Full Press Release Details
Umeclidinium/vilanterol (UMEC/VI) once daily (OD) vs fluticasone/salmeterol combination (FSC) twice daily (BD) in patients with moderate-to-severe COPD and infrequent COPD exacerbations
Singh D,(1) Worsley S,(2) Zhu C-Q,(2) Hardaker L,(2) Church A(3)
(1)University of Manchester and University Hospital of South Manchester Foundations Trust, Manchester, UK; (2)GSK, London, UK; (3)GSK, Research Triangle Park, NC, USA
Umeclidinium/vilanterol (UMEC/VI), a long-acting muscarinic antagonist (LAMA)/long-acting beta(2) agonist (LABA) combination(1) is an approved COPD maintenance treatment in the EU(2) and USA(3) and several other countries. The inhaled corticosteroid (ICS)/LABA combination fluticasone propionate/salmeterol(4) (FSC) is also approved for COPD in the EU (500/50mcg twice daily).
Guidelines recommend treatment with an ICS/LABA combination in COPD patients with moderate-to-very-severe lung function impairment and/or a history of exacerbations (GOLD C and D).(5) A LAMA/LABA combination is one treatment recommendation for GOLD B patients.(5) In clinical practice, treatment of patients in various GOLD categories diverges from current recommendations based on clinical judgement.
For COPD patients with dyspnoea and without frequent exacerbations (i.e. GOLD B and a subset of GOLD D), a key clinical question is whether non-ICS combinations are more efficacious than ICS-containing treatments.
The objective of this study was to compare the efficacy and safety of once-daily UMEC/VI 62.5/25mcg with twice-daily FSC 500/50mcg over 12 weeks in patients with moderate-to-severe COPD with a history of infrequent COPD exacerbations.
Study design and population
Phase IIIb, multicentre, randomised, double-blind, double-dummy, parallel-group study (GSK study code: DB2116134; clinicaltrials.gov: NCT01822899).
Inclusion criteria were: males or females >40 years old; pre- and post-salbutamol forced expiratory volume in 1s (FEV1)/forced vital capacity (FVC) ratio <0.70 and post-salbutamol FEV1 >30% and >70% of predicted normal values; dyspnoea score >2 (modified Medical Research Council [mMRC] Dyspnoea Scale); current or former smokers (history of cigarette smoking >10 pack-years).
Key exclusion criteria were: other respiratory disorders; hospitalisation for pneumonia; a documented history of >1 COPD exacerbation requiring oral corticosteroids, antibiotics and/or hospitalisation in the previous 12 months.
After a 7 14 day run-in, patients were randomised 1:1 to receive 12 weeks of treatment
once-daily UMEC/VI 62.5/25mcg (delivered doses 55/22mcg; via ELLIPTA dry powder inhaler [DPI]) + twice-daily placebo (via DISKUS )
twice-daily FSC 500/50mcg (via DISKUS ) + once-daily placebo (via ELLIPTA DPI).
Endpoints and analyses
Lung-function endpoints included: 0 24h weighted mean (wm) FEV1 (day 84, primary); trough FEV1 (day 85, secondary); other (selected) endpoints are listed in the Results.
Symptomatic endpoints and health outcomes: rescue medication use; dyspnoea (Transition Dyspnoea Index [TDI] focal score); St George s Respiratory Questionnaire for COPD patients (SGRQ-C); EuroQoL-5D (EQ-5D) questionnaire and the COPD Assessment Test (CAT).
Safety assessments included adverse events (AEs) and COPD exacerbations.
Primary endpoint was analysed using analysis of covariance (covariates: baseline [BL] FEV1, smoking status, treatment). Secondary endpoint was analysed using a mixed model for repeated measures analysis (covariates: BL FEV1, smoking status, day, treatment, day by BL interaction, day by treatment). Multiplicity across primary and secondary endpoints was accounted for by a step-down statistical hierarchy.
Baseline characteristics
Of 1009 patients enrolled, 870 were screened, 717 were randomised, 716 were included in the ITT population and 674 completed the study (UMEC/VI: 334; FSC: 340).
All patients were of White race. At BL, patient demographics and characteristics were similar between groups (Table 1) and 55% and 45% of patients overall had percent-predicted FEV1 >50% (moderate COPD) and <50% (severe COPD), respectively.
Mean (SD) treatment compliance was 100.4% (28.3%) UMEC/VI and 99.3% (3.7%) FSC.
Table 1. Baseline and disease characteristics (ITT population)
| UMEC/VI 62.5/25mcg (N=358) | FSC 500/50mcg (N=358) | ||||
| Age, mean SD, years | 61.8 7.94 | 61.4 8.06 | |||
| Sex: male, n (%) | 261 (73) | 254 (71) | |||
| Current smoker, n (%) | 204 (57) | 217 (61) | |||
| Screening lung function: pre-salbutamol FEV 1 , mean SD, L | 1.423 0.4573 | 1.457 0.4555 | |||
| GOLD stage (percent predicted FEV 1 ) and reversibility, n (%) | |||||
| Stage II ( 50% to < 80%) = moderate | 193 (54) | 201 (56) | |||
| Stage III ( 30% to < 50%) = severe | 165 (46) | 157 (44) | |||
| Reversible to salbutamol | 100 (28) | 108 (30) | |||
| mMRC dyspnoea scale, mean (SD) | 2.2 (0.41) | 2.2 (0.42) |
Efficacy lung function
UMEC/VI resulted in statistically significant improvements in 0 24h wmFEV1 and trough FEV1 (both p<0.001, Table 2, Figs. 1 and 2), and all other lung function measures (Table 2) compared with FSC
UMEC/VI also significantly improved forced vital capacity endpoints versus FSC (data not shown).
In a descriptive summary, UMEC/VI improved lung function versus FSC for each GOLD stage for the primary endpoint (see below) and trough FEV1 (day 85; data not shown). The mean (SD) change from BL in 0 24h wmFEV1 (day 84) was
GOLD stage II: 0.181 (0.2476) L (UMEC/VI) and 0.096 (0.2230) L (FSC)
GOLD stage III: 0.152 (0.2111) L (UMEC/VI) and 0.071 (0.2038) L (FSC).
Symptomatic endpoints and health outcomes
No treatment differences in rescue salbutamol use were seen either in terms of mean number of puffs taken daily or in percentage of rescue-free days over 12 weeks.
Both UMEC/VI and FSC demonstrated clinically meaningful improvements in dyspnoea (TDI focal score >1 unit increase) and health outcomes (SGRQ-C Total score >4 unit decrease from baseline) over 12 weeks
Least squares (LS) mean (SE) changes from BL in TDI focal score (day 84) were 2.0 (0.14) for UMEC/VI and 2.1 (0.13) for FSC; difference (95% CI): 0.1 ( 0.4, 0.3), p=0.702
LS mean (SE) changes from BL in SGRQ-C Total score (day 84) were 5.10 (0.626) for UMEC/VI and 5.64 (0.619) for FSC; difference (95% CI): 0.53 ( 1.20, 2.26), p=0.545.
Mean change from BL in EQ-5D utility score was 0.03 on day 84 for both treatments.
On day 84, no treatment differences were seen in mean change from BL CAT scores.
Table 2. Analyses of lung function endpoints (ITT population)
| Endpoint | UMEC/VI 62.5/25mcg (N=358) | FSC 500/50mcg (N=358) | Difference | |||
| 0 24h wmFEV 1 on day 84, L(a) | 0.166 (0.0122)(b) | 0.087 (0.0121)(c) | 0.080 (0.046, 0.113)(d) p < 0.001 | |||
| Trough FEV 1 on day 85, L(a) | 0.151 (0.0126)(e) | 0.062 (0.0125)(f) | 0.090 (0.055, 0.125)(d) p < 0.001 | |||
| Peak FEV 1 0 6h, L, on day 1(a) | 0.266 (0.0083) | 0.231 (0.0083) | 0.034 (0.011, 0.057)(d) p=0.003 | |||
| Peak FEV 1 0 6h, L, on day 84(a) | 0.327 (0.0131)(g) | 0.229 (0.0130)(h) | 0.097 (0.061, 0.134)(d) p < 0.001 | |||
| Median time to onset on day 1, min (FEV 1 increase 100mL vs BL) | 17 | 60 | 1.3 (1.1, 1.5)(i) p=0.002 | |||
| Patients with FEV 1 increase 100mL vs BL at 5-min post-dose on day 1, n (%) | 137 (39) | 104 (30) | 1.50 (1.10, 2.06)(j) p=0.011 | |||
| Patients with FEV 1 increase 12% and 200mL on day 1 vs BL, n (%) | 211 (59) | 177 (49) | 1.47 (1.09, 1.97)(j) p=0.011 | |||
| Patients with trough FEV 1 increase 100mL on day 85 vs BL, n (%) | 192 (58)(e) | 139 (41)(f) | 1.94 (1.42, 2.64)(j) p < 0.001 |
(a)values are LS mean (SE) change from BL; (b)n=332; (c)n=337; (d)treatment difference (95% CI); (e)n=333; (f)n=338; (g)n=335; (h)n=340; (i)hazard ratio (95% CI); (j)odds ratio (95% CI); BL: baseline
Safety and tolerability
The AE incidence was similar between UMEC/VI (28%) and FSC (29%). The incidence of fatal on-treatment AEs was 1% (UMEC/VI) and 0% (FSC).
Headache, nasopharyngitis, back pain and dysphonia were the most common AEs reported in both groups. The incidence of drug-related AEs was lower with UMEC/VI (2%) than with FSC (4%).
The incidence of cardiac disorders was low (2% UMEC/VI; <1% FSC). Pneumonia was reported by 1 patient in the FSC group and none in the UMEC/VI group. The incidence of on-treatment COPD exacerbations was higher with UMEC/VI (2%) than with FSC (<1%).
Once-daily UMEC/VI 62.5/25mcg over 12 weeks resulted in significant, sustained and clinically meaningful improvements in lung function versus twice-daily FSC 500/50mcg in moderate-to-severe COPD patients with infrequent COPD exacerbations.
Both UMEC/VI and FSC demonstrated clinically meaningful improvements in dyspnoea and QoL over 12 weeks, with no treatment differences.
The safety and tolerability of UMEC/VI was consistent with previous studies and no difference was observed in AEs between UMEC/VI and FSC.
For GOLD B and D patients with dyspnoea and infrequent exacerbations, our findings suggest that the LAMA/LABA combination UMEC/VI could provide greater lung function benefits than the ICS/LABA combination FSC.
(1) Celli B, et al. Chest 2014;145:981 91.
(2) ANORO US prescribing information, May 2014. Available at https://www.gsksource.com/gskprm/htdocs/documents/ANORO-ELLIPTA-PI-MG.PDF. Date last accessed: 21 August 2014.
(3) ANORO EU summary of product characteristics, 16 May 2014. Available at http://www.medicines.ie/medicine/16007/SPC/ANORO+55+micrograms+22+micrograms+inhalation+powder,+pre-dispensed/. Date last accessed: 21 August 2014.
(4) Calverley PM, et al. N Engl J Med 2007;356:775 89.
(5) GOLD 2014 guidelines for COPD. http://www.goldcopd.org/guidelines-global-strategy-for-diagnosis-management.html. Date last accessed: 21 August 2014.
The presenting author, D Singh, declares the following real or perceived conflicts of interest during the last 3 years in relation to this presentation: has served as consultant to Almirall, AstraZeneca, Boehringer Ingleheim, Chiesi, Cipla, GSK, Novartis, Nycomed and Roche; has received research grants from AstraZeneca, Almirall, Boehringer Ingleheim, Chiesi, Cipla, GSK, Novartis, Nycomed and Roche; has received payment for lectures including service on speakers bureaus from AstraZeneca, Almirall, Boehringer Ingleheim, Chiesi, Cipla, GSK, Novartis, Nycomed, Roche and Takeda. S Worsley, C-Q Zhu, L Hardaker and A Church are employed by and hold stock in GSK.
This study was funded by GSK (GSK study code: DB2116134; clinicaltrials.gov: NCT01822899).
Editorial support (in the form of writing assistance, assembling tables and figures, collating author comments, grammatical editing and referencing) was provided by Jackie Phillipson, PhD at Gardiner-Caldwell Communications (Macclesfield, UK) and was funded by GSK.
ELLIPTA and DISKUS are trade marks of the GlaxoSmithKline group of companies
Presented at the European Respiratory Society (ERS) International Congress, Munich, Germany, 6 10 September 2014