Fergie 2
Fergie 2
Fergie 2
R. Casaburi*, D.A. Mahler#, P.W. Jones}, A. Wannerz, G. San Pedro, R.L. ZuWallack,
S.S. Menjoge**, C.W. Serby**, T. Witek Jr**
A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive *Harbor-UCLA Research and Edu-
pulmonary disease. R. Casaburi, D.A. Mahler, P.W. Jones, A. Wanner, G. San cation Institute, Torrance, CA, #Dart-
Pedro, R.L. ZuWallack, S.S. Menjoge, C.W. Serby, T. Witek Jr. #ERS Journals Ltd mouth Hitchcock Medical Center,
2002. Lebanon, NH, zUniversity of Miami
School of Medicine, Miami, FL,
ABSTRACT: Currently available inhaled bronchodilators used as therapy for chronic
Louisiana State University Medical
obstructive pulmonary disease (COPD) necessitate multiple daily dosing. The present Center, Shreveport, LA, St Francis
study evaluates the long-term safety and efficacy of tiotropium, a new once-daily Hospital and Medical Center, Hart-
anticholinergic in COPD. ford, CT, and **Boehringer Ingelheim
Patients with stable COPD (age 65.28.7 yrs (meanSD), n=921) were enrolled Pharmaceuticals, Inc., Ridgefield, CT,
in two identical randomized double-blind placebo-controlled 1-yr studies. Patients USA. }St George9s Hospital, London,
inhaled tiotropium 18 mg or placebo (mean screening forced expiratory volume in UK.
one second (FEV1) 1.01 versus 0.99 L, 39.1 and 38.1% of the predicted value)
Correspondence: R. Casaburi, Harbor-
once daily as a dry powder. The primary spirometric outcome was trough FEV1 (i.e. UCLA Research and Education Insti-
FEV1 prior to dosing). Changes in dyspnoea were measured using the Transition tute, Building RB-2, 1124 W. Carson
Dyspnea Index, and health status with the disease-specific St. George9s Respiratory Street, Torrance, CA 90502, USA.
Questionnaire and the generic Short Form 36. Medication use and adverse events Fax: 1 310 3289849
were recorded. E-mail: casaburi@ucla.edu
Tiotropium provided significantly superior bronchodilation relative to placebo for
trough FEV1 response (y12% over baseline) (pv0.01) and mean response during the 3 h Keywords: Chronic obstructive
following dosing (y22% over baseline) (pv0.001) over the 12-month period. Tiotropium pulmonary disease
dyspnoea
recipients showed less dyspnoea (pv0.001), superior health status scores, and fewer exacerbations
COPD exacerbations and hospitalizations (pv0.05). Adverse events were comparable quality of life
with placebo, except for dry mouth incidence (tiotropium 16.0% versus placebo 2.7%, tiotropium
pv0.05).
Tiotropium is an effective, once-daily bronchodilator that reduces dyspnoea and Received: August 9 2001
chronic obstructive pulmonary disease exacerbation frequency and improves health Accepted after revision November 2
status. This suggests that tiotropium will make an important contribution to chronic 2001
obstructive pulmonary disease therapy.
Eur Respir J 2002; 19: 217224. This study was supported by Boehrin-
ger Ingelheim Pharmaceuticals, Inc.
Chronic obstructive pulmonary disease (COPD) is making once-daily dosing a possibility [7]. The present
characterized by reduced expiratory airflow and the article reports 1-yr data concerning the efficacy and
symptoms of cough, sputum production and dys- safety of tiotropium in COPD patients in terms of
pnoea [1]. The breathlessness associated with COPD bronchodilation, symptoms and other health out-
develops over many years, is a major reason for comes including adverse events. It characterizes
seeking medical care and eventually limits daily tiotropium as a new therapy for COPD.
activities [2].
Bronchodilators are the mainstay of drug therapy
for COPD given their ability to improve airflow and Methods
reduce breathlessness, the latter probably being
related to reduced hyperinflation [3]. Inhaled anti- Study design and conduct
cholinergic drugs such as ipratropium have been used
since the 1970s in COPD and have emerged as a safe Two identical clinical trials were designed to
and effective therapy [1, 4]. A limitation of these establish the efficacy and safety of tiotropium
agents is the need for frequent (i.e. four times daily) (Spiriva1; Boehringer Ingelheim, Ingelheim am
dosing. Tiotropium, an agent in a new class of Rhein, Germany), including health outcomes. These
anticholinergics, exhibits a longer duration of action two trials have been combined in the present report to
due to prolonged muscarinic receptor antagonism [5, provide a comprehensive efficacy and safety profile.
6]. These effects have the therapeutic advantage of Fifty clinical centres participated in the double-blind
218 R. CASABURI ET AL.
placebo-controlled trials. These trials were approved In order to ensure standardized conditions on
by each centre9s Institutional Review Board. All spirometric test days, subjects discontinued theophyl-
patients provided written informed consent. line 24 h prior to spirometric testing (compliance
The study groups consisted of outpatients of either was assessed by measuring theophylline levels prior
sex who were 40-yrs-old and had a clinical diagnosis to testing and noting patients with levels of
of COPD, as defined by the American Thoracic 5.0 mg?mL-1; this threshold was exceeded in only
Society (ATS) [8]. Participants were required to have 12% of measurements). Albuterol and inhaled
at least a 10 pack-yr smoking history, clinically stable corticosteroids were stopped 12 h prior to spiro-
airway obstruction, and a forced expiratory volume in metric testing.
one second (FEV1) of 65% of predicted normal
values and 70% of forced vital capacity (FVC).
Patients were excluded if they had a history of asthma, Other observations
allergic rhinitis or atopy or a total blood eosinophil
count of 600 cells?mm-3. Bronchodilator responsive- Before entry and upon trial completion, patients
ness was not an entry criterion. Patients were also underwent medical history checks, physical exami-
excluded if they required regular daytime supple- nation, and routine blood chemistry and haematology
mental oxygen or were on doses exceeding the equi- testing as well as 12-lead electrocardiography to
valent of 10 mg prednisone daily during the month exclude other important diseases and to monitor
prior to entering the study. In addition, patients were study medication safety. Each subject also performed
excluded if they had a recent history of myocardial peak expiratory flow rate (PEFR) measurements in
infarction (1 yr), heart failure (3 yrs) or cardiac their home twice daily (upon arising and at bedtime)
arrhythmia requiring drug therapy. using the AirWatchTM Monitor (Enact Health
Management Systems, Mountain View, CA, USA).
Study clinic visits were scheduled on the first day of
Treatments
study drug administration, at the end of the first
week of therapy, every 3 weeks thereafter through-
Following a 2-week baseline period, patients were
out the first 13 weeks of treatment and every 6 weeks
randomly assigned within each study centre to receive
for the next 36 weeks, in order to assess adverse
either tiotropium (18 mg) or placebo. Patients were
events, concomitant medication use and clinical sta-
randomized in a 3:2 tiotropium:placebo ratio in order
tus. An exacerbation, detected through monitoring of
to expose a greater number of patients to tiotro-
adverse events, was defined as a complex of respira-
pium for safety evaluation. Subjects took, by inhala-
tory events (i.e. cough, wheezing, dyspnoea or sputum
tion, active medication (tiotropium in lactose) or
production) lasting w3 days. These were generally
placebo (lactose) once each morning from identically
treated with antibiotics and/or oral steroids.
appearing capsules via a dry powder inhaler device
(HandiHaler1; Boehringer Ingelheim, Ingelheim am
Rhein, Germany) [9]. Patients were permitted an
Diary and interview assessments
albuterol metered-dose inhaler, as needed, stable
doses of theophylline (i.e. unchanging doses that
Dyspnoea at baseline was assessed using the Base-
had been used for 6 weeks prior to entry),
line Dyspnea Index (BDI) [12]. This instrument has
inhaled glucocorticosteroids and the equivalent of
three domains (functional impairment, magnitude of
10 mg?day-1 oral prednisone throughout the study
task and magnitude of effort), the sum of the values
period. Finally, to treat acute COPD exacerba-
giving a combined focal score. Changes in impairment
tions during the trial, investigators were permitted
from baseline were measured using the Transition
to administer any additional medication deemed
Dyspnea Index (TDI) [12] on days 50 and 90 and
necessary (excluding anticholinergic or long-acting
every 3 months thereafter. Generic and disease-
b-agonists). After 13 weeks, the investigators were
specific health status was evaluated by patients using
permitted to prescribe glucocorticosteroids or theo-
Short Form 36 (SF-36) [13] and St George9s
phylline preparations as necessary.
Respiratory Questionnaire (SGRQ) [14]. At each
visit during the treatment period, the investigator
Spirometric testing recorded COPD symptom scores after reviewing the
patient9s daily diary (for wheezing, shortness of
Spirometric testing was conducted on treatment day breath, coughing and chest tightness) and recorded
1 and after 1, 7, 13, 25, 37 and 49 weeks of therapy. a global evaluation of the patient9s overall condition
Drug was administered at the same time each day (1: poor; 8: excellent).
(between 07:00 and 09:00 h). On test days, FEV1 and
FVC were recorded 1 h prior to dosing, just prior
to dosing, and 30, 60, 120 and 180 min after study Statistical analysis
drug administration. Spirometric manoeuvres were
conducted in triplicate and the greatest FEV1 and The statistical model was an analysis of covariance
FVC used in subsequent analyses. Predicted normal with terms for treatment, clinic and baseline as
values for FEV1 and FVC were derived from standard covariates. Discontinuation rates and proportions of
equations [10]. Spirometers were required to meet patients showing clinically meaningful responses were
ATS standards [11]. compared across treatment groups using Fisher9s
EVALUATION OF TIOTROPIUM IN COPD 219
exact test. Proportions of patients experiencing at Table 1. Demographics and baseline characteristics of
least one COPD exacerbation and hospitalization the randomized patients
associated with such exacerbations were compared Tiotropium Placebo
across treatment groups using logistic regression
analysis. Only those COPD exacerbations recorded
as adverse events were used for comparison in order Patients n 550 371
Sex male/female 366/184 233/138
to eliminate day-to-day fluctuations in symptoms. Age yrs 659 659
The intention-to-treat principle of including all ran- Height cm 171.19.6 170.59.5
domized patients was used in all efficacy analyses. Weight kg 76.917.7 75.517.5
Patients who had missing baseline data, or v2 weeks Smoking history 6331 5930
of data for certain end points, were excluded from pack-yrs
the 1-yr comparisons for those end points. Patients Duration of 8.67.4 8.16.8
who were unable to complete all of their visits due disease yrs
to drug expiration discontinued their study drug at the FEV1 L 1.040.41 1.000.44
9-month visit but were considered complete patients. FEV1 % pred 39.113.7 38.114.1
When patients discontinued due to worsening of FVC L 2.310.79 2.230.78
FEV1/FVC % 45.811.6 45.511.6
disease (5% of patients), missing data were imputed Prestudy medication for
using the least favourable data observed prior to COPD n (%)
discontinuation. In all other cases, missing data Anticholinergics 302 (55) 217 (59)
following patient withdrawal were imputed by carry- b2-agonist, inhaled 546 (99) 368 (99)
ing the last observation forward. In order to assess the Inhaled steroids 239 (44) 149 (40)
impact of imputation, data were also analysed based Oral steroids 31 (6) 33 (9)
on patients who completed the study to 12 months Theophylline 123 (22) 94 (25)
alone. This sensitivity analysis showed that the results Data are presented as meanSD unless otherwise indicated.
were consistent with those obtained after imputation No significant differences were seen between the two groups.
of missing data. FEV1: forced expiratory volume in one second; FVC: forced
vital capacity; COPD: chronic obstructive pulmonary
disease; % pred: percentage of the predicted value.
Sample size
(pv0.01) (fig. 1). With chronic therapy, predose
A sample size of 60 patients per group was FEV1 (i.e. trough) was elevated 1101013010 mL
calculated as adequate to detect a difference of (111131%) over baseline (meanSEM); this was
0.13 L in trough FEV1 based on an SD of 0.215 L. superior to placebo by 1201015020 mL (pv0.01)
To ensure adequate safety exposure, a sample size on the various assessment days. Significant differ-
of 240 patients was selected for each trial. ences from placebo were also observed for peak
response and mean (i.e. over the 3 h following dosing)
response. The mean FEV1 increase over baseline
Results during the 3 h following dosing for tiotropium ranged
1901022010 mL (191221%); this was superior
Of 921 patients enrolled (n=550 for tiotropium; to placebo by 1401022020 mL. Figure 1 reveals
n=371 for placebo), a higher percentage completed the
study in the tiotropium group (81.3%) than in the
placebo group (72.2%) (pv0.05). A lower percentage 1.3
failed to complete due to adverse events (9.6%) and
lack of efficacy (2.4%) in the tiotropium group than
in the placebo group (13.7 and 7.0%, respectively) 1.2
(pv0.05 for both). In addition, 24% of patients
discontinued the trial prior to the end of the study
FEV1 L
due to drug expiration. Although further supply of the
1.1
study drug was originally planned, it was deemed
unnecessary as the target sample size was attained due
to the lower-than-expected frequency of early with-
drawals. 1.0
The study population characteristics are listed in
table 1. Patients were generally in their seventh decade
of life, had a mean cigarette exposure of 61 pack-yrs 0.9
and a mean FEV1 of 1.02 L, and were predominantly -1 0 1 2 3
male. Groups were balanced for all characteristics. Time after administration h
Fig. 1. Mean response to tiotropium (+) or placebo (%) on
days 1 (), 8 (.......), 92 (- - - -), 176 ( ) and 344 ( -- --)
Spirometry of the 1-yr trial. Note that the elevation over baseline prior to
drug administration on days subsequent to the first treatment day
in the tiotropium group is evidence of tiotropium9s 24-h duration
Tiotropium produced acute bronchodilation upon of action. The SEM for the mean differences between groups
initial dosing superior to that produced by placebo ranged 0.010.02 L. FEV1: forced expiratory volume in one second.
220 R. CASABURI ET AL.
Health outcomes
210
Exacerbations. The proportion of patients experi-
200 encing at least one COPD exacerbation was lower
in the tiotropium group (36%) than in the placebo
190 group (42%) (14% reduction, pv0.05). There was a
significant increase in the time to first exacerbation in
b) 240 the tiotropium group relative to placebo (p=0.011).
There were significantly fewer exacerbations in the
tiotropium group (0.76 events?patient-yr-1) compared
Mean weekly PEFR Lmin-1
The recent clinical development of tiotropium has also been shown in some studies to reduce
represents an advance in bronchodilator therapy exacerbation rate [26, 27] and severity [28], suggesting
in that its pharmacological features translate into a role for airway inflammation in disease exacerba-
clinically important attributes. Tiotropium binds tion. In another report, salmeterol was associated
significantly longer (hours) to the M3 muscarinic with a prolonged time to exacerbation, but this study
receptor (responsible for bronchodilation) than does was limited to 3 months [29]. In another 12-week
ipratropium (minutes). This observation finds its study, exacerbations were significantly reduced in
clinical correlate in sustained improvements in air- patients treated with ipratropium plus salmeterol,
flow. Tiotropium also dissociates more rapidly from but not salmeterol alone [30]. The mechanism(s)
the M2 receptor (whose stimulation reduces acetylcho- by which tiotropium reduces COPD exacerbations
line release) than from the M3 receptor, antagonism of is not yet clear. Health status was improved with
which promotes bronchodilation. Although func- tiotropium relative to placebo, confirming the overall
tional correlates of these features have been demon- benefit of therapy to the patient. Improvements that
strated in experimental test systems of acetylcholine were at or around the level of clinical significance
release and smooth muscle relaxation [18], the clinical (a decrease of 4 units) [14] were observed in all SGRQ
effects of "kinetic receptor subtype selectivity" [19] domains compared with placebo. Further, a signi-
have not been directly studied. ficantly higher proportion of patients exceeded a
Single- [20] and multiple-dose [5] studies of tiotro- 4-unit improvement in the group receiving tiotropium.
pium in COPD have demonstrated its prolonged The largest difference between groups was observed
duration of action. In a multiple-dose study of tio- in the impact domain of the SGRQ. This component
tropium, doses ranging 4.536 mg showed little dose reflects disturbances to everyday life imposed by the
dependency in spirometric outcomes, and the optimal disease, including aspects of psychological distress
therapeutic dose was judged to be 18 mg [5]. The 24-h as well as limitations put upon daily activities and
effectiveness of this dose was confirmed in a trial in social function. Although an unproved hypothesis, the
which serial spirometry over the entire dosing interval reductions in dyspnoea and exacerbation frequency
demonstrated significant bronchodilation [21]. The may account for the improvements seen in health
first 13 weeks9 spirometric results from one of the status.
trials reported here have recently been published [22], It is interesting to contrast these SGRQ score
and those findings were confirmed during the 1-yr changes with those recently reported in COPD
study period. The elevation of trough FEV1 over patients taking the inhaled glucocorticosteroid fluti-
baseline (fig. 1) demonstrates the appropriateness of
casone (Inhaled Steroids in Obstructive Lung Disease
once-daily administration. The persistence of FEV1
(ISOLDE) trial, [26, 27]). That study assessed health
response over a full year of therapy indicates that
status every 6 months over a 3-yr period. Health
tachyphylaxis does not occur during this time period.
Higher evening PEFR responses in the tiotropium status was shown to decline (rising SGRQ scores) in
group (fig. 2b) are notable in light of their lesser use the group receiving placebo. Fluticasone reduced the
of rescue albuterol. The daily patient recordings of rate of deterioration compared with placebo-treated
morning PEFR prior to dosing (fig. 2a) reinforce the patients, but at no time (including the first year) did
concept that tiotropium9s action persists for 24 h. fluticasone induce a significant improvement in health
Although spirometric assessment is important for status. In contrast, although the overall observation
the characterization of airflow impairment and period was shorter, the present study demonstrated
improvements following therapy, other consequences that tiotropium produced an improvement in health
of chronic disease relate to a patient9s disability and status that was sustained over a 1-yr period. Few data
handicap. Patients assigned to tiotropium experienced are available with other interventions, particularly
a significant improvement in dyspnoea relative to the beyond 3 months of observation. Over 16 weeks, the
placebo group, as assessed by the TDI. In addition, a b-agonist salmeterol has been reported to improve
significantly greater proportion of patients manifested health status as measured by the SGRQ at 50 mg; it
an increase of 1 unit on the TDI, a change that did not do so, however, at 100 mg (both twice daily)
inherently reflects a clinically meaningful improve- [31]. Longer-term data are not available.
ment based on the instrument9s scoring description The present trial results indicate that tiotropium is
[12]; this is supported by analyses against general an effective once-daily bronchodilator. Tiotropium
outcome measures [23]. The reduction in breath- was associated with consistent physiological and
lessness with tiotropium is further supported by the health outcome benefits including reduced dyspnoea,
significant reduction in the use of rescue albuterol as fewer exacerbations and improved health status; these
well as significant improvements in physician9s global benefits were sustained over a 1-yr period. Compa-
evaluation and the symptom diary rating of dyspnoea. rator 1-yr clinical trials versus ipratropium have been
Alteration in COPD exacerbation frequency may be performed and indicate consistency of the improve-
one of the most important health outcomes, as it ments with tiotropium across multiple clinical out-
significantly impacts upon the patient9s quality of life comes [32]. Its attributes, defined in these long-term
[24] and is a major contributor to healthcare utili- clinical trials, together with its demonstrated safety
zation [25]. In the present studies, tiotropium was suggest that tiotropium is likely to provide an
associated with both fewer exacerbations and hospi- important contribution to the therapy of patients
talizations as well as prolonging the time to the first with symptomatic chronic obstructive pulmonary
exacerbation. Treatment with inhaled corticosteroids disease.
EVALUATION OF TIOTROPIUM IN COPD 223
Acknowledgements. The authors are grateful 12. Mahler DA, Weinberg DH, Wells CK, Feinstein AR.
to the patients and their families, and the The measurement of dyspnea: contents, interobserver
coordinators, nurses and therapists for their agreement and physiologic correlates of two new
dedication to the study.
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