Spiriva Handihaler

The efficacy of Spiriva Handihaler was evaluated in six phase 3 studies which included 2663 patients with COPD (1308 receiving Spiriva Handihaler): two 1-year, placebo-controlled studies, two 6-month, placebo-controlled studies and two 1-year, ipratropium-controlled studies. Eligible patients included a clinical diagnosis of COPD, were 40 years of age or older, had a history of smoking greater than 10 pack-years, had a forced expiratory volume in one second (FEV₁) less than or equal to 60% or 65% of predicted, and a ratio of FEV₁/FVC of less than or equal to 0.7. Patients received Spiriva Handihaler once-daily in the morning. Results showed that treatment with Spiriva Handihaler provided improvement in lung function (FEV₁), with peak effect occurring within 3 hours following the first dose.

The efficacy of Spiriva Handihaler was also evaluated for exacerbations in 2 additional trials: a 6-month, randomized, double-blind, placebo-controlled, multicenter clinical trial of 1829 COPD patients in a US Veterans Affairs setting and a 4-year, randomized, double-blind, placebo-controlled, multicenter, clinical trial of 5992 COPD patients. Long-term effects on lung function and other outcomes, were also evaluated in the 4-year multicenter trial.

6-Month to 1-Year Effects on Lung Function

In the 1-year, placebo-controlled trials:

• Mean improvement in FEV₁ at 30 minutes was 0.13 liters (13%) with a peak improvement of 0.24 liters (24%) relative to baseline after the first dose (Day 1).

• Mean peak improvement in FEV₁, relative to baseline, was 0.28 to 0.31 liters (28% to 31%), after 1 week (Day 8) of once-daily treatment.

• Improvement of lung function was maintained for 24 hours after a single dose and consistently maintained over the 1-year treatment period with no evidence of tolerance. 

In the two 6-month, placebo-controlled trials: (see full labeling for Figure 1 and 2)

• Serial spirometric evaluations were performed throughout daytime hours in Trial A (12 hours) and limited to 3 hours in Trial B. The serial FEV₁ values over 12 hours (Trial A) are displayed in Figure 1. These trials further support the improvement in pulmonary function (FEV₁) with Spiriva Handihaler, which persisted over the spirometric observational period. Effectiveness was maintained for 24 hours after administration over the 6-month treatment period. 

• Results of each of the 1-year ipratropium-controlled trials were similar to the results of the 1-year placebo-controlled trials. The results of one of these trials are shown in Figure 2.

In a randomized, placebo-controlled clinical study, the administration of Spiriva Handihaler in the morning or in the evening to 105 patients with COPD showed that bronchodilation was maintained throughout the 24-hour dosing interval compared with placebo. 

Throughout each week of the 1-year treatment period in the two placebo-controlled trials, treatment with Spiriva Handihaler had a reduced requirement for the use of rescue short-acting beta2-agonists. In 1 of the two 6 month studies, there was also a reduction in the use of rescue short-acting beta2-agonists with Spiriva Handihaler compared with placebo.

4-Year Effects on Lung Function: (see full labeling for Figure 3)

In a 4-year, randomized, double-blind, placebo-controlled, multicenter clinical trial, the long-term effects of Spiriva Handihaler were evaluated in 5992 COPD patients on disease progression (rate of decline in FEV₁). Patients were allowed to use all respiratory medications (including short-acting and longacting beta-agonists, inhaled and systemic steroids, and theophyllines) other than inhaled anticholinergics. 

The trial included patients 40 to 88 years of age, 75% male, and 90% Caucasian with a diagnosis of COPD and a mean pre-bronchodilator FEV₁ of 39% predicted (range = 9% to 76%) at study entry. There was no difference between the groups in either of the co-primary efficacy endpoints, yearly rate of decline in pre- and post-bronchodilator FEV₁, as demonstrated by similar slopes of FEV₁ decline over time. 

Spiriva Handihaler maintained improvements in trough (pre-dose) FEV₁ (adjusted means over time: 87 to 103 mL) throughout the 4 years of the study.

Exacerbations

The effect of Spiriva Handihaler on COPD exacerbations was evaluated in 2 clinical trials: a 4-year clinical trial described above and a 6-month clinical trial of 1829 COPD patients in a Veterans Affairs setting. 

In the 6-month trial, COPD exacerbations were defined as a complex of respiratory symptoms (increase or new onset) of more than 1 of the following: cough, sputum, wheezing, dyspnea, or chest tightness with a duration of at least 3 days requiring treatment with antibiotics, systemic steroids, or hospitalization. Patients were permitted to use respiratory medications (including short-acting and long-acting beta-agonists, inhaled and systemic steroids, and theophyllines) other than inhaled anticholinergics. The coprimary endpoints were the proportion of patients with COPD exacerbation and the proportion of patients with hospitalization due to COPD exacerbation. 

Results showed that treatment with Spiriva Handihaler significantly reduced the proportion of COPD patients who experienced exacerbations compared to placebo (27.9% vs. 32.3%, respectively; Odds Ratio (OR) (tiotropium/placebo) = 0.81; 95% CI, 0.66-0.99; P =.037). There was a lower proportion of patients treated with Spiriva Handihaler who were hospitalized due to COPD exacerbations compared to those treated with placebo, 7.0% vs. 9.5%, respectively (OR = 0.72; 95% CI, 0.51-1.01; P =.056). 

In the 4-year multicenter trial, exacerbations were evaluated as a secondary outcome and were defined as an increase or new onset of more than 1 of the following respiratory symptoms (cough, sputum, sputum purulence, wheezing, dyspnea) with a duration of 3 or more days requiring treatment with antibiotics and/or systemic (oral, intramuscular, or intravenous) steroids. Spiriva Handihaler significantly reduced the risk of an exacerbation by 14% (Hazard Ratio (HR) = 0.86; 95% CI, 0.81-0.91; P <.001) and reduced the risk of exacerbation-related hospitalization by 14% (HR = 0.86; 95% CI, 0.78-0.95; P <.002) compared to placebo. The median time to first exacerbation was delayed from 12.5 months (95% CI, 11.5-13.8) in the placebo group to 16.7 months (95% CI, 14.9-17.9) in the Spiriva Handihaler group. 

All-Cause Mortality

In the 4-year placebo-controlled lung-function trial described above, the effects of Spiriva Handihaler on all-cause mortality was assessed compared to placebo. There were no significant differences in all-cause mortality rates between Spiriva Handihaler and placebo. The all-cause mortality of Spiriva Handihaler was also compared to tiotropium inhalation spray 5 mcg (Spiriva Respimat 5 mcg) in an additional long-term, randomized, double-blind, double-dummy active-controlled study with an observation period up to 3 years. All-cause mortality was similar between Spiriva Handihaler and Spiriva Respimat.