Donohue 2010 [INHANCE].

Methods	Design: This study was performed in two stages in an adaptive seamless design. In stage 1, patients were randomized to receive indacaterol 75, 150, 300, or 600 mg once daily, formoterol 12 mg twice daily, or placebo, all double‐blind, or open‐label tiotropium 18 mg once daily. An independent committee used predefined efficacy criteria to select two indacaterol doses based on 2‐week efficacy and safety data. As reported elsewhere, the two indacaterol doses selected were 150 and 300 mg (18). In stage 2, the four treatment groups were the two selected doses of indacaterol, tiotropium, and placebo. Treatment continued to 26 weeks, with additional patients recruited and randomized Duration: 26 weeks (+ 2 week run‐in) Location: 345 centres in 12 countries
Participants	Population: 1683 participants were randomised to indacaterol at two doses (416 and 416), open‐label tiotropium (415), and placebo (418) Baseline characteristics Age (mean years): ind150 63.4, ind300 63.3, tio 64.0, pbo 63.6 % Male: ind150 62.3, ind300 63.2, tio 64.8, pbo 61.0 % FEV1 predicted: ind150 56.1, ind300 56.3, tio 53.9, pbo 56.1 Pack‐years (mean): ind150 48.3, ind300 50.8, tio 50.0, pbo 49.7 Inclusion criteria: Male and female adults aged ≥ 40 years, who have signed an Informed Consent Form prior to initiation of any study‐related procedure. Co‐operative outpatients with a diagnosis of COPD (moderate to severe as classified by the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) Guidelines, 2005) and smoking history of at least 20 pack yearsPost‐bronchodilator FEV1 < 80% and ≥ 30% of the predicted normal value. Post‐bronchodilator FEV1/FVC < 70% (Post refers to within 30 min of inhalation of 400 µg of salbutamol) Exclusion criteria: lactating females; hospitalised for a COPD exacerbation in the 6 weeks prior to Visit 1 or during the run‐in period; requiring long term oxygen therapy (> 15 h a day); respiratory tract infection 6 weeks prior to V1; concomitant pulmonary disease, pulmonary tuberculosis, or clinically significant bronchiectasis; history of asthma; Type I or uncontrolled Type II diabetes; contraindications for tiotropium; clinically relevant laboratory abnormalities or a clinically significant abnormality; active cancer or a history of cancer with less than 5 years disease free survival time; history of long QT syndrome or whose QTc interval is prolonged; hypersensitivity to any of the study drugs or drugs with similar chemical structures; treatment with the investigational drug (with further criteria); live attenuated vaccinations within 30 days prior to visit 1, or during run‐in period; known history of non compliance to medication; unable to satisfactorily use a dry powder inhaler device or perform spirometry measurements
Interventions	1. Indacaterol 150 qd (LABA) 2. Indacaterol 300 qd (LABA) 3. Tiotropium 18 qd (LAMA) ‐ open‐label 4. Placebo (PBO) Inhaler device: 1, 2, and 4 via single‐dose dry powder inhaler, open‐label tiotropium via HandiHaler Allowed co‐medications: Patients could continue inhaled corticosteroid (ICS) monotherapy if stable for 1 month before screening; dose and regimen were to remain stable throughout the study. Before the start of the run‐in period, treatment with anticholinergic bronchodilators or with β2‐agonists was discontinued with appropriate washout, and patients receiving fixed‐combination β2‐agonist/ICS were switched to ICS monotherapy at an equivalent dose. All patients were supplied with albuterol for use as needed.
Outcomes	The primary efficacy outcome was trough FEV1 at 12 weeks. Additional analyses (not adjusted for multiplicity) included transition dyspnoea index (TDI), health status (St George’s Respiratory Questionnaire [SGRQ]), and exacerbations. Serum potassium, blood glucose, and QTc interval were measured.
Notes	Funding: Novartis Identifier(s): NCT00463567 and CQAB149B2335S
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization was performed using an automated interactive voice response system, and was stratified by smoking status (current or ex‐smoker).
Allocation concealment (selection bias)	Low risk	Interactive voice response system
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding procedures were sound, but tiotropium was delivered open label which introduced bias for these comparisons. On completion of stage 1, the independent dose selection committee had access to unblinded data. The only information communicated with the sponsor and investigators was the two selected indacaterol doses, and personnel involved in the continuing clinical study remained blinded for the remainder of the study. The blinding of indacaterol and placebo continued until the study database was locked at the end of stage 2.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding procedures were sound, but tiotropium was delivered open label which introduced bias for these comparisons. Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) [clinicaltrials.gov]
Incomplete outcome data (attrition bias) All outcomes	Low risk	Efficacy was evaluated for the intention‐to‐treat population, comprising all randomized patients who received at least one dose of study drug. Dropout was variable and generally high across groups (ranging from 18 to 31%). 98.9% were included in the analysis
Selective reporting (reporting bias)	Low risk	Study was prospectively registered, and all results were available from the published reports and clinicaltrials.gov