Spiriva HandiHaler (Page 4 of 7)

14 CLINICAL STUDIES

The SPIRIVA HANDIHALER (tiotropium bromide inhalation powder) clinical development program consisted of six Phase 3 studies in 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. These studies enrolled patients who had 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.

In these studies, SPIRIVA HANDIHALER, administered once-daily in the morning, provided improvement in lung function (FEV₁ ), with peak effect occurring within 3 hours following the first dose.

Two additional trials evaluated exacerbations: 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, the 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). Further improvements in FEV₁ and forced vital capacity (FVC) were observed with pharmacodynamic steady state reached by Day 8 with once-daily treatment. The 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, 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.

* Means adjusted for center, treatment, and baseline effect. On Day 169, a total of 183 and 149 patients in the SPIRIVA HANDIHALER and placebo groups, respectively, completed the trial. The data for the remaining patients were imputed using the last observation or least favorable observation carried forward.
Figure 1 Mean FEV1 Over Time (prior to and after administration of study drug) on Days 1 and 169 for Trial A (a Six-Month Placebo-Controlled Study)*
Day 1	Day 169
(click image for full-size original)	(click image for full-size original)

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.

* Means adjusted for center, treatment, and baseline effect. On Day 92 (primary endpoint), a total of 151 and 69 patients in the SPIRIVA HANDIHALER and ipratropium groups, respectively, completed through 3 months of observation. The data for the remaining patients were imputed using the last observation or least favorable observation carried forward.
Figure 2 Mean FEV1 Over Time (0 to 6 hours post-dose) on Days 1 and 92, Respectively for One of the Two Ipratropium-Controlled Studies *
Day 1	Day 92
(click image for full-size original)	(click image for full-size original)

A randomized, placebo-controlled clinical study in 105 patients with COPD demonstrated that bronchodilation was maintained throughout the 24-hour dosing interval in comparison to placebo, regardless of whether SPIRIVA HANDIHALER was administered in the morning or in the evening.

Throughout each week of the 1-year treatment period in the two placebo-controlled trials, patients taking SPIRIVA HANDIHALER had a reduced requirement for the use of rescue short-acting beta₂ -agonists. Reduction in the use of rescue short-acting beta₂ -agonists, as compared to placebo, was demonstrated in one of the two 6-month studies.

4-Year Effects on Lung Function

A 4-year, randomized, double-blind, placebo-controlled, multicenter clinical trial involving 5992 COPD patients was conducted to evaluate the long-term effects of SPIRIVA HANDIHALER on disease progression (rate of decline in FEV₁ ). Patients were permitted to use all respiratory medications (including short-acting and long-acting beta-agonists, inhaled and systemic steroids, and theophyllines) other than inhaled anticholinergics. The patients were 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 (Figure 3).

SPIRIVA HANDIHALER maintained improvements in trough (pre-dose) FEV₁ (adjusted means over time: 87 to 103 mL) throughout the 4 years of the study (Figure 3).

Figure 3 Trough (pre-dose) FEV₁ Mean Values at Each Time Point

Repeated measure ANOVA was used to estimate means. Means are adjusted for baseline measurements. Baseline trough FEV₁ (observed mean) = 1.12. Patients with ≥3 acceptable pulmonary function tests after Day 30 and non-missing baseline value were included in the analysis.

Exacerbations

The effect of SPIRIVA HANDIHALER on COPD exacerbations was evaluated in two 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 one 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. The population had an age ranging from 40 to 90 years with 99% males, 91% Caucasian, and had COPD with a mean pre-bronchodilator FEV₁ percent predicted of 36% (range = 8% to 93%). 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. In the 6-month trial, the co-primary endpoints were the proportion of patients with COPD exacerbation and the proportion of patients with hospitalization due to COPD exacerbation. 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 = 0.037). The proportion of patients with hospitalization due to COPD exacerbations in patients who used SPIRIVA HANDIHALER compared to placebo was 7.0% vs. 9.5%, respectively; OR = 0.72; 95% CI = 0.51, 1.01; p = 0.056.

Exacerbations were evaluated as a secondary outcome in the 4-year multicenter trial. In this trial, COPD exacerbations were defined as an increase or new onset of more than one of the following respiratory symptoms (cough, sputum, sputum purulence, wheezing, dyspnea) with a duration of three 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<0.001) and reduced the risk of exacerbation-related hospitalization by 14% (HR = 0.86; 95% CI = 0.78, 0.95; p<0.002) 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, all-cause mortality compared to placebo was assessed. 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.