Tiotropium (Spiriva; Ba679BR) is a new-generation, long-acting anticholinergic bronchodilator that has muscarinic M1 and M3 receptor subtype selectivity. A multicenter, randomized, double-blind, parallel group, placebo-controlled study was conducted to evaluate the dose–response characteristics of tiotropium inhalation powder given once daily to stable patients with chronic obstructive pulmonary disease (COPD). Patients (mean FEV1 = 1.08 L [42% predicted]) were randomized to receive 0, 4.5, 9, 18, or 36 μ g tiotropium once daily at noon for 4 wk, with spirometry done before and hourly for 6 h after dosing. Patients measured and recorded their peak expiratory flow rates (PEFRs) three times each day. Significant dose-related improvement in FEV1 and significant improvement in FVC occurred within 1 h after the first dose of tiotropium as compared with placebo. Over the 29 d of the study, all doses of tiotropium produced significant increases over placebo in trough (i.e., as measured spirometrically at 20 to 24 h after the previous dose and just before the next dose of tiotropium), peak, and 6-h postdose average FEV1 and FVC, and in PEFR, without a significant difference among the different doses investigated. PEFR gradually returned to pretreatment baseline levels over a 3-wk evaluation period following the discontinuation of tiotropium. The overall safety profile for the tiotropium doses was similar to that for placebo. In summary, tiotropium was shown to be safe and effective in doses ranging from 4.5 to 36 μ g delivered once daily. The improvements in spirometry with once-daily dosing confirm the long duration of action of tiotropium reported in single-dose studies, and its sustained improvement of spirometric measures over the 1 mo of testing in the study points to utility of tiotropium as a maintenance bronchodilator for patients with COPD. On the basis of the comparable bronchodilator response at doses from 9 to 36 μ g, and advantages suggested by the safety profile at doses below 36 μ g in this study, a dose of 18 μ g once daily was selected for use in long-term studies of the safety and efficacy of tiotropium.
Bronchodilation is a critical part of the management of chronic obstructive pulmonary disease (COPD), and treatment with inhaled anticholinergic drugs is an important part of the pharmacologic armamentarium for this disease (1-3). Tiotropium (Spiriva) is a new-generation anticholinergic agent that is structurally related to the quaternary ammonium compound ipratropium bromide (4). A unique property of tiotropium is its long duration of action, which is probably due to slow dissociation of the compound from the muscarinic M3 receptor found on bronchial smooth muscle (5). In studies of isolated guinea pig and human airway, tiotropium demonstrated prolonged muscarinic blockade (6). Thus, subsequent clinical development focused on the potential of tiotropium as for maintenance bronchodilator treatment of patients with COPD.
In early human pharmacology studies, tiotropium produced bronchodilation and prolonged muscarinic antagonism following single doses in patients with mild asthma. O'Connor and colleagues (7) demonstrated bronchodilation (> 24 h) and protection against methacholine-induced bronchoconstriction at doses of 10, 40, and 80 μg of tiotropium bromide (equivalent to 9, 36, and 72 μg of tiotropium base). In their study, protection was demonstrated for 48 h. In early trials in patients with COPD, prolonged bronchodilation was observed after single inhalations of tiotropium bromide at doses ranging from 9 to 72 μg (8, 9).
This report describes the first evaluation of the efficacy and safety of multiple dosing of tiotropium in patients with COPD. We evaluated 169 patients who were randomized to receive placebo or tiotropium at doses of 4.5, 9, 18, and 36 μg over a period of 29 d.
Male or female patients, aged 40 yr or older, with a smoking history of at least 10 pack-year and a diagnosis of COPD, were eligible for the study. COPD was defined as relatively stable, moderate to severe airway obstruction, with an FEV1 above 30% and less than 65% of predicted normal and an FEV1-to-FVC ratio of less than 70% (10). Reversibility of obstruction in response to any bronchodilator was not required. Subjects were excluded from the study if they had a clinical diagnosis of asthma, allergic rhinitis, or atopy; a total blood eosinophil count above 600/mm3; or other significant disease. Patients were also excluded if they had a viral infection (including upper respiratory tract infections) within 6 wk before the screening visit for the study or at any time during the baseline period. Written informed consent was obtained from each subject in a form approved by the institutional review board of each study institution.
Patients were randomly assigned to one of the following five treatment groups: placebo, 4.5 μg tiotropium, 9 μg tiotropium, 18 μg tiotropium, or 36 μg tiotropium. Tiotropium and placebo were formulated as capsules containing dry powder for oral inhalation. The doses were administered once daily at noon, through a dry powder inhalation device. This device utilizes a single capsule that is punctured by pressing a side button on the device. Powder is evacuated and carried into the lungs by the patient's inspiratory flow (11).
Concomitant medications allowed during the course of the study included short-acting β-agonists on an as-needed basis. Theophylline and inhaled glucocorticosteroids were allowed only if the dose of these drugs had been stabilized for at least 6 wk before randomization, and remained so throughout the study period. These medications were washed out for 12 to 24 h before testing on pulmonary function test days. Oral glucocorticosteroids were prohibited for at least 3 mo before randomization and throughout the study period. Anticholinergic drugs were allowed during the baseline period but not during the treatment or posttreatment periods of the study. Long-acting inhaled bronchodilators (salmeterol) were not allowed during the study or for 2 wk before baseline and randomization. Likewise, oral β-agonists and cromolyn sodium were not allowed during the study and were prohibited for 1 mo before (oral β-agonists) and 6 mo before (cromolyn sodium) screening.
On pulmonary function test days, the study medication was administered in the presence of the study-site personnel. On all other days the patient returned the empty capsules for an assessment of compliance.
The study comprised 10 visits, of which Visit 1 was the screening visit and Visits 2 and 3 the first and second baseline visits. The 29-d double-blind, randomized treatment period extended from Visits 3 to 7. Visits 8 to 10 were weekly posttreatment visits.
At the initial screening visit, eligibility for enrollment was assessed through a complete medical history, physical examination, laboratory evaluation, and 12-lead electrocardiogram (ECG). Pulmonary function testing for qualification was conducted in the morning, between 7:00 a.m. and noon. At the first baseline visit (Visit 2), subjects underwent pulmonary function testing at 8:00, 10:00, and 12:00 noon. Pulmonary function tests were performed with the patient in a seated position. The tests were performed in triplicate, and the results from the spirometric maneuver with the greatest sum of FEV1 and FVC were recorded.
During the 29-d double-blind treatment period, visits were made weekly. Visit 3, at 1 wk after Visit 2, was used to obtain a second set of baseline readings and to administer the first double-blind, randomized dose of study medication (tiotropium or placebo). Pulmonary function testing was conducted over a period of 4 h beginning at 8:00 a.m., with testing at 8:00, 10:00, and 12:00 noon. Study medication was then administered in the clinic, followed by testing at hourly intervals for 6 h. Visits 4 through 7 occurred on a weekly basis over the next 28 d. At Visits 4, 5, and 7, pulmonary function testing and administration of study medication were done in the same way as for Visit 3. The first 4 h of testing occurred from 20 to 24 h after the previous dose of study medication taken by the patient at home. At Visit 6, testing was done only for 4 h before study medication was administered. These times were chosen in order to characterize the 24-h dosing period.
Vital signs were measured at the same times as pulmonary function testing was done. A 12-lead ECG was obtained within 1 h before dosing and at 1, 3, and 5 h after dosing on each of the four test days.
During the 3-wk posttreatment period, patients were again seen weekly, when pulmonary function testing was performed (but only at the three times of 8:00, 10:00, and 12:00 a.m.). Throughout the baseline period, the double-blind treatment period, and the posttreatment period, patients recorded their peak expiratory flow rate (PEFR) three times daily. Patients made morning PEFR measurements immediately upon arising, after having cleared mucus from the chest. The midday measurement was made just before administration of study medication at noon, and the evening measurement was made at bedtime. Adverse events were identified at each visit, when the investigator asked patients how they felt since their last visit.
The efficacy data were analyzed with an analysis of covariance model with terms for treatment, center, and treatment-by-center interaction. The baseline data were used as covariates. Baseline spirometric data were defined as the average of the six measurements obtained on the two baseline study days (i.e., Visits 2 and 3). The dose–response relationship was evaluated with the linear-by-linear association test (12). Missing data for subjects who withdrew from the study before its completion because of worsening of their disease were estimated from these patients' least favorable data observed before their withdrawal. The missing data for those subjects who missed a visit for reasons unrelated to treatment efficacy were estimated from their last previously recorded data.
Efficacy measures in the study consisted of trough (primary endpoint), peak, and average FEV1 responses to the study medication. These were defined as: trough: the mean FEV1 value measured over the 4 h before medication administration, which corresponded to the period from 20 to 24 h after dosing on the previous day; peak: the highest FEV1 observed in the 6-h period immediately after medication administration; and average: the average of the FEV1 values measured over the 6-h postdosing interval. Changes from baseline in peak, average, and trough FVC, and the mean weekly morning, noon, and evening PEFRs, were also assessed.
A total of 252 subjects in nine centers were screened for entry into the study, 169 were randomized to a study group, and 162 completed all visits. Of the seven subjects who withdrew from the study, only one subject (receiving 9 mg tiotropium) did so for lack of efficacy, and only one subject (receiving placebo) withdrew because of an adverse event. The remaining five subjects withdrew for administrative reasons (e.g., noncompliance with the study protocol, loss to follow-up). A total of 165 subjects were included in the efficacy analyses. Four subjects were excluded from the efficacy analyses because of lack of adequate data during the double-blind treatment period. None of these subjects were among those who withdrew because of lack of efficacy or adverse events, and all decisions about their withdrawal were made prior to unblinding.
The baseline demographic features of the study population were similar across all treatment groups (Table 1). Overall, the mean age of the study subjects was 66 yr; 57% were male and 95% were Caucasian. The mean FEV1 at the screening visit was 1.08 L (42% predicted).
Tiotropium Bromide | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Placebo | 4.5 μg | 9 μg | 18 μg | 36 μg | Study Cohort | |||||||
n | 35 | 34 | 33 | 33 | 34 | 169 | ||||||
Age, yr | 67.3 ± 6.7 | 65.1 ± 9.4 | 65.8 ± 6.7 | 65.0 ± 9.7 | 65.5 ± 8.0 | 65.8 ± 8.1 | ||||||
M/F | 21/14 | 24/10 | 16/17 | 18/15 | 17/17 | 96/73 | ||||||
Duration of disease, yr | 6.9 ± 5.4 | 7.7 ± 7.0 | 9.3 ± 7.1 | 6.7 ± 7.1 | 6.9 ± 5.1 | 7.5 ± 6.4 | ||||||
Screening FEV1, (L) absolute | 1.01 ± 0.29 | 1.06 ± 0.33 | 1.10 ± 0.39 | 1.16 ± 0.34 | 1.06 ± 0.34 | 1.08 ± 0.34 | ||||||
Screening FEV1, % predicted | 40.5 ± 8.5 | 38.7 ± 9.7 | 44.0 ± 11.4 | 43.4 ± 10.2 | 42.3 ± 9.8 | 41.7 ± 10.0 |
The use of concomitant medications during the 2-wk baseline period was similar across all treatment groups: 80% of subjects used a β-agonist; 42% used an anticholinergic drug (ipratropium bromide); 41% were taking inhaled glucocorticosteroids; and 26% used theophylline preparations. This pattern was consistent with observations made in other, similar clinical trials (13).
Single dose response. There was a significant dose-related increase in FEV1 over time in response to the first dose of the study medication (p < 0.05) (Figure 1). All doses of tiotropium provided significant improvements in FEV1 as compared with placebo (p < 0.05).

Fig. 1. Mean change from predose FEV1 (liters) following first dose of study medication. A significant dose-related increase was seen over time, with all doses of tiotropium significantly superior to placebo. p < 0.05.
[More] [Minimize]The mean peak and average changes from baseline FEV1 and FVC over the 6-h observation period are summarized in Table 2. A similar pattern was evident with all doses of tiotropium, in that the increases were significantly greater than those after administration of placebo (p < 0.05).
Tiotropium Bromide | ||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Placebo | 4.5 μg | 9 μg | 18 μg | 36 μg | ||||||||||||||||
FEV1 | FVC | FEV1 | FVC | FEV1 | FVC | FEV1 | FVC | FEV1 | FVC | |||||||||||
Sample size | 33 | 33 | 33 | 3.3 | 33 | 33 | 33 | 33 | 33 | 33 | ||||||||||
Baseline: mean | 1.00 | 2.24 | 1.01 | 2.36 | 1.06 | 2.31 | 1.21 | 2.46 | 0.94 | 2.11 | ||||||||||
SE | (0.06) | (0.12) | (0.06) | (0.10) | (0.07) | (0.15) | (0.08) | (0.14) | (0.05) | (0.13) | ||||||||||
Peak response* mean | 0.05 | 0.17 | 0.15‡ | 0.34‡ | 0.22‡ | 0.43‡ | 0.24‡ | 0.47‡ | 0.23‡ | 0.45‡ | ||||||||||
SE | (0.01) | (0.04) | (0.02) | (0.04) | (0.03) | (0.06) | (0.03) | (0.07) | (0.04) | (0.06) | ||||||||||
Average response† mean | −0.02 | −0.01 | 0.05† | 0.13† | 0.12† | 0.25† | 0.13† | 0.29† | 0.16† | 0.28† | ||||||||||
SE | (0.01) | (0.03) | (0.02) | (0.04) | (0.02) | (0.06) | (0.02) | (0.06) | (0.03) | (0.05) |
Multiple dose response. Table 3 lists the mean weekly FEV1 trough response over the course of the treatment and posttreatment periods. There were no significant differences noted among the doses of tiotropium. All four doses of tiotropium provided a greater trough response than did placebo (p < 0.05). The results were consistent across centers. The data demonstrate that trough FEV1 increased by Visit 4 (after 1 wk of daily administration), and then remained consistently greater than that with placebo through the treatment period. These data indicate that a steady state response had been reached within 1 wk of therapy. Within 2 to 3 wk after cessation of treatment, the FEV1 response for all doses of tiotropium gradually returned to baseline, but never fell below baseline, thereby indicating no evidence of rebound deterioration. The FVC response (Table 4) paralleled the FEV1 response, with the exception of a smaller increase in the 36 μg group relative to the 18 μg group. The FVC responses in the 36 μg group were not significantly different from those with placebo at 29 d.
Tiotropium Bromide | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Visit/Study Day | Placebo | 4.5 μg | 9.0 μg | 18.0 μg | 36.0 μg | |||||||
4/8 | Trough | |||||||||||
Mean | −0.03 | 0.07‡ | 0.11‡ | 0.07‡ | 0.12‡ | |||||||
SE | (0.03) | (0.03) | (0.03) | (0.03) | (0.03) | |||||||
Average response | ||||||||||||
Mean | −0.04 | 0.13‡ | 0.11‡ | 0.12‡ | 0.19‡ | |||||||
SE | (0.03) | (0.03) | (0.03) | (0.03) | (0.03) | |||||||
5/15 | Trough | |||||||||||
Mean | −0.03 | 0.09‡ | 0.08‡ | 0.08‡ | 0.13‡ | |||||||
SE | (0.03) | (0.03) | (0.03) | (0.03) | (0.03) | |||||||
Average response | ||||||||||||
Mean | −0.02 | 0.19‡ | 0.13‡ | 0.13‡ | 0.18‡ | |||||||
SE | (0.04) | (0.04) | (0.03) | (0.04) | (0.04) | |||||||
6/22 | Trough† | |||||||||||
Mean | −0.01 | 0.13‡ | 0.10‡ | 0.11‡ | 0.17‡ | |||||||
SE | (0.03) | (0.03) | (0.03) | (0.03) | (0.03) | |||||||
7/29 | Trough | |||||||||||
Mean | −0.02 | 0.12‡ | 0.09‡ | 0.13‡ | 0.17‡ | |||||||
SE | (0.04) | (0.04) | (0.03) | (0.04) | (0.04) | |||||||
Average response | ||||||||||||
Mean | 0.00 | 0.18‡ | 0.11‡ | 0.15‡ | 0.20‡ | |||||||
SE | (0.04) | (0.04) | (0.04) | (0.04) | (0.04) |
Tiotropium Bromide | ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Visit/Study Day | Placebo | 4.5 μg | 9.0 μg | 18 μg | 36 μg | |||||||
4/8 | Trough | |||||||||||
Mean | −0.04 | 0.04 | 0.19‡ | 0.27‡ | 0.17‡ | |||||||
SE | (0.06) | (0.06) | (0.03) | (0.03) | (0.03) | |||||||
Average response | ||||||||||||
Mean | −0.08 | 0.28‡ | 0.24‡ | 0.35‡ | 0.26‡ | |||||||
SE | (0.07) | (0.07) | (0.07) | (0.07) | (0.07) | |||||||
5/15 | Trough | |||||||||||
Mean | −0.02 | 0.23‡ | 0.20‡ | 0.28‡ | 0.20‡ | |||||||
SE | (0.05) | (0.05) | (0.05) | (0.05) | (0.05) | |||||||
Average response | ||||||||||||
Mean | −0.05 | 0.44‡ | 0.25‡ | 0.34‡ | 0.25‡ | |||||||
SE | (0.08) | (0.08) | (0.08) | (0.08) | (0.08) | |||||||
6/22 | Trough† | |||||||||||
Mean | −0.01 | 0.31‡ | 0.23‡ | 0.35‡ | 0.27‡ | |||||||
SE | (0.07) | (0.07) | (0.07) | (0.07) | (0.07) | |||||||
7/29 | Trough | |||||||||||
Mean | −0.03 | 0.28‡ | 0.19 | 0.34‡ | 0.19 | |||||||
SE | (0.06) | (0.06) | (0.06) | (0.06) | (0.06) | |||||||
Average response | ||||||||||||
Mean | 0.03 | 0.40‡ | 0.28‡ | 0.40‡ | 0.21 | |||||||
SE | (0.07) | (0.07) | (0.07) | (0.07) | (0.07) |
Figure 2 illustrates the mean FEV1 response averaged over the 6-h postdosing interval for Visits 4 through 7 for each dose of study medication. All doses of tiotropium produced significantly greater responses than did placebo (p < 0.05).

Fig. 2. Mean ± SE FEV1 (liters) response averaged over the 6-h postdosing interval across the 4 wk treatment period. Means were adjusted for center, treatment-by-center interaction, and baseline FEV1. All doses of tiotropium produced significantly greater responses than did placebo. †p < 0.05.
[More] [Minimize]All doses of tiotropium produced greater PEFR values than did placebo at all test points (i.e., morning, noon, and evening). The data for the mean change from baseline in morning and evening PEFRs are presented in Figures 3 and 4. The mean daily PEFRs reveal that the achievement of a steady-state effect occurred within 2 d after beginning treatment for tiotropium at doses of 9 to 36 μg, with increases of 13 to 20 L/m being evident by the second day. This level was not achieved until Day 4 for the lowest dose. The gradual return to baseline over the 3 wk after discontinuation of tiotropium treatment corroborates the long duration of action and lack of rebound deterioration with this bronchodilator (Figures 3 and 4).

Fig. 3. Mean change from baseline in mean weekly morning PEFRs. Means were adjusted for treatment, center, treatment-by-center interaction, and baseline. All tiotropium doses produced significantly greater increases than did placebo (p < 0.05) during the treatment period. Note the gradual return to baseline over the 3 wk following discontinuation of treatment.
[More] [Minimize]
Fig. 4. Mean change from baseline in mean weekly evening PEFRs. Means were adjusted for treatment, center, treatment-by-center interaction, and baseline. All tiotropium doses produced significantly greater increases than did placebo (p < 0.05) during the treatment period. Note the gradual return to baseline over the 3 wk following discontinuation of treatment.
[More] [Minimize]The adverse event profile revealed a low incidence of individual adverse events at all dose levels of tiotropium during the 29-d double-blind portion of the study. There were no dose-dependent increases in incidence or severity of any adverse event, although the largest proportion of patients with any adverse event was seen with the highest dose of 36 μg (50% of patients). The numbers of adverse events reported within each body system across all doses are shown in Table 5. The overall safety profile for the four tiotropium doses was similar to that of placebo. The most frequently reported adverse event for tiotropium was dry mouth. Two patients in the 4.5 μg treatment group, two in the 9 μg group, and three in the 36 μg group reported having dry mouth. Bitter taste was not reported. Seven patients had an exacerbation of COPD during the study, one in the placebo group and one in the 9 μg tiotropium group, two in the 4.5 μg tiotropium group, and three in the 36 μg tiotropium group. Only one subject (in placebo group) was withdrawn because of an adverse event (anxiety).
No. of Patients (%) | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|
Tiotropium | ||||||||||
Placebo | 4.5 μg | 9 μg | 18 μg | 36 μg | ||||||
Total treated | 35 | 34 | 33 | 33 | 34 | |||||
Total with any adverse event | 13 (37.1) | 10 (29.4) | 6 (18.2) | 10 (30.3) | 17 (50.0) | |||||
Body as a whole: general disorders | ||||||||||
Fatigue | 1 (2.9) | 2 (5.9) | 0 | 0 | 0 | |||||
Headache | 1 (2.9) | 1 (2.9) | 1 (3.0) | 0 | 0 | |||||
Accidents: household and vehicular | 1 (2.9) | 1 (2.9) | 1 | 2 (6.1) | 2 (5.9) | |||||
Central and peripheral nervous system disorders | ||||||||||
Dizziness | 1 (2.9) | 1 (2.9) | 1 (3.0) | 0 | 1 (2.9) | |||||
Gastrointestinal system disorders | ||||||||||
Nausea | 1 (2.9) | 0 | 0 | 2 (6.1) | 2 (5.9) | |||||
Diarrhea | 0 | 2 (5.9) | 0 | 1 (3.0) | 0 | |||||
Flatulence | 0 | 1 (2.9) | 0 | 0 | 1 (2.9) | |||||
Dry mouth | 0 | 2 (5.9) | 0 | 2 (6.1) | 3 (8.8) | |||||
Vomiting | 0 | 0 | 0 | 2 (6.1) | 0 | |||||
Respiratory system disorders (Lower) | ||||||||||
Bronchitis (COPD exacerbation) | 1 (2.9) | 2 (5.9) | 1 (3.0) | 0 | 3 (8.8) | |||||
Coughing | 1 (2.9) | 0 | 0 | 1 (3.0) | 1 (2.9) | |||||
Respiratory system disorders (Upper) | ||||||||||
Rhinitis | 3 (8.6) | 1 (2.9) | 0 | 0 | 1 (2.9) | |||||
Upper respiratory tract infection | 2 (5.7) | 2 (5.9) | 0 | 2 (6.1) | 1 (2.9) |
There were no clinically significant effects of tiotropium on vital signs, ECG, or clinical laboratory parameters. The two serious adverse events were a wrist fracture (placebo group) and COPD exacerbation/respiratory failure (9 μg tiotropium group).
Although single-dose studies of tiotropium in COPD (8, 9) have shown it to have long-acting bronchodilatory properties, the efficacy and safety of repeated doses had not previously been established. The present study evaluated multiple doses over a 4 wk period in order to examine the dose–response characteristics of tiotropium and to further explore its therapeutic potential.
We demonstrated acute bronchodilation in COPD patients following the first administration of each dose of tiotropium (Figure 1), which persisted over the 4 wk of period of its use. Trough FEV1, which was defined as the response before daily dosing (i.e., 20 to 24 h after dosing), was improved after 1 wk of administration of tiotropium, and this improvement was maintained over the 4-wk observation period. The ability of tiotropium to maintain significant bronchodilation at 20 to 24 h after dosing probably reflects its sustained binding to muscarinic receptors in the airway, and supports once daily dosing. This, coupled with the observed safety of tiotropium, suggests that it may be an ideal maintenance bronchodilator.
Although there was a rank ordering of FEV1 according to the response to the first dose of tiotropium, little dose-dependency was observed in longer-term responses, with the exception of some additional improvement (10 to 15 L/min) in serial PEFRs following the 36 μg dose relative to other doses. There were no dose-dependent effects in reported adverse events with tiotropium other than a trend toward dry mouth. The most frequent adverse event was dry mouth, reported in a total of seven tiotropium-treated patients, of whom three (10%) were in the 36 μg group. Overall, tiotropium was well tolerated.
The main implication of these observations had to do with selecting a dose for longer-term testing in larger numbers of patients that will ultimately determine therapeutic recommendations for use of tiotropium in practice. Beyond the 4.5 μg dose, little dose-dependent improvement was seen in spirometric results. Although there was a trend toward a higher PEFR in the 36 μg group, the FVC trough response was not consistently improved at the highest dose (i.e., 36 μg). Additionally, there was a trend toward a higher proportion of adverse events at the 36 μg dose level. Taken together, the study findings led to the selection of 18 μg as the dose for long-term clinical trials.
The potential for daily maintenance bronchodilator therapy with tiotropium is evidenced by the improvement in trough FEV1 that continued throughout the 4-wk study period. In other words, the patients' FEV1 in the morning, before taking their tiotropium dose, remained significantly increased relative to values before initiating therapy. The bronchodilation observed at 20 to 24 h after tiotropium was of at least comparable magnitude to that observed at the end of the dosing interval (i.e., 4 to 6 h) in previous studies (14, 15) of short-acting bronchodilators such as ipratropium and albuterol. Thus, tiotropium maintains the bronchodilation observed with current bronchodilator therapy, but with once-daily dosing.
The response to tiotropium relative to other bronchodilators was not directly assessed in this Phase II dose-ranging study; however, a preliminary report (16) of a head-to-head comparison of tiotropium and ipratropium found tiotropium to produce greater peak, average, and trough responses. It has been previously shown that ipratropium provides comparable bronchodilation to albuterol at recommended doses (14, 15). Peak effects of ipratropium and salmeterol are also comparable (17). These indirect comparisons suggest that the magnitude of bronchodilation produced by tiotropium is within the general spectrum of that with other bronchodilators; however, it will take direct comparisons to evaluate the relative efficacy and safety of tiotropium.
The onset of steady-state bronchodilation was not directly assessed in the present study. Nevertheless, daily PEFR measurements indicated improvement after the first days of therapy. These observations have subsequently been confirmed in a separate trial in which daily spirometry revealed that a steady state was achieved within the first week of therapy (18).
Following cessation of treatment with tiotropium, pulmonary function parameters gradually returned to pretreatment levels, with no evidence of rebound deterioration. This return to baseline did appear to occur more rapidly with lower doses of tiotropium, suggesting some dose dependency of the maintenance of improvement in airflow. No adverse respiratory events were reported in this washout period.
In summary, we have shown that once-daily dosing with tiotropium provides effective bronchodilation over a 4-wk period in patients with COPD. Significant bronchodilation was evident within 1 h after the first dose of tiotropium, and was maintained at trough values of FEV1 throughout the trial. Trough FEV1 values averaged 7 to 19% above baseline values across the doses tested. The study found that tiotropium was well tolerated, and it should prove to be a safe and effective bronchodilator with once-daily dosing in patients with COPD. Longer-term studies are underway to confirm the safety and efficacy of tiotropium as a maintenance bronchodilator for patients with COPD.
Supported by Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT.
1. | American Thoracic SocietyStandards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD). Am. J. Respir. Crit. Care Med.152(Suppl.)1995S77S120 |
2. | Siafakas N. M., Vermeire P., Pride N. B., Paoletti P., Gibson J., Howard P., Yernault J. C., Decramer M., Higgenbottom T., Postma D. S., Rees J.Optimal assessment and management of chronic obstructive pulmonary disease (COPD). Eur. Respir. J.8199513981420 |
3. | Ferguson G. T., Cherniack R. M.Management of chronic obstructive pulmonary disease. N. Engl. J. Med.328199310171022 |
4. | Witek, T. J., J. F. Souhrada, C. W. Serby, and B. Disse. 1999. Tiotropium (Ba679): pharmacology and early clinical observations. In S. S. Spector, editor. Anticholinergics in Clinical Practice. Marcel Decker, New York. 137–152. |
5. | Disse B., Reichl R., Speck G., Traunecker W., Rominger K. L., Hammer R.Ba679 Br, a novel anticholinergic bronchodilator: predicted and clinical aspects. Life Sci521993537544 |
6. | Takahaski T., Belvisi M. G., Patel H., Ward J. K., Tadjkarimi S., Yocub M. H., Barnes P. J.Effect of BA679 BR: a novel long-acting anticholinergic agent, on cholinergic neurotransmission in guinea pig and human airways. Am. J. Respir. Crit. Care Med.150199416401645 |
7. | O'Connor B. J., Towse L. J., Barnes P. J.Prolonged effect of tiotropium on methacholine-induced bronchoconstriction in asthma. Am. J. Respir. Crit. Care Med.1541996876880 |
8. | Maesen F. P. V., Smeets J. J., Costongs M. A. L., Wald F. D. M., Cornelissen P. J. D.BA 679 BR, a new long-acting antimuscarinic bronchodilator: a pilot dose-escalation study. Eur. Respir. J.6199310311036 |
9. | Maesen F. P. V., Smeets J. J., Sledsens T. J. H., Wald F. D. M., Cornelissen P. J. G.Tiotropium, a new long-acting antimuscarinic bronchodilator: a pharmacodynamic study in patients with chronic obstructive pulmonary disease (COPD). Eur. Respir. J.8199515061513 |
10. | Morris J. F., Koski A., Temple W. P., Claremont A., Thomas D. R.Fifteen year interval spirometric evaluation of the Oregon predictive equations. Chest931998123127 |
11. | Chodosh S., Flanders J., Serby C. W., Hochrainer D., Witek T. J.Effective use of HANDIHALER dry powder inhalation system over a broad range of COPD disease severity (abstract). Am. J. Respir. Crit. Care Med.1591999A524 |
12. | Agresti A., Mehta C. R., Patel N. R.Exact inference for contingency tables with ordered categories. J. Am. Stat. Assoc.851990453458 |
13. | Van Andel A. E., Reisner C., Menjoge S. S., Witek T. J.Analysis of inhaled corticosteroid and oral theophylline use among stable COPD patients from 1987 to 1995. Chest1151999703707 |
14. | COMBIVENT Inhalation Aerosol Study GroupIn chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone: an 85-day multicenter trial. Chest105199414111419 |
15. | Wilson J. D., Serby C. W., Menjoge S. S., Witek T. J.The efficacy and safety of combination bronchodilator therapy. Eur. Respir. Rev.391996286289 |
16. | Van Noord J. V., Bantje T., Eland M., Korducki L., Cornelissen P.Superior efficacy of tiotropium (TIO) compared to ipratropium (IpBr) as a maintenance bronchodilator in COPD (abstract). Am. J. Respir. Crit. Care Med.1591999A525 |
17. | Mahler D. A., Donahue J. F., Barbee R. A., Goldman M. D., Gross N. J., Wisniewski M. E., Yancey S. W., Zakes B. A., Rickard K. A., Anderson W. H.Efficacy of salmeterol xinafoate in the treatment of COPD. Chest1151999957965 |
18. | Van Noord J. A., Smeets J. J., Maesen F. P., Korducki L., Cornelissen P. J.The onset of spirometric response following once daily inhalation of tiotropium in patients with COPD. Eur. Respir. J.121998A1S |