Landmark TIOSPIRTM trial reinforces importance of SPIRIVA® in both available formulations as the world’s leading maintenance therapy for chronic obstructive pulmonary disease (COPD)

Professor Antonio Anzueto, Professor of Medicine Pulmonary/Critical Care Medicine, University of Texas Health Science Center at San Antonio, Texas, USA

TIOSPIR™ (TIOtropium Safety and Performance In Respimat), with over 17,000 COPD patients included and one of the largest international COPD trials ever conducted, confirmed the comparable safety and efficacy profile of the two available SPIRIVA® formulations – SPIRIVA® Respimat® 2.5 μg (once a day, 2 puffs) and SPIRIVA® HandiHaler® 18 μg.1 The trial included two SPIRIVA® delivery devices, the unique Respimat® Soft Mist™ Inhaler and the dry powder inhaler HandiHaler®.1

The highly anticipated results from the three year trial were published in the New England Journal of Medicine (on 8 September 2013). TIOSPIR™ was designed to provide evidence of the relative safety and efficacy profile of SPIRIVA® Respimat® 2.5 μg (once a day, 2 puffs) or an investigational dose of Respimat® 1.25 μg (once a day, 2 puffs)§ compared with SPIRIVA® HandiHaler® 18 µg. TIOSPIR™ was specifically designed to be of an adequate size and duration, to enable analysis of all-cause mortality and time to first COPD exacerbation in a large COPD patient population, with broad inclusion criteria, that closely reflects the real-world COPD patient population.1

Professor Antonio Anzueto, Professor of Medicine Pulmonary/Critical Care Medicine, University of Texas Health Science Center at San Antonio, Texas, USA

Commenting on the results, trial investigator Professor Antonio Anzueto, Professor of Medicine Pulmonary/Critical Care Medicine, University of Texas Health Science Center at San Antonio, Texas, USA, said “TIOSPIR™ is a landmark clinical trial providing a robust data set that reinforces the safety and efficacy of tiotropium delivered by either HandiHaler® or Respimat®. Importantly, this large and rigorous clinical trial provides evidence that tiotropium is safe in a broad population of COPD patients, including those with a history of cardiac disease. The critical message from this large-scale TIOSPIR™ trial is that physicians can be confident that they can prescribe this proven maintenance therapy across the severity spectrum of COPD patients.”

Efficacy as measured by time to first COPD exacerbation

The TIOSPIRTM trial demonstrated comparable results for time to first COPD exacerbation for all available formulations of SPIRIVA®. In particular, the median time to COPD exacerbation was more than 2 years for both formulations. For SPIRIVA® Respimat® 2.5 µg (once a day, 2 puffs) this was 756 days compared to 719 days for SPIRIVA® HandiHaler® 18 µg.1

COPD exacerbations have a significant impact on patients’ lives3,4,5,6 and reducing their frequency and severity are principal goals of COPD treatment.7 The TIOSPIR™ results demonstrate that Respimat® and HandiHaler® showed comparable results for time to first COPD exacerbation, exacerbation frequency as well as rate of COPD exacerbations associated with hospitalisation. TIOSPIR™ builds upon the established efficacy profile of SPIRIVA® as demonstrated in several trials, including the four year UPLIFT®**2 trial as well as a large-scale trial, POET-COPD®†† , that was specifically powered to investigate COPD exacerbations.8

• In the UPLIFT®** trial, SPIRIVA® 18 µg via HandiHaler® was associated with a reduction in the risk of exacerbations, related hospitalisations and respiratory failure vs. control (placebo)2,9
• SPIRIVA® 18 µg via HandiHaler® demonstrated a 28% reduction in the risk of a COPD exacerbation leading to hospitalisation vs. the active comparator, the long-acting beta2 agonist salmeterol, as observed in the POET-COPD®†† trial8
• In a separate trial, SPIRIVA® Respimat® 2.5 µg (once a day, 2 puffs)had a significant reduction in the risk of COPD exacerbations vs placebo in the magnitude of 31%‡‡10

Safety as measured by survival rates

The three year TIOSPIR™ trial also showed an equal impact on survival – as measured by all-cause mortality for tiotropium (SPIRIVA® Respimat® 2.5 µg (once a day, 2 puffs) vs. HandiHaler® 18 µg).1 This adds to evidence from the UPLIFT®** trial in which SPIRIVA® HandiHaler® (18 µg) reduced the risk of on-treatment mortality in COPD patients by 16% vs. control (placebo) (P=0.016) and suggests an equally beneficial effect of the two available SPIRIVA® formulations on survival.2

Importantly TIOSPIR™ also demonstrated that:

• The incidence of adverse events and major adverse cardiovascular events was similar between the treatment groups1
• In patients with a history of cardiac arrhythmia, SPIRIVA® Respimat® 2.5 μg (once a day, 2 puffs) and SPIRIVA® HandiHaler® 18 µg showed similar impact on survival as measured by all-cause mortality1

About TIOSPIR™1

TIOtropium Safety and Performance In Respimat® (TIOSPIR™), a global landmark trial in more than 17,000 patients, was one of the largest chronic obstructive pulmonary disease (COPD) trials ever conducted. Participants were recruited between May 2010 and April 2011 and were randomised to treatment in more than 1,200 investigator sites in 50 countries. The trial compared the safety and efficacy of SPIRIVA® Respimat® Soft Mist™ Inhaler 2.5 μg (once a day, 2 puffs)§§ or the investigational dose Respimat® 1.25 μg (once a day, 2 puffs)*** with SPIRIVA® HandiHaler® 18 µg. Over the 3-year duration of the trial, TIOSPIR™ demonstrated that SPIRIVA® Respimat® 5 μg or 2.5 µg have similar exacerbation safety and efficacy outcomes to the well-established profile of SPIRIVA® HandiHaler® 18 µg in COPD. In a spirometry substudy of TIOSPIR™, involving 1,370 participants, Respimat® 5μg was non-inferior to HandiHaler® for FEV1, but the investigational dose Respimat® 2.5 μg was not.

SPIRIVA® is delivered via HandiHaler®, a breath-actuated, single-dose dry powder inhaler, or by SPIRIVA® Respimat® Soft Mist Inhaler™ propellant-free, new generation inhaler that combines innovative technology with the proven efficacy of SPIRIVA®.

About SPIRIVA® (tiotropium bromide) in COPD

SPIRIVA®, a long-acting anticholinergic medication, is the first inhaled maintenance treatment to provide significant and sustained improvements in lung function with once-daily dosing. SPIRIVA® positively impacts the clinical course of COPD, helping to change the way patients live with their disease.11 It is the most prescribed maintenance therapy for COPD worldwide.12 SPIRIVA® helps COPD patients breathe more easily by opening narrowed airways and helping to keep them open for 24 hours. SPIRIVA® works through targeting of a dominant reversible mechanism of COPD – cholinergic bronchoconstriction.

SPIRIVA® is delivered via HandiHaler®, a breath-actuated, single-dose dry powder inhaler, or by SPIRIVA® Respimat® Soft Mist Inhaler™ propellant-free, new generation inhaler that combines innovative technology with the proven efficacy of SPIRIVA®.

References

1. Wise RA, Anzueto A, Cotton D, et al. Tiotropium Respimat Inhaler and the Risk of Death in COPD: The TIOSPIR Trial. N Engl J Med 2013; 369(10) DOI: 10.1056/NEJMoa1303342. (Presented at European Respiratory Society Congress 2013, Barcelona, Spain. TIOSPIR®: Large scale trial of tiotropium Respimat® vs HandiHaler® (HH) in patients (pts) with COPD. Abstract P752, Sunday 8 September 2013).
2. Tashkin DP, Celli B, Senn S, et al, on behalf of the UPLIFT® (Understanding Potential Long-term Impacts on Function with Tiotropium) study investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359:1543-1554.
3. Soler-Cataluña JJ, Martínez-García MÁ, Román Sánchez P, et al. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax 2005;60:925–31.
4. Wedzicha JA, Seemungal TA. COPD exacerbations: defining their cause and prevention. Lancet 2007;370:786–96.
5. Miravitlles M, Anzueto A, Legnani D, et al. Patient’s perception of exacerbations of COPD – the PERCEIVE study. Respir Med 2007;101(3):453–60.
6. Donaldson GC, Seemungal TAR, Bhowmik A, et al. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax 2002;57:847–52.
7. GOLD. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease. 2013. http://www.goldcopd.org/guidelines-global-strategy-for-diagnosis-management.html. (Accessed: June 2013).
8. Vogelmeier C, Hederer B, Glaab T, et al. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. N Engl J Med 2011;364(12):1093-1103.
9. Celli B, Decramer M, Kesten S, et al. Mortality in the 4-Year Trial of Tiotropium (UPLIFT) in Patients with Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med 2009;180:948-955.
10. Bateman E, Tashkin D, Siafakas N, et al. The one-year trial of tiotropium Respimat plus usual therapy in COPD patients. Respir Med 2010; 104: 1460-1472.
11. Vincken W, van Noord JA, Greefhorst APM, et al. Improved health outcomes in patients with COPD during 1 year’s treatment with tiotropium. Eur Respir J 2002;19:209-216.
12. IMS Health, IMS MIDAS™, Q2 2012.

*This is the marketed dose referred to in the NEJM TIOSPIR™ publication as tiotropium Respimat® 5 µg

†In UPLIFT®, a trial of nearly 6,000 patients, SPIRIVA® 18 µg via HandiHaler® reduced risk of on-treatment mortality vs. control (placebo). While SPIRIVA® 18 µg via HandiHaler® did not alter the rate of decline in lung function, a coprimary study endpoint in the UPLIFT® study, it sustained greater improvements in lung function vs. control (placebo)

‡The GOLD report (international guidelines developed by the Global Initiative for Obstructive Lung Disease) classifies COPD patients into groups A-D, based on a combination of spirometry results, severity of symptoms, and risk of exacerbations

§The investigational dose of SPIRIVA® Respimat®, 1.25 µg (once a day, 2 puffs) is referred to in the NEJM TIOSPIR™ publication as tiotropium Respimat® 2.5 µg

**While SPIRIVA® 18 µg via HandiHaler® did not alter the rate of decline in lung function, a coprimary study endpoint in the UPLIFT® study, it sustained greater improvements in lung function vs. control (placebo)

†† The POET-COPD® trial was a 1-year, randomised, double-blind, double-dummy, parallel-group trial with a primary endpoint of time to first exacerbation, comparing once-daily SPIRIVA® 18 μg via HandiHaler® with twice-daily salmeterol 50 μg via HFA-pMDI

‡‡SPIRIVA® Respimat® should be used with caution in patients with known cardiac rhythm disorders.

§§This is the marketed dose referred to in the NEJM TIOSPIR™ publication as tiotropium Respimat® 5 µg

***The investigational dose of SPIRIVA® Respimat®, 1.25 µg (once a day, 2 puffs) is referred to in the NEJM TIOSPIR™ publication as tiotropium Respimat® 2.5 µg