Zheng 2014.

Methods	Study ID and dates performed: NCT01636713; dates not reported. Study design: Multicentre, randomised, double‐blind, placebo‐controlled, parallel‐group study. Duration of study: 7–14 day run‐in; 24‐week treatment period. Study setting, location, number of centres: People’s Republic of China, Philippines, South Korea, Taiwan, Thailand. Key inclusion criteria: Aged ≥ 40 years at screening; established clinical history of COPD (ATS/ERS criteria); current or former smokers with a smoking history ≥ 10 pack‐years; post‐albuterol FEV1/FVC < 0.70 and a post‐albuterol FEV1 ≤ 70% of predicted normal values (NHANES III reference equations at visit 1); dyspnoea score of ≥ 2 on the mMRC Dyspnea Scale at screening. Key exclusion criteria: Current diagnosis of asthma or any other known respiratory disorder, including α1‐anti‐trypsin deficiency or active lung infection, e.g. tuberculosis, lung cancer, clinically significant bronchiectasis, pulmonary hypertension, sarcoidosis, or interstitial lung disease; previous history or current evidence of clinically significant or uncontrolled cardiovascular, neurological, psychiatric, renal, hepatic, immunological, endocrine, or haematological abnormalities. Concomitant medications: Permitted: Supplemental albuterol as rescue medication; ICS < 1000 µg/day of FP or equivalent; ICS not initiated or discontinued within 30 days prior to study entry.
Participants	N randomised: UMEC/VI 62.5/25 µg: n = 194; UMEC/VI 125/25 µg: n = 193; placebo: n = 193. N analysed, n/N (100): UMEC/VI 62.5/25 µg: 194/194 (100); UMEC/VI 125/25 µg: 193/193 (100); placebo: 193/193 (100). Mean age (SD), years: UMEC/VI 62.5/25 µg: 64.0 (8.71); UMEC/VI 125/25 µg: 63.7 (8.26); placebo: 64.3 (8.78). Gender ‐ male, n (%): UMEC/VI 62.5/25 µg: 183 (94); UMEC/VI 125/25 µg: 182 (94); placebo: 177 (92). Baseline lung function ‐ mean (SD) post‐bronchodilator FEV1, L: UMEC/VI 62.5/25 µg: 1.131 (0.3965); UMEC/VI 125/25 µg: 1.195 (0.3889); placebo: 1.168 (0.3708). Smoking status, current smoker, n/N (%): UMEC/VI 62.5/25 µg: 56/194 (29); UMEC/VI 125/25 µg: 48/193 (25); placebo: 65/193 (34).
Interventions	Intervention: Once‐daily UMEC/VI 62.5/25 µg; once‐daily UMEC/VI 125/25 µg. Comparator: Once‐daily placebo.
Outcomes	Prespecified outcomes: Primary: Change from baseline in trough FEV1 on day 169 (week 24). Secondary: Transition Dyspnea Index (TDI) Focal Score at day 168 (week 24); change from baseline weighted mean 0‐6 hour FEV1 obtained post‐dose at day 1. Reported outcomes: Prespecified outcomes (clinicaltrials.gov) were well reported, plus trough FEV1 at other time points; serial FEV1 over 0–6 hours post‐dose at day 1; the proportion of participants achieving an increase in FEV1 of ≥ 12% and ≥ 0.200 L above baseline at any time 0–6 hours post‐dose on day 1; the proportion of participants achieving an increase of ≥ 0.100 L above baseline in trough FEV1; and trough and serial FVC and time to onset 0–6 hours post‐dose at day 1; TDI focal score recorded at other time points; proportion of TDI responders (a responder to TDI was defined as a participant who reported a TDI score of ≥ 1 unit); rescue‐albuterol use (percentage of rescue‐free days and puffs/day) and time to first COPD exacerbation (defined as an acute worsening of symptoms of COPD requiring the use of rescue albuterol or any treatment beyond study medication); safety.
Notes	Funding for trial; notable author COIs: GSK funded this study. Lead author has received lecture fees from GSK. 3 of 4 co‐authors are employees of GSK.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The randomisation schedule was generated by GSK using the validated computerised system RandAll version 2.5.
Allocation concealment (selection bias)	Low risk	Used the sponsors formal system for randomisation so although concealment not specifically stated, it seems likely that this was done.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants and investigators were blinded to treatment allocation.
Blinding of participants and personnel (objective outcomes ‐ performance bias) Objective outcomes	Low risk	Participants and investigators were blinded to treatment allocation.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Participants for subjective outcomes were the outcome assessors; therefore, low risk of bias.
Blinding of outcome assessment (objective outcomes ‐ detection bias) All outcomes	Low risk	Assessment of objective outcomes would be unlikely to be influenced by knowledge of treatment allocation.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Attrition based on completion rates < 20% across arms. Data reported for ITT population.
Selective reporting (reporting bias)	Low risk	Prespecified outcomes (clinicaltrials.gov) were well reported.
Other bias	High risk	Higher proportion of participants with GOLD Stage IV in the UMEC/VI 62.5/25 µg group compared with placebo; may skew the treatment effect in favour of placebo. Lower proportion of current smokers than comparable studies.

AE: adverse event; AUC: area under the curve; ATS: American Thoracic Society; BD: bronchodilator; bpm: beats per minute; CDLM: capacity of daily living during the morning; COI: conflict of interest; COPD: chronic obstructive pulmonary disease; CR10: category ratio 10; ECG: echocardiogram; ERS: European Respiratory Society; FEV1: forced expiratory volume in 1 second; FP: fluticasone propionate; FPI‐SF: functional performance inventory‐short‐form; FRC: functional residual capacity; FVC: forced vital capacity; GOLD: Global Initiative for chronic obstructive pulmonary disease; H1: histamine 1; IC: inspiratory capacity; ICS: inhaled corticosteroid; IgE: immunoglobulin E; IND: indacaterol; IRT: interactive voice response system; ITT: intent to treat; IVRS: interactive voice response system; LABA: long‐acting beta‐adrenoceptor agonist; LAMA: long‐acting muscarinic antagonist; LSM: least squares mean; MACE: major adverse cardiovascular event; MCID: minimally clinically important difference; mITT: modified intent‐to‐treat; mMRC: modified Medical Research Council; MRC: Medical Research Council; N: number; O_{2: oxygen;} OCS: oral corticosteroids; OLO: olodaterol; PDE4: phosphodiesterase 4; PK Cmax: pharmacokinetic maximum plasma concentration; prn: pro re nata (as needed); QT: Q‐T interval; RAMOS: registration and medical ordering system; SABA: short‐acting beta‐adrenoceptor agonist; SAE: serious adverse event; SaO2: oxygen saturation; SD: standard deviation; SGRQ: St George's Respiratory Questionnaire; SOBDA: shortness of breath with daily activities; SpO2: peripheral capillary oxygen saturation; SSRI: selective serotonin reuptake inhibitor; TDI: transition dyspnoea index; TIO: tiotropium; tmax:time to maximum plasma concentration; UMEC: umeclidinium; VI: vilanterol; W: Watt.