The Tiotropium Safety and Performance in Respimat® (TIOSPIR®) Trial: Spirometry Outcomes

Background Tiotropium Safety and Performance in Respimat® (TIOSPIR®) compared the safety and efficacy of tiotropium Respimat® and tiotropium HandiHaler® in patients with chronic obstructive pulmonary disease (COPD). A prespecified spirometry substudy compared the lung function efficacy between treatment groups. Methods TIOSPIR® was a large-scale, long-term (2.3-year), event-driven, randomized, double-blind, parallel-group trial of 17,135 patients with COPD. In the spirometry substudy, trough forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) were measured at baseline and every 24 weeks for the duration of the trial. Results The substudy included 1370 patients who received once-daily tiotropium Respimat® 5 μg (n = 461), 2.5 μg (n = 464), or tiotropium HandiHaler® 18 μg (n = 445). Adjusted mean trough FEV1 (average 24–120 weeks) was 1.285, 1.258, and 1.295 L in the Respimat® 5 μg, 2.5 μg, and HandiHaler® 18 μg groups (difference versus HandiHaler® [95 % CI]: −10 [−38, 18] mL for Respimat® 5 μg and, −37 [−65, −9] mL for Respimat® 2.5 μg); achieving noninferiority to tiotropium HandiHaler® 18 μg for tiotropium Respimat® 5 but not for 2.5 μg (prespecified analysis). Adjusted mean trough FVC was 2.590, 2.544, and 2.593 L in the Respimat® 5 μg, 2.5 μg, and HandiHaler® 18 μg groups. The rates of FEV1 decline over 24 to 120 weeks were similar for the three treatment arms (26, 40, and 34 mL/year for the tiotropium Respimat® 5-μg, 2.5-μg, and HandiHaler® 18-μg groups). The rate of FEV1 decline in GOLD I + II patients was greater than in GOLD III + IV patients (46 vs. 23 mL/year); as well as in current versus ex-smokers, in patients receiving combination therapies at baseline versus not, and in those experiencing an exacerbation during the study versus not. Conclusions The TIOSPIR® spirometry substudy showed that tiotropium Respimat® 5 μg was noninferior to tiotropium HandiHaler® 18 μg for trough FEV1, but Respimat® 2.5 μg was not. Tiotropium Respimat® 5 μg provides similar bronchodilator efficacy to tiotropium HandiHaler® 18 μg with comparable rates of FEV1 decline. The rate of FEV1 decline varied based on disease severity, with a steeper rate of decline observed in patients with moderate airway obstruction. Trial registration NCT01126437. Electronic supplementary material The online version of this article (doi:10.1186/s12931-015-0269-4) contains supplementary material, which is available to authorized users.


Conclusions:
The TIOSPIR® spirometry substudy showed that tiotropium Respimat® 5 μg was noninferior to tiotropium HandiHaler® 18 μg for trough FEV 1 , but Respimat® 2.5 μg was not. Tiotropium Respimat® 5 μg provides similar bronchodilator efficacy to tiotropium HandiHaler® 18 μg with comparable rates of FEV 1 decline. The rate of FEV 1 decline varied based on disease severity, with a steeper rate of decline observed in patients with moderate airway obstruction.

Background
Tiotropium is delivered via the Respimat® Soft Mist™ Inhaler (SMI; 5 μg once daily) or the HandiHaler® device (18 μg once daily). Both provide similar improvements in lung function, exacerbation outcomes, symptoms and health-related quality of life (HRQoL) compared with placebo in patients with chronic obstructive pulmonary disease (COPD) [1][2][3][4]. While a decrease in mortality was observed for tiotropium HandiHaler® versus placebo in the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) trial [4], a numerical increase in all-cause mortality was observed with tiotropium Respimat® versus placebo in a pooled analysis of Respimat® trials, in particular in patients with known cardiac rhythm disorders [5].
These observations led to the development of the Tiotropium Safety and Performance in Respimat® (TIOS-PIR®) trial [6,7], the first large-scale, long-term trial of tiotropium Respimat® and tiotropium HandiHaler® to compare directly the safety and efficacy of the two formulations in patients with COPD. The primary endpoints were risk of death and risk of first COPD exacerbation. TIOSPIR® showed that tiotropium Respimat® 2.5 or 5 μg once daily have a similar safety and exacerbation efficacy profile to tiotropium HandiHaler® 18 μg once daily in patients with COPD [7].
Although there is a wealth of spirometry data on tiotropium HandiHaler®, less information is available for tiotropium Respimat®, and data on the rates of lung function decline are lacking in particular [1,2]. A prespecified spirometry substudy was performed on 1370 patients within the TIOSPIR® trial and showed that Respimat® 5 μg was noninferior to HandiHaler® for the trough forced expiratory volume in 1 second (FEV 1 ), while Respimat® 2.5 μg was not [7].
In these predefined analyses, we assessed additional lung function outcomes from the spirometry substudy, including forced vital capacity (FVC) and annual rates of decline in FEV 1 and FVC. We wished to determine whether these outcomes differed between the tiotropium HandiHaler® and Respimat® arms, and assessed if rates of decline differed by patient baseline characteristics or between subgroups of patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) Stages I + II (predominantly GOLD II, as described in the Results) or III + IV COPD.

Study population
Patients enrolled were aged ≥40 years, had a clinical diagnosis of COPD, ≥10 pack-years, smoking history, a post-bronchodilator FEV 1 /FVC ratio ≤0.70, and an FEV 1 ≤ 70 % predicted. Patients with concomitant cardiac disease were included, except for patients with unstable or recent events (myocardial infarction within the last 6 months, hospitalization for class III or IV heart failure, or unstable or life-threatening arrhythmia requiring new treatment within the last 12 months). Patients with other clinically significant lung diseases or a COPD exacerbation within the last month, moderate or severe renal impairment, cancer requiring therapy within the last 5 years, or drug or alcohol abuse within the last year were excluded. All COPD medications except other inhaled anticholinergic agents were allowed.
The trial was performed in accordance with the provisions of the Declaration of Helsinki, and the study protocol and procedures were approved by relevant institutional review boards and ethics committees. All the patients provided written informed consent.

Spirometry substudy
The spirometry substudy was a predefined analysis which covered the duration of the study. The objective was to demonstrate that there were no differences between the interventions by testing the noninferiority of Respimat® 2.5 and 5 μg versus HandiHaler® 18 μg.
In the spirometry substudy population, trough FEV 1 and FVC were measured at baseline and every 24 weeks (±14 days) for the duration of the trial (Weeks 24, 48, 72, 96, 120, 144, 168). The pulmonary function tests (PFTs) were done in the clinic at a single time point (in triplicate) prior to the daily dosing of tiotropium, and approximately 24 hours after dosing on the previous day (between 7:00 and 10:00 am). Spirometers and their use, including daily calibration, met American Thoracic Society (ATS)/European Respiratory Society (ERS) criteria. The highest FEV 1 and FVC values from an acceptable maneuver were recorded regardless of whether they came from different spirometric maneuvers or from the same maneuver (preferably with a maximum of five attempts, but up to eight attempts were allowed). Predicted normal FEV 1 values were calculated for patients using the European Community for Coal and Steel (ECCS) equations [8].
A number of medication restrictions were set on pulmonary function days for the substudy. Short-acting betaadrenergic bronchodilators could not be taken for at least 8 hours prior to PFTs, and long-acting beta-adrenergic bronchodilators or combination beta-adrenergic bronchodilator/inhaled steroid could not be taken for at least 24 hours prior to PFTs. The morning dose of inhaled steroids could not be taken prior to PFTs and the morning dose of the study medication could not be taken prior to test-day pre-dose PFT. Short-acting (twice-daily or more frequent administration) theophylline preparations required at least a 24-hour washout, while long-acting (once-daily) theophylline preparation required at least a 48-hour washout.

Statistical analysis
Summary statistics are used for presentation of the demographic data.
Noninferiority testing of tiotropium Respimat® 5 and 2.5 μg compared with tiotropium HandiHaler® 18 μg for trough FEV 1 (average 24-120 weeks) was predefined. Noninferiority testing on trough (i.e., morning pre-dose) FEV 1 was based on a noninferiority delta of 50 mL, assuming a standard deviation of 225 mL. The sample size needed was estimated at 427 patients per group for 90 % power and one-sided α = 0.025. Rounding to 435 patients per group, 1305 patients was the target sample size for the substudy. There were no predefined tests for FVC .
Trough FEV 1 (24 to 120 weeks) was analyzed between treatment groups using a mixed model repeated measures (MMRM) model [9] with an autoregression-1 covariance structure and the Kenwood-Roger approximation to estimate denominator degrees of freedom. Analyses included the fixed terms for treatment, investigative site, visit, treatment-by-visit interaction, baseline FEV 1 , and baseline FEV 1 -by-visit interaction, and a random term for patient. Superiority tests were clarified to be two-sided with α = 0.05 rather than onesided with α = 0.025.
Mean FEV 1 and FVC are reported as absolute values, adjusted by investigative site, visit, treatment-by-visit interaction, baseline FEV 1 , and baseline FEV 1 -by-visit interaction, within the MMRM model.
In a post-hoc analysis, the annual rate of decline for FEV 1 , FVC, and FEV 1 /FVC by treatment was estimated using a MMRM model that included the fixed terms of treatment, visit, and treatment-by-visit interaction, and a random intercept and slope, using data from Week 24 until the end of the treatment period. Annual rate of decline by GOLD stage (treatment arms pooled) was estimated using a similar MMRM model that included the fixed terms of GOLD stage, visit, GOLD-by-visit interaction, and a random intercept and slope.
Forest plots (showing means and 95 % CIs) were created for the spirometry substudy population to show rates of decline in FEV 1 , FVC, and FEV 1 /FVC by patient baseline characteristic or on-study exacerbation, estimated using the same MMRM model for post-hoc analysis.
Baseline demographics and use of respiratory medication were similar among the three treatment arms (Table 1). Baseline FEV 1 and FVC were, however, slightly elevated in the Respimat® 5 μg arm, which also exhibited slightly less lung function impairment (with a higher proportion of patients in GOLD II, and a higher FEV 1 % predicted compared with the other arms), though these differences are not clinically significant. Baseline characteristics within the substudy were mostly similar to those of the total TIOSPIR® population (Additional file 1: Table S1) [7]. There were, however, proportionally fewer male patients in the substudy, since the substudy was not conducted in Asian sites, which typically have proportionally more male patients. Substudy patients also had a longer smoking history and used slightly more respiratory medication at baseline than patients not included in the substudy.
Mean annual changes in FEV 1 , FVC, and FEV 1 /FVC by baseline characteristics for the substudy population (treatment arms pooled) are shown in Fig. 3 (FEV 1 ) and in the Additional file 2: Figure S1 (FVC and FEV 1 /FVC). Similar declines in lung function were observed across most subgroups. The declines in FEV 1 and FVC appeared slightly higher in patients who were current smokers versus ex-smokers; in patients receiving a longacting beta-adrenergic bronchodilator combined with a long-acting muscarinic antagonist/inhaled corticosteroid at baseline compared with those not receiving these medications; and in the subgroup of patients experiencing an exacerbation during the study (vs. no exacerbation). A relatively high rate of decline was observed for patients with a low body mass index (BMI), and minimal decline in patients of Black race; however, these subgroups had small sample sizes (n = 51 and n = 35, respectively) and wide CIs. The proportion of Black patients was higher (2.6 %) in the spirometry substudy than in the overall TIOSPIR® population (1.5 %).
Based on lung function severity at baseline, the rate of decline of FEV 1 for patients from GOLD Stages I + II (GOLD I, n = 4; GOLD II, n = 632) was larger than for patients from GOLD Stages III + IV (GOLD III, n = 580; GOLD IV, n = 130) (46 vs. 23 mL/year, respectively; difference [95 % CI]: 23 [9,38]; p = 0.0017) ( Table 3). The rates of decline of FVC and FEV 1 /FVC were similar for patients from GOLD Stages I + II and III + IV (Table 3).
The TIOSPIR® spirometry substudy provided an opportunity to examine further lung function outcomes with tiotropium HandiHaler® and Respimat®. Our results also showed no significant difference in the improvement from baseline in trough FVC with tiotropium Respimat® 5 μg or tiotropium HandiHaler®. Similar trends in both FEV 1 and FVC increases over baseline were observed over time (from 24 to 120 weeks) in the tiotropium Respimat® 5 μg and HandiHaler® arms, suggesting that there is no tachyphylaxis following treatment, and supporting previous 1-year trial results [3,10]. The improvements in FEV 1 and FVC with tiotropium Respimat® 2.5 μg were, however, consistently lower than those for Respimat® 5 μg or HandiHaler® 18 μg, validating the higher tiotropium doses as those that are approved and available [11,12].
The spirometry substudy of TIOSPIR® is the first to report rates of lung function decline for tiotropium Respimat®. Annual rates of FEV 1 , FVC, and FEV 1 /FVC decline were similar for tiotropium HandiHaler® 18 μg and Respimat® at the 5 μg or 2.5 μg daily dose. The annual rate of decline in FEV 1 in the TIOSPIR® substudy was 26 mL for tiotropium Respimat® 5 μg and 34 mL for HandiHaler® 18 μg. These findings are comparable to the annual rate of decline in FEV 1 that was reported in previous studies [4,13,14], even though this substudy  [7]. Noninferiority was evaluated for treatment main effects using a noninferiority δ of 50 mL. Abbreviations: FEV 1 = forced expiratory volume in 1 second trial reported a rate of FEV 1 decline of 33 mL/year [14]. The reduction in the rate of lung function decline may reflect improvements in COPD treatments and, at least in the case of the UPLIFT® trial, the use of other concomitant COPD medications in the placebo arm.
It has previously been reported that the rate of decline in FEV 1 in patients with COPD is highly variable, and that rates of decline are increased among current smokers, patients with bronchodilator reversibility, and patients with emphysema [14]. Rates of decline in trough  FEV 1 and FVC among the TIOSPIR® spirometry substudy population appeared higher among current smokers, in those receiving a long-acting betaadrenergic bronchodilator combined with a long-acting muscarinic antagonist/inhaled corticosteroid at baseline, and in those experiencing an exacerbation during the study. It remains to be determined whether the relative change in FEV 1 could be used as a predictor for subsequent exacerbations or whether an improvement in FEV 1 could be related to a reduction in exacerbation rate.
The rate of FEV 1 decline reflects the composition of the population and was less marked in more severe patients. When the mean rate of FEV 1 decline in the substudy population was calculated by disease severity (GOLD Stages I + II vs. III + IV), it was shown that the patients with less severe disease (GOLD I + II) exhibited a significantly faster annual rate of decline (46 mL) than  those with more severe disease (GOLD III + IV; 23 mL; p = 0.0017). This is in contrast with the landmark study of Fletcher and Peto (1977) [15], which described that the rate of decline ("slope") of FEV 1 was increased with time in susceptible smokers (showing a steeper decline with lower FEV 1 ), although this study did not include many patients with severe disease. However, Tantucci and Modina reviewed spirometric data of COPD patients included in the placebo arms of recent clinical trials to assess the lung function decline at different GOLD stages, and found that the loss of lung function, assessed as FEV 1 decline expiratory airflow reduction, seems accelerated and therefore more relevant in the initial phases of COPD (in particular GOLD Stage II), where FEV 1 is higher [16]. The results seen in the TIOS-PIR® substudy population support this observation. In the UPLIFT® study of tiotropium HandiHaler® 18 μg versus placebo, which was performed in 5992 patients over 4 years, the rate of FEV 1 decline also decreased with increasing disease severity (mean FEV 1 decline of 49, 38 and 23 mL/year for GOLD Stages II, III, and IV, respectively) [16,17]. Similar to a previous post-hoc analysis [18], the rate of FVC decline of patients in GOLD Stages I + II showed a trend toward being higher than that in GOLD III + IV patients in this substudy, but this did not reach statistical significance. We speculate that the loss of lung function in GOLD III and IV patients is likely to result from worsening air-trapping (increase in residual volume) as opposed to worsening airflow obstruction and expiratory flow limitation. Therefore, the rates of change of FVC and of the FEV 1 /FVC ratio are similar in the higher GOLD stages, while the loss of FEV 1 is slower, and the overall change in the FEV 1 /FVC ratio reflects this composite effect.
A limitation of this study is that TIOSPIR® did not include a placebo arm. It was, however, designed as such because high adherence and follow-up would have been difficult to achieve in a placebo group without effective symptom relief, and since tiotropium HandiHaler® 18 μg was previously shown to be associated with reduced ontreatment mortality compared with placebo [4,19,20], it was used as a control. Another limitation is the fact that although the TIOSPIR® study itself was very large (N = 17,135), the spirometry substudy included only 1370 patients. Nonetheless, the rate of decline observed in this study is within the same range as that observed in previous larger studies [4,13,14], validating the result in which there was no difference between the three treatment arms. Additionally, the analyses of rates of decline were post-hoc, and the trial was not designed to calculate rates of decline. As described in the Methods, rates of decline were calculated using data from Week 24 as an anchor, and the decline was calculated every 24 weeks afterwards. Strengths of the study include the use of spirometry centers with high expertise in performing PFTs, across nine countries and 112 sites. Furthermore, the period analyzed, although not as long as in the UPLIFT and TORCH studies (4 and 3 years, respectively), was substantial at over 2 years.