NCT01172808.

Methods	Study design: RCT Study grouping: parallel group Open Label: no Cluster RCT: no
Participants	Baseline characteristics LAMA add‐on (low) Number randomised: 262 Number completed: 249 Mean age (SD): 43.7 (13.1) years % Male: 40.5 % Predicted FEV1: NR % White: NR Duration of asthma: NR LAMA add‐on (high) Number randomised: 264 Number completed: 241 Mean age (SD): 44.4 (12.6) years % Male: 41.7 % Predicted FEV1: NR % White: NR Duration of asthma: NR LABA add‐on N umber randomised: 275 N umber completed: 260 Mean age (SD): 42.6 (12.6) years % Male: 42.2 % Predicted FEV1: NR % White: NR Duration of asthma: NR Inclusion criteria: informed consent; men or women aged 18‐75 years; ≥ 3 months of asthma at enrolment; diagnosed before 40.5 years of age, confirmed with FEV1 increase of ≥ 12% and ≥ 200 mL after salbutamol; on maintenance treatment with a medium, stable dose of ICS for ≥ 4 weeks; ACQ (≥ 1.5) prior to randomisation; pre‐bronchodilator FEV1 60‐90% of predicted normal at screening; variation of absolute FEV1 of screening (pre‐bronchodilator) as compared with visit 2 (pre‐dose) must be within ± 30%; non‐smoker for at least 1 year, and history < 10 pack‐years; able to use inhalers and perform trial procedures correctly Exclusion criteria: lung disease or significant medical illness other than asthma; clinically relevant abnormal screening, haematology or blood chemistry; hospitalised for cardiac failure during the past year; any unstable or life‐threatening cardiac arrhythmia; known active TB; resection, radiotherapy or chemotherapy within 5 years for malignancy (treated basal cell carcinoma allowed); thoracotomy with pulmonary resection; significant alcohol or drug abuse within 2 years; current or recent (6 weeks) pulmonary rehabilitation; known hypersensitivity to the study drugs or any other components of the delivery systems; pregnant or nursing women; women of childbearing potential not using effective contraception; investigational drug, beta‐blockers, tiotropium, oral or patch beta‐adrenergic blockers, OCS or "experimental" drugs for asthma not recommended by international guidelines within 4 weeks; anti‐IgE antibodies (e.g. omalizumab) within 6 months; cromone, methylxanthines or phosphodiesterase‐4 inhibitors within 2 weeks; asthma exacerbation or respiratory tract infection within 4 weeks; previously randomised in this trial or in the respective twin trial (205.419) or currently participating in another trial
Interventions	Intervention characteristics LAMA add‐on (low) ICS type/dose: not part of randomised treatment, participants continued their medium dose of usual ICS Add‐on type/dose: tiotropium 2.5 mcg once daily (evening) Co‐medications: all, participants were taking maintenance treatment with a medium, stable dose of ICS for ≥ 4 weeks prior to visit 1 Type of inhaler: Respimat (+ HFA MDI placebo twice daily to blind for salmeterol) Duration of treatment: 24 weeks LAMA add‐on (high) ICS type/dose: not part of randomised treatment, participants continued their medium dose of usual ICS Add‐on type/dose: tiotropium 5 mcg once daily (evening) Co‐medications: all, participants were taking maintenance treatment with a medium, stable dose of ICS for ≥ 4 weeks prior to visit 1 Type of inhaler: Respimat (+ HFA MDI placebo twice daily to blind for salmeterol) Duration of treatment: 24 weeks LABA add‐on ICS type/dose: not part of randomised treatment, participants continued their medium dose of usual ICS Add‐on type/dose: salmeterol 50 mcg twice daily (morning and evening) Co‐medications: all, participants were taking maintenance treatment with a medium, stable dose of ICS for ≥ 4 weeks prior to visit 1 Type of inhaler: HFA MDI (+ Respimat once daily to blind for tiotropium) Duration of treatment: 24 weeks
Outcomes	Continuous Trough FEV1 (L, change) ACQ total Trough PEF (L/min, change) Trough FVC (L, change) AQLQ total Peak FEV1 (L, change) Peak FVC (L, change) Dichotomous AEs (all) SAEs (all) Exacerbations (hospital) ACQ responder
Identification	Sponsorship source: Boehringer Ingelheim Country: US, Brazil, China, Guatemala, India, Japan, Latvia, Mexico, Peru, Poland, Russian Federation Setting: 114 Boehringer Ingelheim investigational sites in 11 countries Comments: no publications listed, available only on manufacturer's website and clinicaltrials.gov IDs: 205.418, NCT01172808 Authors name: Boehringer Ingelheim Institution: N/A Email: clintriage.rdg@boehringer‐ingelheim.com Address: Boehringer Ingelheim Pharmaceuticals, tel: (+1) 800‐243‐0127
Notes	Pre‐treatment: minimal baseline characteristics reported, no differences noted TWIN TRIAL WITH NCT01172821 (205.419)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Described as 'randomised' on the clinicaltrials.gov record. Previous contact with study sponsors confirmed standard practice with computerised codes
Allocation concealment (selection bias)	Low risk	Described as 'randomised' on the clinicaltrials.gov record. Previous contact with study sponsors confirmed concealed automated allocation systems are used
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Masking described as 'double‐blind' in the clinicaltrials.gov record. Details of inhalers used made it clear that inhalers were double dummy to maintain the blind
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Double‐blind but no specific details about outcome assessors
Incomplete outcome data (attrition bias) All outcomes	Low risk	Drop‐out was < 10% in all groups and the full analysis set was used for all safety and efficacy analyses. "There was 1 patient in the TIO R5 group randomised but not treated"
Selective reporting (reporting bias)	Low risk	Study results were reported on clinicaltrials.gov but did not give time to first exacerbation as "less than 50% of patients in each treatment group experienced an asthma exacerbation". Numbers in each group having exacerbations were not reported but were subsequently reported in a publication as a pooled result with NCT01172821
Other bias	Unclear risk	Data were provided by Boehringer Ingelheim, who sponsored the study and manufacturer of tiotropium Respimat. Minimal demographic/baseline characteristics reported