Spiriva Respimat

Chronic Obstructive Pulmonary Disease (COPD) 

The efficacy of Spiriva Respimat was compared with placebo in 6 clinical trials: one dose-ranging trial and 5 confirmatory trials (Trials 1–5). In addition, Spiriva Respimat was compared with Spiriva Handihaler in a long-term active-controlled trial in COPD (Trial 6).

COPD – 5 Confirmatory Trials

• The trials included a total of 6614 COPD patients who were randomly assigned 1:1 to receive either Spiriva Respimat 5 mcg (n=2801) or placebo (n=2798). Study participants had a clinical diagnosis of COPD, were 40 years of age and older, had a history of smoking greater than 10 pack-years, had an FEV1 ≤60% of predicted and a ratio of FEV1/FVC ≤0.7.

• Trials 1 and 2 were 12-week, randomized, double-blind, placebo- and active- (ipratropium) controlled trials that evaluated bronchodilation.

• Trials 3–5 were 48-week, randomized, double-blind, placebo-controlled, trials that evaluated bronchodilation and effects on COPD exacerbations.

• Trials 1-4 included both the tiotropium Respimat 5 mcg and 10 mcg doses; Trial 5 included only the 5 mcg dose. 

• Effect on Lung Function: All 5 confirmatory trials demonstrated that treatment with Spiriva Respimat 5 mcg achieved significant improvement in trough FEV1 compared with placebo. The following results are the difference in mean change from baseline in trough FEV1 (L) at end of treatment for Spiriva Respimat 5 mcg:

• Trial 1 – Difference from placebo, 0.11 (95% CI, 0.04-0.18)

• Trial 2 – Difference from placebo, 0.13 (95% CI, 0.07-0.18)

• Trial 3 – Difference from placebo, 0.14 (95% CI, 0.10-0.18)

• Trial 4 – Difference from placebo, 0.11 (95% CI, 0.08-0.15)

• Trial 5 – Difference from placebo, 0.14 (95% CI, 0.10-0.18)

• Exacerbations: Trials 3–5 also evaluated the effect of Spiriva Respimat 5 mcg on COPD exacerbations.

• In a pooled analysis, the Spiriva Respimat arm had a significant reduction in the number of COPD exacerbations with 0.78 exacerbations/patient year vs 1.0 exacerbations/patient year in the placebo arm (rate ratio of 0.78 [95% CI, 0.67-0.92]).

• Time to first exacerbation was also delayed in patients treated with Spiriva Respimat. In Trial 5, Spiriva Respimat 5 mcg delayed the time to first COPD exacerbation compared with placebo (hazard ratio of 0.69 [95% CI, 0.63-0.77]). Moreover, in Trial 5, the risk of COPD exacerbation-related hospitalization was reduced in the Spiriva Respimat 5 mcg arm  vs the placebo arm (hazard ratio of 0.73 [95% CI, 0.59-0.90]). 

• Survival: In a pooled analysis of Spiriva Respimat placebo-controlled trials with complete vital status (mortality) follow-up, including Trials 3–5 and one 24-week placebo-controlled trial, the Spiriva Respimat 5 mcg treatment arm had 68 deaths (Incidence Rate 2.64 deaths per 100 patient years) vs the placebo arm had 51 deaths (Incidence Rate 1.98 deaths per 100 patient years). Spiriva Handihaler had a similar incidence rate of death in a 4-year, randomized, double-blind, placebo-controlled trial.

• In the long-term, randomized, double-blind, double dummy, active-controlled trial (Trial 6), the all-cause mortality associated with Spiriva Respimat vs Spiriva Handihaler was evaluated with an observation period of up to 3 years. 

• A total of 5711 patients received Spiriva Respimat 5 mcg and 5694 received Spiriva Handihaler. The vital status (mortality) was confirmed in 99.7% of patients.

• All-cause mortality was similar between both treatment arms with an estimated hazard ratio of 0.96 (95% CI, 0.84-1.09).

• In a lung function sub-study, the effect on trough FEV1 was similar between both treatment arms with a mean difference of -0.010 L (95% CI, -0.038, 0.018 L).

• Spiriva Respimat 5 mcg did not achieve superiority to Spiriva Handihaler with a similar time to first COPD exacerbation (hazard ratio of 0.98 [95% CI, 0.93-1.03]).

Asthma

The efficacy of Spiriva Respimat was evaluated in six 4-week to 8-week crossover design clinical trials and ten 12-week to 48-week parallel-arm design trials in adult, adolescent (12–17yrs) and pediatric (1–11yrs) patients with asthma symptomatic on at least ICS. In all trials, Spiriva Respimat was administered on a background of ICS therapy. 

Asthma – 12-week to 48-week Parallel-Arm Design Trials in Adults

• Spiriva Respimat was evaluated in a total of 3476 adults with persistent asthma, which included one 12-week (Trial 1), two replicate 24-week (Trials 2 and 3), and two replicate 48-week (Trials 4 and 5) clinical trials. Patients were randomly assigned to receive Spiriva Respimat 2.5 mcg once daily (n=673), Spiriva Respimat 5 mcg once daily (n=1128), salmeterol 50 mcg twice daily (n=541), or placebo (n=1134).

• Trial 1 included 3 treatment arms: Spiriva 2.5 mcg, 5 mcg, and placebo. 

• Trials 2 and 3 included 4 treatment arms: Spiriva Respimat 2.5 mcg and 5 mcg, salmeterol 50 mcg, and placebo. Trials 4 and 5 included 2 treatment arms: Spiriva 5 mcg and placebo.

• Results from Trials 1, 2, and 3 showed that treatment with Spiriva 2.5 mcg achieved statistically significant improvements in lung function compared with placebo. In these trials, the 5 mcg dose had a generally lower FEV1 response compared with the 2.5 mcg dose. 

• In Trials 2 and 3, the rate of exacerbations and time to first asthma exacerbation was evaluated for the Spiriva Respimat 5 mcg dose. Compared with placebo, the rate of asthma exacerbations for the 5 mcg dose was 0.78 (95% CI, 0.55-1.10) in Trial 2 and 0.76 (95% CI, 0.50-1.16) in Trial 3. Compared with placebo, the hazard ratio for time to first asthma exacerbation for the 5 mcg dose was 0.72 (95% CI, 0.39-1.35) in Trial 2 and 0.72 (95% CI, 0.36-1.43) in Trial 3.

Asthma – 12-week to 48-week Parallel-Arm Design Trials in Adolescents 12-17 Years of Age

• The efficacy of Spiriva Respimat in adolescents was based on partial extrapolation of efficacy in adults and 2 trials of 12 and 48 weeks duration. A total of 789 patients 12 to 17 years of age with asthma were randomly assigned to receive either Spiriva Respimat 2.5 mcg once daily, 5 mcg once daily or placebo. The 12-week trial included patients with severe asthma on background ICS plus 1 or more controller medications (eg, LABA). The 48-week trial included patients with moderate asthma on at least background ICS.

• In adolescent patients, the mean difference in peak FEV1 (0-3hr) from placebo for Spiriva Respimat 2.5 mcg were 0.13 L (95% CI, 0.03-0.23) for the 48-week trial and 0.11 L (95% CI, 0.002-0.22) for the 12-week trial.

Asthma – 12-week to 48-week Parallel-Arm Design Trials in Adolescents 6-11 Years of Age

• The efficacy of Spiriva Respimat in adolescents was based on partial extrapolation of efficacy in adults and 2 trials of 12 and 48 weeks duration. A total of 801 patients 6 to 11 years of age with asthma were randomly assigned to receive either Spiriva Respimat 2.5 mcg once daily, 5 mcg once daily or placebo. The 12-week trial included patients with severe asthma on background ICS plus 1 or more controller medications (eg, LABA). The 48-week trial included patients with moderate asthma on at least background ICS.

• Compared with placebo, Spiriva Respimat 2.5 mcg once daily had a significant effect on the primary endpoint in the 48 week, but not the 12 week trial, with mean differences in peak FEV1 (0-3hr) from placebo of 0.17 L (95% CI 0.11, 0.23) and 0.04 L (95% CI -0.03, 0.10) for the 48-week and 12-week trials, respectively.