidities did not influence the rate of cardiovascular events. Please refer to page A261 for declarations of interest in relation to abstract P276. Abstract P276 Table 1 Patients (%) with MACE, and MACE rate per 1000 patient years in TRILOGY and TRINITY TRILOGY TRINITY BDP/FF/GB (Fixed Triple)(n=687) BDP/FF (Fostair®)(n=680) BDP/FF/GB (Fixed Triple)(n=1077) Tiotropium (n=1076) BDP/FF+ Tiotropium (Free Triple)n=537 Treatment-emergent MACEs, n(%) 15 (2.2%) 15 (2.2%) 20 (1.9%) 23 (2.1%) 7 (1.3%) Acute Myocardial infarction 1 (0.1%) 6 (0.9%) 2 (0.2%) 4 (0.4%) 0 Arrhythmias 3 (0.4%) 2 (0.3%) 1 (0.1%) 1 (0.1%) 1 (0.2%) Cardiovascular death 3 (0.4%) 3 (0.4%) 8 (0.7%) 6 (0.6%) 2 (0.4%) Heart failure 6 (0.9%) 3 (0.4%) 0 8 (0.7%) 2 (0.4%) Stroke 2 (0.3%) 2 (0.3%) 9 (0.8%) 3 (0.3%) 2 (0.4%) Unknown cause of death 0 0 0 1 (0.1%) 0 Any fatal MACE 4 (0.6%) 5 (0.7%) 10 (0.9%) 12 (1.1%) 2 (0.4%) MACE rate per 1000 patient years 24.9 25.6 19.5 23.5 13.6

The efficacy of extrafine beclomethasone dipropionate–formoterol fumarate in COPD patients who are not "frequent exacerbators": a post hoc analysis of the FORWARD study

The GOLD 2017 strategy document recommends that the pharmacological management of COPD patients be based on the risk of future exacerbations and the severity of symptoms. A threshold of two moderate exacerbations or one hospitalization is used to define high-risk patients. The FORWARD study was a randomized, double-blind, parallel-group trial that compared 48 weeks’ treatment with extrafine beclomethasone dipropionate plus formoterol fumarate (BDP-FF) versus FF in severe COPD patients with a history of one or more exacerbations in the previous year. The new GOLD 2017 recommendations mean that many patients in the FORWARD study are now reclassified as GOLD B. We conducted a post hoc analysis of the FORWARD study, in order to investigate the effects of extrafine BDP/FF in patients with one exacerbation in the previous year, focusing on those categorized as group B using the GOLD 2017 definition. The analysis showed a 35% reduction in exacerbation rate with an inhaled corticosteroid (ICS) + long-acting β-agonist (LABA) versus LABA. We propose that ICS-LABA treatment is a therapeutic option for COPD patients with one exacerbation in the previous year.