Vogelmeier 2011.
| Methods |
Design: 12‐month, randomised, double‐blind, double‐dummy, parallel‐group study Setting: the study was conducted in 725 centres in 25 countries Date of study: January 2008 to April 2009 |
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| Participants |
Participants: n = 7384 (tiotropium: 3711, salmeterol: 3673) Baseline characteristics: mean age (tiotropium: 62.9 years, salmeterol 62.8 years); gender (tiotropium 74% male, salmeterol 75% male); mean % predicted FEV1 (tiotropium 49.2%, salmeterol 49.4%); mean smoking pack year history (tiotropium 38.8 years, salmeterol 37.8 years) Diagnostic criteria: American Thoracic Society classification COPD severity: moderate to severe Inclusion criteria: patients who were ≥ 40 years of age, with a cigarette smoking history of ≥ 10 pack years, and a clinical diagnosis of COPD, were eligible for inclusion in the study if they had a FEV1 % predicted ≤ 70% and FVC ≤ 70%, and a documented history of at least 1 exacerbation leading to treatment with systemic glucocorticoids or antibiotics or hospitalisation within the previous year Exclusion criteria: significant diseases other than COPD (particular chronic lung disease), diagnosis of asthma, bladder neck obstruction, narrow angle glaucoma, past cardiac event or severe cardiovascular disorder or recent hospitalisation. Renal or thyroid disease, untreated diabetes, drug insensitivities, unable systemic corticosteroid use, previous participation in a clinical study. Recent infection or exacerbation in the 4 weeks prior to participation. |
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| Interventions |
Run‐in period: during the 2‐week run‐in period, patients who were receiving tiotropium were required to switch to 40 µg of ipratropium 4 times a day, and this therapy was discontinued at the time of randomisation. Patients who were receiving a long‐acting beta2‐agonist were permitted to continue the use of that medication during the run‐in period. Interventions: 1. 18 µg of tiotropium once daily, delivered through the HandiHaler inhalation device, plus placebo twice daily, delivered through a pressurised, metered‐dose inhaler; or 2. 50 µg of salmeterol twice daily, delivered through a pressurised, metered‐dose inhaler, plus placebo once daily, delivered through the HandiHaler device Concomitant medication
"Patients receiving fixed‐dose combinations of long‐acting beta2‐agonists and inhaled glucocorticoids were instructed to switch to inhaled glucocorticoid monotherapy at the start of the treatment phase of the study. Patients were allowed to continue their usual medications for COPD, except for anticholinergic drugs and long‐acting beta2‐agonists, during the double‐blind treatment phase. Concomitant medication at baseline was defined as the therapy the patients were receiving at the time of the screening visit". |
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| Outcomes |
Primary outcome(s): time to first exacerbation Secondary outcome(s): (1) occurrence of at least one exacerbation, (2) number of COPD exacerbations, (3) time to first hospitalisation due to COPD exacerbation, (4) occurrence of at least 1 hospitalisation due to COPD exacerbations, (5) number of hospitalisations due to COPD exacerbations, (6) time to premature discontinuation of trial medication, (7) occurrence of premature discontinuation of trial medication, (8) pre‐dose morning PEFR measured by patients at home during the first 4 months of randomised treatment (weekly means will be calculated), (9) time to first COPD exacerbation or time to discontinuation of study medication because of worsening of underlying disease, whichever comes first |
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| Notes |
Funding: this study was funded by Boehringer Ingelheim and Pfizer Boehringer Ingelheim trial number 205.389 Clinicaltrials.gov study code NCT00563381 |
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| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | A randomisation list was generated by the sponsor using a validated system involving a pseudo‐random number generator. Patients were randomised to treatment via an Interactive Voice Response System (IVRS, Perceptive Informatics Inc., Berlin, Germany). Patients were randomised in a 1:1 ratio in blocks of 4, with equal allocation of treatment within each block per country site. |
| Allocation concealment (selection bias) | Low risk | The access to the randomisation code was supervised by Clinical Trial Support (Medical Data Services). Blinding of the study medications was such that the treatments were indistinguishable. |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Blinding was maintained by allocation of a dummy placebo MDI to those randomised to the tiotropium arm and a dummy placebo HandiHaler to those in the salmeterol arm. Tiotropium and placebo capsules were identical in size and colour and were therefore indistinguishable. |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | Mortality Adjudication Committee: provided consistent, systematic and independent assessment of the primary cause of death (blinded to treatment group) by reviewing the information provided in the Council for International Organisation of Medical Sciences (CIOMS) form for each patient |
| Incomplete outcome data (attrition bias) All outcomes | Unclear risk | Patients who prematurely discontinued treatment were followed for vital status (i.e. whether they were alive and, if they had died, the primary cause of death) until the end of the planned treatment period of 360 days. Information on vital status was considered to be complete for patients who attended all trial visits through day 360 and for those who prematurely discontinued study medication but whose vital status was confirmed at day 360. Exacerbations were not systematically followed up after a patient’s premature discontinuation of the trial medication. Patients who withdrew from the trial prematurely without having had an exacerbation were considered as having had no exacerbation, and in the time‐to‐event analysis, their data were censored at the time of withdrawal. There were a statistically significant higher number of withdrawals in the salmeterol group (17.7%, 648/3669), compared with the tiotropium group (15.8%, 585/3707) |
| Selective reporting (reporting bias) | Low risk | All outcome data reported |
AUC: area under the curve; bid: twice a day; CEA: cost‐effectiveness analysis; CI: confidence interval; COPD: chronic obstructive pulmonary disease; CUA: cost utility analysis; ED: emergency department; FEV1: forced expiratory volume in one second; FVC: forced vital capacity; GOLD: Global Initiative for Chronic Obstructive Pulmonary Disease; h: hour; HRQL: health‐related quality of life; ICER: incremental cost‐effectiveness ratio; ICS: inhaled corticosteroids; IVRS: interactive voice response system; LABA: long‐acting beta2‐agonist; MDDPI; metered dose dry powder inhaler;MDI: metered dose inhaler; QALM: quality‐adjusted life month; QALY: quality‐adjusted life year; PEF: peak expiratory flow; PEFR: peak expiratory flow rate; RCT: randomised controlled trial; SGRQ: St George's Respiratory Questionnaire; TDI: Transitional Dyspnoea Index