Donohue 2010.
| Methods |
Design: 26‐week, randomised, double‐blind, placebo‐controlled trial (with open‐label tiotropium). Adaptive seamless extension of 2‐week dose finding study, with 150 mcg and 300 mcg indacaterol doses selected from 4 possible indacaterol doses (75 mcg, 150 mcg, 300 mcg, 600 mcg). Intention‐to‐treat analysis. Spirometry, quality of life and dyspnoea data analysed at 12 weeks Run‐in: no run‐in. Continuation of a 2‐week dose‐finding trial via adaptive seamless design methodology. Participants randomly assigned to indacaterol, tiotropium or placebo continued for a further 26 weeks with additional participants recruited |
|
| Participants |
Population: 1250 participants randomly assigned to indacaterol or placebo (416 to indacaterol 150 mcg, 416 to indacaterol 300 mcg, 418 to placebo). Participants were recruited from the United States, Europe, the Middle East, Asia, India and the UK. Mean age was 63 years. Of the indacaterol 150 mcg, indacaterol 300 mcg and placebo populations, 38.2%, 37.3% and 38.5%, respectively, were receiving concurrent ICS. Mean FEV1 was between 53% and 56% predicted in all arms Inclusion criteria: patients 40 years of age or older with 20‐pack‐year or longer smoking history, FEV1/FVC < 70%, FEV1 < 80% and > 29% Exclusion criteria: asthma, hospitalisation with COPD exacerbation or lower respiratory tract infection within previous 6 weeks, requirement for long‐term oxygen therapy, concomitant pulmonary disease, diabetes, active malignancy, history of long QT syndrome or prolonged QTc, hypersensitivity to study drugs and drugs related to study drugs, recent administration of live attenuated vaccine, history of poor medication adherence, inability to use a dry powder inhaler |
|
| Interventions | 1. Indacaterol 150 mcg 2. Indacaterol 300 mcg 3. Placebo 4. Tiotropium 18 mcg |
|
| Outcomes |
Primary outcome: trough FEV1 at 12 weeks Secondary outcomes: 'days of poor control,' Transitional Dyspnoea Index, SGRQ, non‐inferiority (of at least 1 dose of indacaterol) to tiotropium, adverse events |
|
| Notes | Trial supported by Novartis. Novartis directly supplied data for Indacaterol versus placebo (peak FEV1, number of participants experiencing at least one exacerbation) |
|
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Automated interactive voice response system |
| Allocation concealment (selection bias) | Low risk | Allocation via interactive voice system. The only information communicated with sponsor and investigators was the selected doses. Personnel involved in the study remained blinded for the remainder of the study. Tiotropium arm was open label |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Sponsor, investigators and participants remained blinded until the study database was locked. An independent dose selection committee had access to unblinded data at the end of stage 1 but communicated to sponsor and investigators only the chosen doses for stage 2 All participants received medication via single‐dose dry powder inhaler |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Data were analysed by a separate body (Datamap GmbH, funded by Novartis); treatment decodes were received only by programmers and statisticians after stage 2 database was locked |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Completion rates were reported for each arm but reasons for dropout were not further specified. Higher dropout rates were reported from the placebo arm |
| Selective reporting (reporting bias) | Unclear risk | Low risk for primary outcomes Subjective secondary safety outcomes were not prespecified. 'Days of poor control' (a key secondary outcome) was not reported on |