The TIOSPIR™ Trial

THE TIOTROPIUM safety and performance in RESPIMAT® (TIOSPIR™) landmark trial.

TIOtropium Safety and Performance In Respimat® (TIOSPIR™), a landmark global 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 the two available SPIRIVA® formulations - SPIRIVA® Respimat® Soft Mist™ Inhaler 2.5 μg (once a day, 2 puffs*) and SPIRIVA® HandiHaler® 18 µg. A SPIRIVA® Respimat® 1.25 µg dose (once a day, 2 puffs † ) was also included for investigational purposes.

Over the 3-year duration of the trial, TIOSPIR™ demonstrated that SPIRIVA® Respimat® 2.5 μg or 1.25 μg has similar safety outcomes and exacerbation efficacy to the well-established profile of SPIRIVA® HandiHaler® 18 µg in COPD.1
 

Rationale

From the extensive large-scale SPIRIVA® clinical trials with over 31 million patient-years of experience, ‡ SPIRIVA® has proven to be an effective maintenance therapy for COPD patients2,3,4,5,6

  • In the UPLIFT®§ trial SPIRIVA® HandiHaler® 18 µg reduced the risk of exacerbations leading to hospitalisations by 14% and the risk of on-treatment mortality in COPD patients by 16% versus control (placebo)7
  • The POET-COPD® ** study results demonstrated that SPIRIVA® HandiHaler® 18 µg was superior to the long-acting beta2-agonist salmeterol in reducing the risk of COPD exacerbations leading to hospitalisation by 28% (P<0.001) over the course of one year2

  • In a 1-year trial SPIRIVA®Respimat®2.5 μg (once a day, 2 puffs) reduced the risk of COPD exacerbations by 31% versus control (placebo) (P<0.0001)6 

Certain meta-analyses of earlier SPIRIVA®Respimat®data have shown a numerical imbalance in the number of deaths with SPIRIVA®Respimat®2.5 μg (once a day, 2 puffs) as compared to Respimat®placebo (which was not statistically significant), particularly in patients with known cardiac disorders.8,9To provide further evidence on the relative safety and efficacy of the two formulations of SPIRIVA®, Boehringer Ingelheim initiated the TIOSPIR™ trial. 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.10In addition, the trial results enabled further analysis of specific sub-populations of patients such as those with prior cardiac disorders. 
 

Study Design

TIOSPIR™ was an event-driven trial that ran for three years. This large-scale, randomised, double-blind, double-dummy, parallel-group, trial was designed to continue until a pre-defined number of deaths was reached based on all-cause mortality rates observed in previous trials. The three treatment arms were: 

  • SPIRIVA®Respimat®2.5 μg (once a day, 2 puffs) 
  • SPIRIVA®Respimat®1.25 μg (once a day, 2 puffs) 
  • SPIRIVA®HandiHaler®18 μg 

The Respimat®1.25 μg (once a day, 2 puffs) arm was included because it is being investigated in clinical trials in a fixed-dose combination with a long-acting beta2-agonist.10A placebo arm was not included because it would be impractical to maintain high levels of adherence and follow up without effective symptom-controlling therapy in such a large population.1 

In order to closely reflect the real-world COPD patient population, a broad spectrum of COPD patients – all COPD disease assessment categories (GOLD†† groups A to D) – were included in TIOSPIR™. The trial enrolled participants aged ≥40 years with a clinical diagnosis of COPD, ≥10 pack-years’ smoking history, postbronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio ≤0.70, and FEV1 ≤70% predicted. Participants with concomitant cardiac disease were included unless they had myocardial infarction within six months, were hospitalised for Class III/IV heart failure, or had unstable or life-threatening arrhythmia requiring new treatment within 12 months. All COPD medications except other inhaled anticholinergics were allowed.10
 

Study Endpoints

The primary safety outcome was time to death from any cause. The primary efficacy outcome was time to first COPD exacerbation. COPD exacerbations were defined as ≥2 worsening respiratory symptoms (dyspnoea, cough, sputum, chest tightness, or wheezing) of ≥3 days’ duration requiring specified treatment changes. Mild exacerbations required new prescription of a maintenance bronchodilator only; moderate exacerbations, antibiotics, or systemic corticosteroids or both; and severe exacerbations required hospitalisation.1 

Secondary outcome measures included:1 

  • Number of COPD exacerbations 
  • Time to first moderate or severe exacerbation 
  • Time to and number of severe exacerbations 
  • Time to first major adverse CV even 
     

Efficacy Results

SPIRIVA®Respimat®2.5 μg (once a day, 2 puffs) and SPIRIVA®HandiHaler®18 μg demonstrated comparable COPD exacerbation efficacy1 

  • SPIRIVA®Respimat®2.5 μg (once a day, 2 puffs) and SPIRIVA®HandiHaler®18 μg showed comparable results for median time to COPD exacerbation (the difference between the two treatment groups was not statistically significant):1 
  • SPIRIVA®Respimat®2.5 μg (once a day, 2 puffs) and SPIRIVA®HandiHaler®18 μg showed comparable results for rate of COPD exacerbations and rate of COPD exacerbations associated with hospitalisation1
     

Established Efficacy

In a separate trial, SPIRIVA®Respimat®2.5 μg (once a day, 2 puffs) reduced the risk of COPD exacerbations versus control (placebo)6
 

Safety Results

SPIRIVA®Respimat®and SPIRIVA®HandiHaler®18 μg showed similar impact on survival as measured by all-cause mortality1 

  • 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 
     

Established Safety

In a separate trial, UPLIFT®‡‡, a trial in nearly 6,000 patients, SPIRIVA®HandiHaler®18 μg reduced risk of on-treatment mortality versus control (placebo)7 
 

Adverse Events

In the TIOSPIR™ trial, the incidence of adverse events was similar between treatment groups1 

  • Serious adverse events were reported in 33% of participants. As expected, the highest rates of serious adverse events were lung disorders for all three treatment groups (17.8%, 16.8%, and 17.0%, for Respimat®1.25 μg, 2.5 μg, and HandiHaler®, respectively)1 
  • Overall incidence of major adverse CV events was 3.9%, 3.9%, and 3.6% in the Respimat®1.25 μg, 2.5 μg, and HandiHaler®18 μg treatment groups, respectively1 
     

Conclusion

  • In TIOSPIR™, time to first COPD exacerbation was comparable for both SPIRIVA®available formulations Respimat®2.5 μg (once a day, 2 puffs) and HandiHaler®18 μg1 
  • Building on the survival benefit of SPIRIVA®HandiHaler®18 μg versus control in the milestone trial UPLIFT®‡‡, the TIOSPIR™ trial showed a similar impact on survival between SPIRIVA®Respimat®2.5 μg (once a day, 2 puffs) and SPIRIVA®HandiHaler®18 μg1,7 
  • TIOSPIR™ reinforces the safety and efficacy of SPIRIVA®in COPD patients, with or without a history of cardiac arrhythmias1,6,7 

Footnotes

*This is the marketed dose referred to in the NEJM TIOSPIR™ publication as tiotropium Respimat® 5 μg 
†This is an investigational dose that is referred to in the NEJM TIOSPIR™ publication as tiotropium Respimat® 2.5 μg 
‡Combined figures for HandiHaler® and Respimat® 
§In UPLIFT, a trial of nearly 6,000 patients, SPIRIVA 18 μg via HandiHaler reduced risk of on-treatment mortality versus 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 versus 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  
††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  
‡‡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 versus control (placebo) 

Reference

  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. 
  2. 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. 
  3. Anzueto A, Tashkin D, Menjoge S, et al. One-year analysis of longitudinal changes in spirometry in patients with COPD receiving tiotropium. Pulm Pharmacol Ther 2005;18:75-81. 
  4. Celli B, ZuWallack R, Wang S, et al. Improvement in resting inspiratory capacity and hyperinflation with tiotropium in COPD patients with increased static lung volumes. Chest 2003;124:1743-1748. 
  5. Casaburi R, Mahler DA, Jones PW, et al. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J. 2002;19(2):217-224. 
  6. 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. 
  7. 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. 
  8. Jenkins C, Beasley R. Tiotropium Respimat increases the risk of mortality. Thorax 2013;68(1):1-5. 
  9. Dong YH, Lin HH, Shau WY, et al. Comparative safety of inhaled medications in patients with chronic obstructive pulmonary disease: systematic review and mixed treatment comparison meta-analysis of randomised controlled trials. Thorax 2013;68:48-56. 
  10. Wise RA, Anzueto A, Calverley P, et al. The Tiotropium Safety and Performance in Respimat®Trial (TIOSPIR™), a large-scale, randomized,  controlled, parallel group trial – design and rationale. Respir Res. 2013;14(40):1-7.