Larbig 2015.

Methods	Study ID and dates performed: NCT01610037 (RADIATE); October 2012–February 2015; abstract only; additional info/data sourced from clinicaltrials.gov Study design: Multicentre, double‐blind (participant & investigator), parallel‐group, placebo‐ and active‐controlled study. Duration of study: 52 weeks. Study setting, location, number of centres: 116 locations ‐ international. Key inclusion criteria: Male and female adults aged ≥ 40 years; stable COPD according to GOLD strategy (GOLD 2011); airflow limitation indicated by a post‐bronchodilator FEV1 ≥ 30% and < 80% of the predicted normal, and a post‐bronchodilator FEV1/FVC < 0.70; current or ex‐smokers with a smoking history of at least 10 pack years; participants with an mMRC ≥ grade 2. Key exclusion criteria: History of long QT syndrome or prolonged QTc; COPD exacerbation that required treatment with antibiotics and/or systemic corticosteroids and/or hospitalisation in the 6 weeks prior to visit 1; type I or uncontrolled type II diabetes; history of asthma or have concomitant pulmonary disease; paroxysmal (e.g. intermittent) atrial fibrillation (only patients with persistent atrial fibrillation and controlled with a rate control strategy for at least six months could be eligible); clinically significant renal, cardiovascular, neurological, endocrine, immunological, psychiatric, gastrointestinal, hepatic, or haematological abnormalities which could interfere with the assessment of safety. Concomitant medications: Not reported.
Participants	N randomised: IND/GLY 110/50 µg: N = 407; placebo: N = 404. N analysed, n/N (%): IND/GLY 110/50 µg: 407/407 (100); placebo: 403/404 (99.8). Mean age (SD), years: IND/GLY 110/50 µg: 64.6 (7.89); placebo: 64.9 (7.95). Gender ‐ male, n/N (%): IND/GLY 110/50 µg: 288/407; placebo: 310/404. Baseline lung function ‐ post‐bronchodilator % predicted FEV1: Not reported. Smoking status, current smoker, n/N (%): Not reported.
Interventions	Intervention: Once‐daily IND/GLY 110/50 µg. Comparator: Once‐daily placebo.
Outcomes	Prespecified outcomes: Primary: Number of participants with SAEs during study. Secondary: Percentage of participants with composite endpoint of all‐cause mortality, and serious cardio‐ and cerebrovascular events; post hoc analysis: percentage of participants with composite endpoint of cardiovascular death and MACE change from baseline in pre‐dose FEV1 (days 22, 43, 85, 183, 274, and 364); change from baseline at day 364 in health status as measured by SGRQ for COPD participants; change from baseline at week 52 in daily, morning, and evening symptom scores; change from baseline at week 52 in percentage of nights with no night‐time awakenings; change from baseline at week 52 in percentage of no daytime symptoms; change from baseline at week 52 in percentage of days able to perform usual daily activities; change from baseline in 1 hour post‐dose FVC measurements (days 1, 22, 43, 85, 183, 274, and 364); time to premature discontinuation; change from baseline in 1 hour post‐dose FEV1 measurements (days 1, 22, 43, 85, 183, 274, and 364). Reported outcomes: Prespecified outcome (see above) well reported.
Notes	Funding for trial; notable author COIs: The study was funded by Novartis Pharmaceuticals.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Insufficient information provided (abstract only).
Allocation concealment (selection bias)	Unclear risk	Insufficient information provided (abstract only).
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Clinical trial registry states that 'participant and investigators' were blinded to treatment allocation.
Blinding of participants and personnel (objective outcomes ‐ performance bias) Objective outcomes	Low risk	Clinical trial registry states that 'participant 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	Unclear risk	Insufficient information provided (abstract only).
Selective reporting (reporting bias)	High risk	Abstract did not report key prespecified outcomes.
Other bias	Low risk	None identified.