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Efficacy and safety of umeclidinium added to fluticasone furoate/vilanterol in chronic obstructive pulmonary disease: Results of two randomized studies
Umeclidinium (UMEC) is a long-acting muscarinic antagonist indicated for the treatment of COPD.
•
Fluticasone furoate/vilanterol (FF/VI) is a corticosteroid/long acting beta agonist for COPD.
•
These data show that triple therapy with UMEC + FF/VI significantly improves lung function vs FF/VI.
•
Safety profiles were consistent across all treatment groups in both studies.
Abstract
Objective
The aim of these studies (NCT01957163; NCT02119286) was to evaluate the efficacy and safety of umeclidinium (UMEC 62.5 μg and 125 μg) added to fluticasone furoate/vilanterol (FF/VI, 100/25 μg) in chronic obstructive pulmonary disease (COPD).
Methods
These were 12-week, double-blind, placebo-controlled, parallel-group, multicenter studies. Eligible patients were randomized 1:1:1 to treatment with once-daily blinded UMEC 62.5 μg (delivering 55 μg), UMEC 125 μg (delivering 113 μg) or placebo (PBO) added to open-label FF/VI (delivering 92/22 μg; N = 1238 [intent-to-treat population]). The primary endpoint was trough forced expiratory volume in one second (FEV1) on Day 85; the secondary endpoint was 0–6 h post-dose weighted mean (WM) FEV1 at Day 84. Health-related quality of life was reported using St George's respiratory questionnaire (SGRQ). Adverse events (AEs) were also assessed.
Results
In both studies, trough FEV1 was significantly improved with UMEC + FF/VI (62.5 μg and 125 μg) versus PBO + FF/VI (range: 0.111–0.128 L, all p < 0.001 [Day 85]), as was 0–6 h post-dose WM FEV1 (range: 0.135–0.153 L, all p < 0.001 [Day 84]). SGRQ results were inconsistent, with statistically significant improvements with UMEC + FF/VI versus PBO + FF/VI in one study only and with UMEC 62.5 μg only (difference in SGRQ total score from baseline between treatments: −2.16, p < 0.05). Across all treatment groups, the overall incidences of AEs were similar (30–39%), as were cardiovascular AEs of special interest (<1–3%) and pneumonia AEs (0–1%).
Conclusion
Overall, the addition of UMEC to FF/VI therapy resulted in significant improvements in lung function compared with PBO + FF/VI in patients with COPD, with similar safety profiles, though SGRQ results were inconsistent.
Clinical relevance
The results from these two studies demonstrate that the addition of umeclidinium (62.5 μg and 125 μg) to FF/VI (100/25 μg) provides statistically significant and clinically meaningful improvements in lung function compared with placebo + FF/VI in patients with COPD. Statistically significant improvements in quality of life with UMEC + FF/VI versus placebo + FF/VI were reported in one study only. Safety profiles were consistent across all treatment groups in both studies. These studies support the use of triple therapy in COPD, providing physicians with an alternative treatment option.
Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation, is a substantial contributor to morbidity and mortality worldwide, and imparts a high economic burden [
As disease severity increases, COPD treatment guidelines recommend an incremental approach to pharmacological treatment, involving the use of combinations of drug classes with different or complementary mechanisms of action [
]. Long-acting muscarinic antagonists (LAMAs) have been shown to improve lung function, relieve symptoms, increase exercise capacity, improve quality of life (QoL) and reduce COPD exacerbations to a greater extent than short-acting bronchodilators alone [
]. Inhaled corticosteroid (ICS)/long-acting beta2 agonist (LABA) combination products have been shown to improve lung function, health status and reduce COPD exacerbations compared with either agent alone [
The use of combinations of drug classes with complementary mechanisms of action addresses the multi-component, inflammatory and progressive nature of COPD [
]. Recent studies involving the LAMA tiotropium in patients with COPD have shown that the addition of a LAMA to an ICS/LABA combination was well tolerated and associated with improvements in pulmonary, symptomatic and health-related QoL (HRQoL) endpoints [
Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial.
Observational study on the impact of initiating tiotropium alone versus tiotropium with fluticasone propionate/salmeterol combination therapy on outcomes and costs in chronic obstructive pulmonary disease.
A pilot study to assess the effects of combining fluticasone propionate/salmeterol and tiotropium on the airflow obstruction of patients with severe-to-very severe COPD.
]. Based on the results of several trials, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines now include a recommendation for the use of a LAMA plus an ICS/LABA product as a secondary treatment option for symptomatic COPD with severe airflow obstruction and a high risk of exacerbations [
Although guidelines recommend a LAMA plus ICS/LABA as a treatment for patients with very severe COPD, physician prescribing practices differ from treatment guidelines, which may reflect differences in clinical judgement of the severity of COPD disease. In one study that examined the GOLD strategy in a real-world COPD population, 22.2% of patients categorized as having moderate COPD (according to the GOLD 2010 and 2011 criteria) received treatment with a LAMA plus an ICS/LABA, whereas 58.4% of patients with very severe COPD received a LAMA plus an ICS/LABA [
]. Here, we present the results of two clinical studies investigating the efficacy and safety of once-daily UMEC (62.5 μg and 125 μg) in addition to once-daily FF/VI (100/25 μg) in patients with moderate-to-very-severe COPD.
2. Materials and methods
2.1 Study designs
Two replicate, 12-week, randomized, double-blind, placebo-controlled parallel-group studies were completed between October 2013 and April 2014. Study 1 (ClinicalTrials.gov registration number: NCT01957163; GSK study number: 200109) was conducted in Argentina, Canada, Chile, Romania and the USA. Study 2 (ClinicalTrials.gov registration number: NCT02119286; GSK study number: 200110) was conducted in the Czech Republic, Germany, the Republic of Korea and the USA. Both studies were conducted in accordance with the Declaration of Helsinki [
] and Good Clinical Practice guidelines, were approved by the relevant local ethics review committees, and all patients provided written, informed consent before study participation.
2.2 Patients
Eligible patients were: ≥40 years of age with a clinically established history of COPD [
]; current or former cigarette smokers with ≥10-pack-years smoking history; had a pre- and post-salbutamol (albuterol) forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ratio of <0.7 and predicted FEV1 ≤70%; and had a modified Medical Research Council dyspnea scale score ≥2. Exclusion criteria included: current diagnosis of asthma or other known respiratory disease, hospitalization in the 12 weeks previous to Visit 1 for COPD or pneumonia, pregnancy, or use of long-term oxygen therapy. Patients previously receiving COPD medications were eligible provided they adhered to the following exclusion periods prior to Visit 1 and subsequently avoided their use throughout the study: ICS use was permitted to Visit 1, LAMA use required a 7-day exclusion period and the use of ICS/LABA combination therapies required a 48-h exclusion period (further details of inclusion/exclusion criteria, permitted/prohibited medications and washout periods are provided in Supplementary Materials).
2.3 Treatment
Following screening at Visit 1, patients underwent 4 weeks' run-in treatment with open-label FF/VI 100/25 μg (delivering 92/22 μg) prior to the 12-week treatment period (Visits 2–7). Eligible patients were randomized 1:1:1–12 weeks' treatment with once-daily UMEC 62.5 μg (delivering 55 μg), UMEC 125 μg (delivering 113 μg), or placebo (PBO), plus FF/VI (100/25 μg once daily) administered via the ELLIPTA™ dry powder inhaler. UMEC and PBO treatments were double-blind; FF/VI treatment was open label.
Randomization codes were generated by GSK using a validated computerized system (RandAll v2.13). Concurrent use of salbutamol as rescue medication was permitted throughout the study, except during the 4 h prior to spirometry testing.
2.4 Outcomes and assessments
In both studies, the primary efficacy endpoint was trough FEV1 at Day 85 (defined as the mean of the FEV1 values obtained 23 and 24 h after dosing on Day 84). An increase of 0.100 L was considered as the minimal clinically important difference (MCID) for this endpoint [
]. The secondary efficacy endpoint was weighted-mean (WM) FEV1 over 0–6 h obtained post-dose on Day 84. Other lung function endpoints included: proportion of patients achieving an increase of ≥0.100 L above baseline in trough FEV1; lung function endpoints (trough FEV1 and WM FEV1 over 0–6 h post-dose) at other timepoints; the proportion of patients achieving an increase in FEV1 of ≥12% and ≥0.200 L above baseline at any time during 0–6 h post-dose at Day 1; serial FEV1 over 0–6 h (at each timepoint); peak FEV1 at Days 1, 28 and 84; time to onset of treatment response (defined as an increase of 0.100 L above baseline in FEV1 [not specified in the original protocol]); and serial and trough FVC at each timepoint.
Other endpoints included rescue medication, as assessed by the percentage of rescue-free days and puffs/day (descriptive data only). HRQoL endpoints included the COPD Assessment Test (CAT; descriptive data only) [
]. SGRQ scores were calculated from the SGRQ-C-scores using standardized adjustment. Safety assessments included adverse events (AEs), vital signs (including pulse rate and systolic and diastolic blood pressure) and COPD exacerbations. Patients were withdrawn if they experienced a COPD exacerbation during the run-in or treatment periods. COPD exacerbations were defined as an acute worsening of symptoms requiring the use of any treatment beyond study medication or rescue salbutamol. AEs of special interest included cardiovascular events, pneumonia and lower respiratory tract infections.
2.4.1 Sample size considerations and statistical analyses
Sample size calculations were based on the primary endpoint of trough FEV1 at Day 85. They assumed 90% power and a 2-sided 5% significance level with an estimate of residual standard deviation for trough FEV1 of 0.220 L and a treatment difference of 0.080 L. According to these assumptions, and to account for an estimated withdrawal rate of 20%, 160 patients per arm (480 in total for each study) were required for 90% power to detect a 0.080 L difference between treatments in trough FEV1.
The primary efficacy analysis population was the intent-to-treat (ITT) population, defined as all patients randomized to treatment who received at least one dose of study drug. Primary and secondary endpoints were analyzed using mixed models repeated measures analysis, with treatment, baseline FEV1, smoking status, and day as covariates. Day-by-baseline and day-by-treatment were included as interactions. To account for multiplicity, a step-down closed testing hierarchy was employed (See Supplementary Materials), as reported previously [
Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials.
]. The safety population comprised all patients enrolled in the study, though on-treatment AEs were assessed using the ITT population.
3. Results
3.1 Patients
Study 1 enrolled 727 patients across 55 centers; 26% of patients were enrolled in the USA, 21% in Chile, 20% in Canada, 17% in Romania and 16% in Argentina. Following screening, 619 patients were randomized and included in the ITT population and 575 (93%) patients completed the study (Fig. 1A). Study 2 enrolled 730 patients across 59 centers; 46% of patients were enrolled in study centers in Germany, 29% in the USA, 14% in the Czech Republic and 11% in the Republic of Korea. Of the 730 patients enrolled, 620 were randomized, 619 included in the ITT population and 575 (93%) completed Study 2 (Fig. 1B).
Fig. 1Patient disposition in Study 1 (a) and in Study 2 (b). ASE, all subjects enrolled; COPD, chronic obstructive pulmonary disease; FF/VI, fluticasone furoate/vilanterol combination; RI, run-in; UMEC, umeclidinium. *Lack of efficacy contains patients who withdrew due to COPD exacerbation.
Baseline characteristics are summarized in Table 1. Overall, the only differences were that Study 2 enrolled more current smokers than Study 1 (56–58% and 39–44% across treatment groups, respectively) and the two studies had different proportions of patients at GOLD lung function stages II and III (stage II: Study 1: 40–41%, Study 2: 46–50%; stage III, Study 1: 44–48%, Study 2: 40–42%). No other differences were identified between studies or between treatment groups within each study (Table 1). Across both studies 10–17% of patients were classified as having very severe COPD (GOLD stage IV) (Table 1). Across treatment groups, 25–32% of patients were reversible to salbutamol (defined as an increase in FEV1 of ≥12% and ≥0.200 L following treatment administration) and 39–53% reversible to salbutamol plus ipratropium (Table 1).
Table 1Patient demographics and characteristics (ITT population).
In Study 1, N = 205 in PBO + FF/VI 100/25, N = 205 in UMEC 62.5 + FF/VI 100/25, N = 207 in UMEC 125 + FF/VI 100/25; in Study 2, N = 206 in PBO + FF/VI 100/25, N = 205 in UMEC 62.5 + FF/VI 100/25, N = 207 in UMEC 125 + FF/VI 100/25.
In Study 1, N = 205 in PBO + FF/VI 100/25, N = 205 in UMEC 62.5 + FF/VI 100/25, N = 207 in UMEC 125 + FF/VI 100/25; in Study 2, N = 206 in PBO + FF/VI 100/25, N = 205 in UMEC 62.5 + FF/VI 100/25, N = 207 in UMEC 125 + FF/VI 100/25.
, n (%)
97 (47)
108 (53)
103 (50)
81 (39)
107 (52)
106 (51)
Number (%) of patients with one or more COPD exacerbations, in the 12 months prior to study enrollment
Managed without oral/systemic steroids and/or antibiotics, n (%)
10 (5)
14 (7)
8 (4)
14 (7)
4 (2)
14 (7)
Required oral/systemic steroids, but not involving hospitalization, n (%)
32 (16)
30 (15)
32 (16)
28 (14)
26 (13)
31 (15)
Requiring hospitalization, n (%)
10 (5)
4 (2)
5 (2)
2 (<1)
7 (3)
6 (3)
CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in one second; FF/VI, fluticasone furoate/vilanterol combination; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; ITT, intent-to-treat; PBO, placebo; SGRQ, St George's Respiratory Questionnaire; UMEC, umeclidinium.
Values are reported as mean (standard deviation) unless otherwise stated.
Reversibility was defined as an increase in FEV1 of ≥12% and ≥0.200 L following administration of the stated therapeutic agent.
a Reclassified: patient reclassified as current smoker if they had smoked within 6 months prior to screening.
b In Study 1, N = 205 in PBO + FF/VI 100/25, N = 205 in UMEC 62.5 + FF/VI 100/25, N = 207 in UMEC 125 + FF/VI 100/25; in Study 2, N = 206 in PBO + FF/VI 100/25, N = 205 in UMEC 62.5 + FF/VI 100/25, N = 207 in UMEC 125 + FF/VI 100/25.
Prior to enrollment in Study 1, 63% of patients were receiving treatment with an ICS, 61% were receiving a LABA, and 22% were receiving a LAMA. In Study 2, the percentage of patients with prior use of an ICS was 46%, LABA 62%, and LAMA 46%. In the 12 months before screening, the majority of patients reported no COPD exacerbations that required treatment with oral/systemic corticosteroids and/or antibiotics (Study 1: 85% and Study 2: 86%).
3.2 Outcomes
3.2.1 Lung function
In both studies, addition of UMEC to FF/VI resulted in statistically significant and clinically meaningful improvements in trough FEV1 at Day 85 versus PBO + FF/VI (UMEC 62.5 μg + FF/VI, 0.122–0.124 L; UMEC 125 μg + FF/VI, 0.111–0.128 L; all p ≤ 0.001, Table 2; Fig. 2). Statistically significant improvements with UMEC + FF/VI versus PBO + FF/VI were also observed for trough FEV1 at Days 2, 28, 56 and 84 (p < 0.001, for both doses at each timepoint in both studies; Fig. 2).
Table 2Summary of lung function, symptomatic and health-related quality of life endpoints (ITT population).
Study 1
Study 2
PBO + FF/VI 100/25 (N = 206)
UMEC 62.5 + FF/VI 100/25 (N = 206)
UMEC 125 + FF/VI 100/25 (N = 207)
PBO + FF/VI 100/25 (N = 206)
UMEC 62.5 + FF/VI 100/25 (N = 206)
UMEC 125 + FF/VI 100/25 (N = 207)
Trough FEV1at Day 85, LS mean change from baseline, L (SE)
Response was defined as an SGRQ total score of −4 units below baseline or lower.
, n (%)
72 (35)
81 (40)
68 (33)
43 (21)
71 (35)
64 (31)
Odds ratio (column vs PBO + FF/VI 100/25; 95% CI)
–
1.20 (0.80, 1.80)
0.90 (0.60, 1.36)
–
2.01‡ (1.28, 3.14)
1.77† (1.12, 2.78)
CAT, COPD Assessment Test; CI, confidence interval; FEV1, forced expiratory volume in 1 s; FF/VI, fluticasone furoate/vilanterol combination; FVC, forced vital capacity; ITT, intent-to-treat; LS, least squares; PBO, placebo; SD, standard deviation; SE, standard error; SGRQ, St George's Respiratory Questionnaire; UMEC, umeclidinium.
*p ≤ 0.001; ‡p ≤ 0.01; †p < 0.05 vs PBO.
Analysis performed using a repeated measures model with covariates of treatment, baseline (mean of the two assessments made 30 min and 5 min pre-dose on Day 1), smoking status, Day, Day by baseline, and Day by treatment interactions. The weighted mean was calculated from the pre-dose FEV1 measurements at 15 min, 30 min, 1 h, 3 h and 6 h.
a Values are differences in LS mean (95% CI).
b No formal between-group analyses were planned for these endpoints.
c Response was defined as an SGRQ total score of −4 units below baseline or lower.
Fig. 2Least squares mean (95% CI) change from baseline in trough FEV1 (L) (ITT population) in Study 1 (a) and in Study 2 (b). Analysis performed using a repeated measures model with covariates of treatment, baseline (mean of the two assessments made 30 min and 5 min pre-dose on Day 1), smoking status, Day, Day by baseline and Day by treatment interactions. CI, confidence interval; FEV1, forced expiratory volume in one second; ITT, intent-to-treat; FF/VI, fluticasone furoate/vilanterol combination; LS, least squares; UMEC, umeclidinium.
For the secondary endpoint of 0–6 h post-dose WM FEV1 at Day 84, in both studies the addition of UMEC to FF/VI resulted in statistically significant and clinically meaningful improvements versus PBO + FF/VI (UMEC 62.5 μg + FF/VI, 0.147–0.153 L; UMEC 125 μg + FF/VI, 0.135–0.140 L; all p < 0.001, Table 2; Fig. 3). Statistically significant improvements with UMEC + FF/VI versus PBO + FF/VI were also seen for 0–6 h post-dose WM FEV1 at Days 1 and 28 (p < 0.001, both doses and timepoints in both studies; Fig. 3).
Fig. 3Least squares mean (95% CI) change from baseline in 0–6 h WM FEV1 (L) (ITT population) in Study 1 (a) and in Study 2 (b). Analysis performed using a repeated measures model with covariates of treatment, baseline (mean of the two assessments made 30 min and 5 min pre-dose on Day 1), smoking status, Day, Day by baseline and Day by treatment interactions. CI, confidence interval; FEV1, forced expiratory volume in one second; FF/VI, fluticasone furoate/vilanterol combination; ITT, intent-to-treat; LS, least squares; UMEC, umeclidinium; WM, weighted mean.
Both doses of UMEC in addition to FF/VI were associated with statistically significantly greater odds (versus PBO + FF/VI) of having an increase in FEV1 of ≥0.100 L above baseline versus not having this increase (odds ratio [OR]: UMEC 62.5 μg + FF/VI, 4.8–5.6; UMEC 125 μg + FF/VI, 4.4–5.1; all p < 0.001; Table 2). Improvements versus PBO + FF/VI were also observed for the proportion of patients with an FEV1 increase ≥12% and ≥0.200 L above baseline at Day 1, with a statistically significant OR for having this increase (versus not having the increase; OR: UMEC 62.5 μg + FF/VI, 5.0–6.1; UMEC 125 μg + FF/VI, 5.3–6.3; all p < 0.001; Table 2). Serial FEV1 on Day 1 showed a rapid onset of FEV1 improvements (statistically significantly greater after ∼15 min) with both doses of UMEC + FF/VI compared with PBO + FF/VI, which was maintained at 24 h and through to Day 84 in both studies (p < 0.001 for all comparisons; Fig. 4). Statistically significant improvements in peak FEV1 at Day 84 were observed with UMEC + FF/VI versus PBO + FF/VI (UMEC 62.5 μg + FF/VI, 0.154 and 0.156 L; UMEC 125 μg + FF/VI, 0.140 and 0.146 L; p < 0.001 for the comparison in both studies). Similar results were reported for trough FVC (all comparisons: p < 0.001; Table 2) and serial FVC (0.066–0.248 L improvement versus PBO + FF/VI for both doses at all timepoints and days; all p < 0.001).
Fig. 4Serial FEV1 least squares mean change from baseline on Day 1 and Day 84 (L) (ITT population) in Study 1 (a) and in Study 2 (b). Analysis performed using a repeated measures model with covariates of treatment, baseline (mean of the two assessments made 30 min and 5 min pre-dose on Day 1), smoking status, time, time by baseline and time by treatment interactions. CI, confidence interval; FEV1, forced expiratory volume in one second; FF/VI, fluticasone furoate/vilanterol combination; ITT, intent-to-treat; LS, least squares; UMEC, umeclidinium.
In both studies, patients receiving UMEC + FF/VI experienced a greater change from baseline in the proportion of rescue-free days over Weeks 1–12 (UMEC 62.5 μg + FF/VI, 6.9–14.2%; UMEC 125 μg + FF/VI, 5.9–8.7%) versus PBO + FF/VI (2.3–3.8%; Table 2). In Study 1, statistically significant reductions in rescue salbutamol use were observed for both UMEC + FF/VI groups versus PBO + FF/VI (UMEC 62.5 μg + FF/VI, 0.4 puffs/day [p < 0.001]; UMEC 125 μg + FF/VI, 0.2 puffs/day [p < 0.05]; Table 2). However, in Study 2, statistically significant improvements in rescue-medication use were only observed with UMEC 62.5 μg + FF/VI (0.3 puffs/day, p < 0.01; Table 2).
3.2.3 HRQoL
Numerical improvements from baseline in CAT scores (where a negative number denotes an improvement) were observed in all UMEC + FF/VI treatment groups (UMEC 62.5 μg + FF/VI, −1.1 to −0.6; UMEC 125 μg + FF/VI, −0.5 to −0.1) at Day 84. In both studies, the PBO + FF/VI treatment group showed a numerical deterioration (0.1–0.3) at Day 84.
In Study 1, there were no significant differences in SGRQ scores (where a negative number denotes an improvement) observed between the treatment arms at Days 28 and 84. In Study 2, patients treated with UMEC 62.5 μg + FF/VI showed statistically significant improvements in SGRQ score versus PBO + FF/VI at Day 84 (−2.16; p < 0.05) and also higher odds of being an SGRQ responder (as defined by a reduction from baseline of 4 units in SGRQ score) versus being an SGRQ non-responder (OR: 2.01, p < 0.01; Table 2).
3.2.4 Safety
The incidence of AEs and serious AEs was similar across treatment groups in both studies (Table 3), with nasopharyngitis, headache and back pain most commonly reported AEs (Table 3).
Table 3Summary of on-treatment adverse events (ITT population).
Study 1
Study 2
PBO + FF/VI 100/25 (N = 206)
UMEC 62.5 + FF/VI 100/25 (N = 206)
UMEC 125 + FF/VI 100/25 (N = 207)
PBO + FF/VI 100/25 (N = 206)
UMEC 62.5 + FF/VI 100/25 (N = 206)
UMEC 125 + FF/VI 100/25 (N = 207)
Any on-treatment AE, n (%)
72 (35)
75 (36)
80 (39)
81 (39)
67 (33)
62 (30)
Most common on-treatment AEs reported by ≥ 3% of patients in any treatment group by study, n (%)
Headache
6 (3)
9 (4)
9 (4)
5 (2)
8 (4)
4 (2)
Nasopharyngitis
7 (3)
7 (3)
10 (5)
22 (11)
11 (5)
19 (9)
Back pain
3 (1)
7 (3)
5 (2)
4 (2)
8 (4)
2 (<1)
Dysgeusia
4 (2)
6 (3)
4 (2)
–
–
–
Cough
1 (<1)
3 (1)
7 (3)
–
–
–
Diarrhea
2 (<1)
6 (3)
2 (<1)
–
–
–
Influenza
1 (<1)
2 (<1)
6 (3)
–
–
–
Any on-treatment SAEs, n (%)
6 (3)
2 (<1)
8 (4)
11 (5)
8 (4)
3 (1)
Any on-treatment drug-related AEs, n (%)
15 (7)
15 (7)
24 (12)
7 (3)
6 (3)
7 (3)
Any AEs related to permanent discontinuation of medication/withdrawal, n (%)
The incidence of AEs of special interest was assessed using standardized MedDRA queries for cardiac arrhythmias, cardiac failure, cardiac ischemia (myocardial infarction, other ischemic heart disease), stroke (central nervous system hemorrhages and cerebrovascular conditions). Selected preferred terms were used to define the LRTI excluding pneumonia and pneumonia AEs of special interest.
a The incidence of AEs of special interest was assessed using standardized MedDRA queries for cardiac arrhythmias, cardiac failure, cardiac ischemia (myocardial infarction, other ischemic heart disease), stroke (central nervous system hemorrhages and cerebrovascular conditions). Selected preferred terms were used to define the LRTI excluding pneumonia and pneumonia AEs of special interest.
Six deaths were reported during both studies, none of which were considered related to the study treatment. Five deaths were in the PBO + FF/VI groups (three due to myocardial infarction; one due to cardio-respiratory arrest; one due to pneumonia) and one death was in the UMEC 62.5 μg + FF/VI group (Study 2; due to gastric ulcer hemorrhage, atrial fibrillation, cardiogenic shock and myocardial infarction).
COPD exacerbations were infrequent (≤8% in any group) in both studies. In Study 1, the incidence of on-treatment COPD exacerbations varied between groups, with 7% (n = 14) in the UMEC 125 μg + FF/VI treatment group, 3% (n = 6) in the UMEC 62.5 μg + FF/VI group and 3% (n = 7) in the PBO + FF/VI group. In Study 2, the COPD exacerbation incidences were also infrequent, with 8% (n = 17) in the PBO + FF/VI group, 3% (n = 6) in the UMEC 62.5 μg + FF/VI group and 2% (n = 4) in the UMEC 125 μg + FF/VI group.
The incidence of cardiovascular AEs of special interest was low and similar across all treatment groups in both studies (range: <1–3% [n = 2–6] across treatment groups); additionally, the incidences of pneumonia and lower respiratory tract infection excluding pneumonia were similar across treatment groups (range: 0–1% [n = 0–3] and 0–<1% [n = 0–2], respectively).
No clinically relevant treatment-related changes in vital signs were reported across any treatment group in either study.
4. Discussion
The results of the two randomized, double-blind, placebo-controlled parallel studies presented here demonstrate that once-daily UMEC added to once-daily FF/VI (100/25 μg) provides clinically and statistically significant improvements in lung function compared with PBO + FF/VI in patients with COPD. No substantial clinical benefit was observed with the UMEC 125 μg dose over the UMEC 62.5 μg dose when added to FF/VI, which is consistent with the findings observed in UMEC monotherapy studies [
Despite consistent improvements in lung function measured across both studies, the HRQoL results of the studies were inconsistent. This may be reflective of a weak correlation between HRQoL and FEV1, as demonstrated previously [
], or may be due to differences between the patient populations included in the studies reflected in treatment prior to enrollment: percentages of patients treated with ICS (Study 1 = 63%, Study 2 = 46%) and LAMA (Study 1 = 22%, Study 2 = 46%). The inconsistency could also be related to a possible improvement in patients' HRQoL during the 4-week run-in period, during which patients received treatment with FF/VI, [
] making subsequent improvements more difficult to detect with these patient-reported outcomes (PRO) instruments. The lack of significant improvement in SGRQ results, despite statistical improvements in lung function, has also been reported in the ILLUMINATE study, where the LABA/LAMA combination of indacaterol/glycopyrronium was compared with the ICS/LABA combination of fluticasone propionate/salmeterol [
Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study.
Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study.
Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study.
] suggest that further studies are needed to better understand the correlation between lung function improvement and improvement in SGRQ score.
The disparity between FEV1 and SGRQ results in one of the two studies may also imply that the design of PRO tools and the defined MCIDs may warrant further investigation. While there are generally accepted MCIDs for SGRQ (improvement of greater than 4 units from baseline and compared with placebo) [
], there are no MCIDs reported for comparisons of active treatments. The available PRO tools appear to detect differences between placebo and active treatments, but not necessarily between two (or more) active treatments, for example in ILLUMINATE [
Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study.
], or at least at the same MCID as for placebo comparisons. These points may suggest that the development of new PRO tools to measure differences between active treatments are required, however, this remains debated within the literature [
], consensus needs to be reached as to the most effective way of capturing it within clinical trials.
All treatments were well tolerated, with no notable treatment-related differences in AEs or changes in vital signs, and COPD exacerbations were infrequent (≤8% across all each treatment groups). Overall, the safety profiles of both doses of UMEC (62.5 μg and 125 μg) when added to FF/VI were similar to that previously reported for FF, VI, or UMEC as monotherapies [
Safety and tolerability of once-daily umeclidinium/vilanterol 125/25 mcg and umeclidinium 125 mcg in patients with chronic obstructive pulmonary disease: results from a 52-week, randomized, double-blind, placebo-controlled study.
] and as such are an important consideration in the management of this disease. However, these studies were not designed to examine the treatment effect of the addition of UMEC to FF/VI in patients with COPD on the endpoint of exacerbations, but rather focused on lung function as a first step in determining the efficacy of triple therapy. These studies were only 12 weeks in duration, which is considered a sufficient period of time to observe sustained effects in lung function. However, longer studies with a patient population with a history of exacerbations would be needed to assess the benefit of this triple therapy on COPD exacerbations compared with ICS/LABA therapy.
There are other limitations that should be considered. Firstly, concurrent rescue medication was permitted; however, this was implemented across all study groups, is commonly used in COPD clinical studies and reflects clinical practice [
A pilot study to assess the effects of combining fluticasone propionate/salmeterol and tiotropium on the airflow obstruction of patients with severe-to-very severe COPD.
]. Secondly, the studies were not powered to detect differences in AEs, indicating a possible direction for future studies in this area. In addition, dyspnea was not measured in this study, only rescue use, which could be considered as a surrogate symptomatic outcome. As dyspnea can have a large impact on the daily lives of patients with COPD [
], it will be important to establish if the improvement in rescue use reported with triple therapy can be translated to improvements in dyspnea.
5. Conclusions
The results from these two randomized, double-blind, clinical trials demonstrated that the addition of UMEC (62.5 μg and 125 μg) to FF/VI provides significant improvements in lung function compared with PBO + FF/VI in patients with COPD. The reported safety profiles were similar across all treatment groups.
Conflicts of interest
TMS: is part of a speaker bureau for AstraZeneca, Boehringer Ingelheim, Novartis, and UCB; has received research support from Boehringer Ingelheim, Daiichi-Sankyo, Elevation, Forest Research Institute, GSK, Novartis, Pearl Therapeutics, and Sunovion; and is a consultant for AstraZeneca and Vapotherm. EK has served on advisory boards, speaker panels, or received travel reimbursement from Amphastar, AstraZeneca, Forest, Ironwood, Merck, Mylan, Novartis, Pearl, Pfizer, sanofi aventis, Sunovion, Targacept, Teva, and Theravance. He has conducted multicenter clinical research trials for approximately 70 pharmaceutical companies. ARS, AD, RA, and AC are employees of GSK and own stocks/shares in GSK.
These studies were funded by GSK.
Acknowledgments
Editorial assistance was provided by Gillian Groeger and Stuart Wakelin of Fishawack Indicia Ltd, funded by GSK.
Appendix A. Supplementary data
The following are the supplementary data related to this article:
Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial.
Observational study on the impact of initiating tiotropium alone versus tiotropium with fluticasone propionate/salmeterol combination therapy on outcomes and costs in chronic obstructive pulmonary disease.
A pilot study to assess the effects of combining fluticasone propionate/salmeterol and tiotropium on the airflow obstruction of patients with severe-to-very severe COPD.
Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials.
Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study.
Safety and tolerability of once-daily umeclidinium/vilanterol 125/25 mcg and umeclidinium 125 mcg in patients with chronic obstructive pulmonary disease: results from a 52-week, randomized, double-blind, placebo-controlled study.
The authors regret that in the Abbreviations the following term, ‘long-acting muscarinic agonist’, should appear as ‘long-acting muscarinic antagonist’.
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