Methods	Design: Amulti-centre, multi-national, randomised, double-blind, parallel-group study from March 2009 to March 2010. The trial included 186 study centres in 14 countries: Argentina (10), Australia (6), Colombia (5), Denmark (5), Germany (25), Greece (4), Guatemala (5), Mexico (5), Peru (6), Philippines (2), South Africa (6), Spain (13), Turkey (13), and USA (81)
Participants	Population: 1134 patients with a clinical history of moderate or severe COPD as defined by GOLD guidelines, were randomised to tiotropium + indacaterol (570) and tiotropium (564) Baseline Characteristics: Mean age 64 years, 67% male, mean FEV1 1.3 L, mean FEV1 predicted 49%, 47 pack-years smoking history. Inclusion Criteria: Men and women aged ≥40 years with moderate-to-severe COPD, with a smoking history ≥10 pack-years and post-bronchodilator FEV1 ≤ 65% and ≥ 30% predicted and FEV1/FVC < 70%. Exclusion Criteria: Patients WHO have received systematic corticosteroids and/or antibiotics and/or was hospitalised for a COPD exacerbation in the 6 weeks prior to screening or during the run-in period or had a respiratory tract infection within 6 weeks prior to screening. Patients with concomitant pulmonary disease, a history of asthma, diabetes Type I or uncontrolled diabetes Type II, lung cancer or a history of lung cancer, a history of certain cardiovascular comorbid conditions
Interventions	1. Indacaterol 150 μg through single-dose dry powder inhaler (SDDPI), once daily + tiotropium 18 μg through SDDPI Handihaler, once daily 2. Placebo to indacaterol + tiotropium 18 μg through SDDPI Handihaler, once daily
Outcomes	Primary: Standardised area under the curve (AUC) FEV1 between 5min and 8h post-dose after 12 weeks of treatment. Secondary: Trough FEV1 on day 1 and after 12 weeks treatment, FEV1 AUC (5min-8h) day 1, FEV1 AUC (5min-4h) on day 1 and after 12 weeks of treatment, resting inspiratory capacity (IC), use of albuterol as rescue medication, safety (adverse events and serious adverse events)
Notes	Co-medication: Albuterol was available for rescue use. Patients (53%) receiving inhaled corticosteroids (ICS) at baseline continued treatment (or the ICS component alone if taken as a fixed combination with a bronchodilator) at equivalent dose and regimen throughout the study
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A patient randomisation list was produced by the IVRS provider using a validated system that automates the random assignment of patient numbers to randomisation numbers
Allocation concealment (selection bias)	Low risk	The randomisation numbers were linked to the different treatment arms, which in turn were linked to medication numbers. A separate medication randomisation list was produced by or under the responsibility of Novartis Drug Supply Management using a validated system that automates the random assignment of medication numbers to medication packs containing each of the study drugs
Blinding of participants and personnel (LABA+TIO versus TIO) (performance bias)	Low risk	Patients, investigator staff, persons performing the assessments, data analysts and the Novartis trial team were all blinded
Blinding of outcome assessment (detection bias) Exacerbations	Low risk	Persons performing the assessments were blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	The withdrawal rates were low and even (tiotropium + indacaterol 6.8%, tiotropium 6.2%)
Selective reporting (reporting bias)	Low risk	Results for all listed primary and secondary outcomes were reported