Tiotropium is a long-acting antimuscarinic bronchodilator indicated for maintenance bronchodilation in patients with chronic obstructive pulmonary disease (COPD) for once-daily inhalation treatment. Two formulations of tiotropium have been developed: SPIRIVA® HandiHaler® 18 μg once daily, a dry powder inhaler (DPI), received initial approval in 2002, and is now approved in more than 100 countries. SPIRIVA® Respimat® 5 μg once daily Soft Mist™ Inhaler (SMI) was developed as a novel multi-dose aqueous aerosol delivery device. It is approved in more than 85 countries, with initial approval received in 2007 .
Tiotropium HandiHaler® 18 μg and Respimat® 5 μg have been developed in separate stand-alone programs. Until now, they have only been directly compared in trials up to 4-week duration. Clinical trials with tiotropium HandiHaler® 18 μg and Respimat® 5 μg once daily have demonstrated similar clinically important improvements in lung function, symptoms, and health-related quality of life. In a prespecified pooled analysis of two 4-week, placebo-controlled, crossover trials, the 5 μg dose of tiotropium Respimat® and tiotropium HandiHaler® 18 μg were both significantly superior to placebo on the primary endpoint of trough forced expiratory volume in 1 second (FEV1) response. Tiotropium Respimat® 5 μg was non-inferior to tiotropium HandiHaler® in terms of bronchodilator efficacy and both formulations provided a similar systemic availability . In a 4-week crossover study of 134 Japanese patients with COPD  tiotropium Respimat® 5 μg and tiotropium HandiHaler® 18 μg had similar lung function efficacy, safety, and pharmacokinetic (PK) profiles . Taken together, these findings indicate that tiotropium Respimat® 5 μg and tiotropium HandiHaler® 18 μg have similar efficacy, systemic exposure, and safety.
Exacerbation benefits have been observed in both clinical trial programs. In the 1-year trial with tiotropium Respimat® 5 μg,  the hazard ratio (HR) for time to COPD exacerbation (tiotropium/placebo) was 0.69 (95% confidence interval [CI]: 0.63–0.77). Comparable results using the largest tiotropium HandiHaler® trial, Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) demonstrated an HR of 0.86 (95% CI, 0.81–0.91) after 4 years . Cross-study comparisons therefore suggest potentially superior effects on reducing the risk of an exacerbation with the Respimat® formulation; however, there have not been direct comparisons in clinical trials of sufficient size and duration to determine whether there are true differences in exacerbation outcomes.
Mortality has been evaluated in HandiHaler® and Respimat® trials [6, 7]. Intention-to-treat mortality has been analyzed for the largest study with HandiHaler® formulation (4 years, 5992 patients in UPLIFT®) , for the three, 1-year studies with the Respimat® formulation, and in a further 6-month study [4, 8, 9]. In the UPLIFT® study the risk of a fatal event was lower with tiotropium treatment (in the HandiHaler® formulation) than with placebo. For the 4-year, protocol-defined study period up to day 1440, among patients for whom vital-status information was available, 921 patients died: 14.4% in the tiotropium group and 16.3% in the placebo group (hazard ratio, 0.87; 95% CI, 0.76 - 0.99) . In a retrospective, pooled analysis of the three 1-year and one 6-month placebo-controlled trials with tiotropium Respimat®, including 6096 patients, a numeric increase in all-cause mortality was seen in patients treated with tiotropium Respimat® 5 μg (68; incidence rate [IR]: 2.64 cases per 100 patient-years) compared with placebo (51; IR: 1.98) showing a rate ratio of 1.33 (95% CI: 0.93–1.92) for the planned treatment period; the excess in mortality was observed in patients with known rhythm disorders . The causes of death were diverse and a causal relationship between the use of tiotropium Respimat® and mortality has not been established. In contrast to pooled analyses on trial-level data of three of these studies, including the 10 μg non-marketed dose, [7, 10, 11] the pooled analyses based on patient-level data have shown a numeric, but non-statistically significant increase in all-cause mortality [6, 9]. The Cochrane Review meta-analysis, thus concluded: “Head-to-head trials comparing the dry powder HandiHaler® to the soft mist Respimat® inhaler are required before firm conclusions can be drawn concerning the difference in mortality rates between the inhalers” .
Direct comparison studies of tiotropium HandiHaler® 18 μg with Respimat® 5 μg have been limited to 4-week crossover studies on PK and lung function parameters mentioned above. Therefore, prospective data from a trial of adequate size and duration is the appropriate way to establish whether tiotropium Respimat® 5 μg has comparable safety and efficacy with tiotropium HandiHaler® including rare events, i.e. events of death or exacerbations outcomes. A treatment arm with tiotropium Respimat® 2.5 μg is also included because this dose may be preferred in combination with a long-acting beta-agonist (ongoing clinical development program of a fixed-dose combination).
A recent comprehensive review of meta-analyses and pharmaco-epidemiologic studies have also raised the possibility that mortality is increased by tiotropium delivered by Respimat® . Although it has been theorized that there may be greater system absorption, PK and pharmacodynamic studies have shown similar profiles for the two currently marketed formulations of tiotropium [2, 3]. A recent high-resolution PK study has shown a slightly lower peak serum concentration with Respimat® . Thus, at present, there is no clear mechanistic explanation for an increased risk profile for tiotropium Respimat® compared with HandiHaler®. Because of this unresolved controversy, there is a compelling need to conduct a mortality-endpoint driven trial comparing the two inhaler formulations.
The purpose of this manuscript is to describe the rationale and methods for TIOtropium Safety and Performance In Respimat® (TIOSPIR®) trial (NCT01126437), a multinational, double-blind, comparative trial evaluating the safety and efficacy of two doses of tiotropium Respimat® (once-daily 2.5 or 5 μg), with tiotropium HandiHaler® (once-daily 18 μg). The trial is a large-scale, event-driven, non-inferiority trial with two primary endpoints: time to all-cause mortality and COPD exacerbation.