Shailendra Menjoge

A 4-year trial of Tiotropium in chronic obstructive pulmonary disease

BACKGROUND Previous studies showing that tiotropium improves multiple end points in patients with chronic obstructive pulmonary disease (COPD) led us to examine the long-term effects of tiotropium therapy. METHODS In this randomized, double-blind trial, we compared 4 years of therapy with either tiotropium or placebo in patients with COPD who were permitted to use all respiratory medications except inhaled anticholinergic drugs. The patients were at least 40 years of age, with a forced expiratory volume in 1 second (FEV(1)) of 70% or less after bronchodilation and a ratio of FEV(1) to forced vital capacity (FVC) of 70% or less. Coprimary end points were the rate of decline in the mean FEV(1) before and after bronchodilation beginning on day 30. Secondary end points included measures of FVC, changes in response on St. Georges Respiratory Questionnaire (SGRQ), exacerbations of COPD, and mortality. RESULTS Of a total of 5993 patients (mean age, 65+/-8 years) with a mean FEV(1) of 1.32+/-0.44 liters after bronchodilation (48% of predicted value), we randomly assigned 2987 to the tiotropium group and 3006 to the placebo group. Mean absolute improvements in FEV(1) in the tiotropium group were maintained throughout the trial (ranging from 87 to 103 ml before bronchodilation and from 47 to 65 ml after bronchodilation), as compared with the placebo group (P<0.001). After day 30, the differences between the two groups in the rate of decline in the mean FEV(1) before and after bronchodilation were not significant. The mean absolute total score on the SGRQ was improved (lower) in the tiotropium group, as compared with the placebo group, at each time point throughout the 4-year period (ranging from 2.3 to 3.3 units, P<0.001). At 4 years and 30 days, tiotropium was associated with a reduction in the risks of exacerbations, related hospitalizations, and respiratory failure. CONCLUSIONS In patients with COPD, therapy with tiotropium was associated with improvements in lung function, quality of life, and exacerbations during a 4-year period but did not significantly reduce the rate of decline in FEV(1). (ClinicalTrials.gov number, NCT00144339.)

Tolerance to bronchodilating effects of salmeterol in COPD

Loss of bronchodilator effectiveness or tolerance has been observed with inhaled beta-agonists but not with inhaled anticholinergic medications. Initially, tolerance is reflected in loss of bronchial protection against stimuli followed by loss of bronchodilator properties. However, generally such observations have been reported in asthma. A 6-month randomized, double-dummy placebo-controlled trial comparing tiotropium to salmeterol provided the opportunity to examine spirometric tolerance to long-acting beta-agonists in patients with COPD. Spirometry was measured over 12h at baseline and at days 15, 57, 116 and 169. Changes over time from baseline were compared relative to changes observed with placebo. A total of 623 patients participated (tiotropium = 209, salmeterol = 213, placebo = 201). The groups were similar in age (mean = 65 years), gender (75% men), and baseline FEV1 (mean = 1.08 +/- 0.37l [40 +/- 12% predicted]). Relative to placebo, both active drugs improved morning pre-drug, peak and average FEV1 and FVC throughout the trial. However, from day 1 to 169, salmeterol was associated with a higher decline in average FEV1 and FVC (0-12h) (difference from placebo: -36 and -115 ml, P < 0.05), which was most prominent over the 8-12 h period (difference from placebo: -45 and -138 ml, P < 0.01). Significant declines in peak FVC relative to placebo (-83 ml, P < 0.05) but not FEV1 (-12ml) were observed with salmeterol. Tiotropium was associated with further improvements in spirometry from days 1 to 15 and no evidence of tolerance from day 15 to the end of the trial. In conclusion, tolerance to pharmacologic bronchodilation occurs with long-acting beta-agonists such as salmeterol and not with inhaled anticholinergics.

Healthcare Costs with Tiotropium Plus Usual Care versus Usual Care Alone Following 1 Year of Treatment in Patients with Chronic Obstructive Pulmonary Disorder (COPD)

AbstractBackground: Healthcare costs for chronic obstructive pulmonary disease (COPD) have continued to increase with the increasing prevalence of the disease. New interventions that can reduce the medical costs of COPD are needed. Tiotropium bromide, a once-daily inhaled anticholinergic, has been evaluated in patients with COPD enrolled in two 1-year randomised, double-blind, placebo-controlled (usual care) trials which showed the drug reduced exacerbations and improved spirometry, dyspnoea, and health status. Objective: To retrospectively assess the direct costs of medical care for COPD in a US healthcare setting for patients treated with tiotropium in addition to usual care compared with usual care alone over a 1-year timeframe. The study was based on resource utilisation in the two previously described trials. Methods: Resource utilisation and clinical data were prospectively collected for the two 1-year, randomised, double-blind trials of tiotropium plus usual care versus usual care alone (placebo) in 921 patients with COPD. Usual care was defined as any medication for COPD used prior to the trial except anticholinergics and long-acting β-adrenoceptor agonists. Medical care resource utilisation was recorded at every scheduled visit in each trial. Mean total costs were calculated retrospectively by combining the resources utilised with the appropriate unit costs (1999 US dollars), excluding study drug (tiotropium) costs. Results: Compared with usual care, patients receiving tiotropium in addition to usual care had significantly fewer COPD exacerbations (20% decrease), hospitalisations (44% reduction) and hospital days (50% reduction). Utilisation of resources other than hospitalisation did not differ between study groups. As a consequence, patients receiving tiotropium had significantly lower mean per- patient costs of hospitalisation compared with patients receiving usual care alone (tiotropium

Assessment of Consistency of Treatment Effects in Multiregional Clinical Trials

US1738 ±

Assessing consistent treatment effect in a multi-regional clinical trial: a systematic review†

US259; placebo

Patient-level pooled analysis of the effect of tiotropium on COPD exacerbations and related hospitalisations.

US2793 ±

Consistency of Treatment Effect across Regions in Multiregional Clinical Trials, Part 2: Monitoring, Reporting, and Interpretation

US453). The mean difference in the cost of hospitalisation (resulting from all causes, including COPD) between treatment groups was -

One-sample run tests of symmetry

US1056 (95% CI -

Consistency of Treatment Effect across Regions in Multiregional Clinical Trials, Part 1: Design Considerations

US2078, -

Impact of Different Regulatory Requirements for Trial Endpoints in Multiregional Clinical Trials

US34), and the difference in total healthcare costs (excluding study drug acquisition cost) was -