PhRMA Web Synopsis

Protocol A4471008 – 01 December 2010 – Final

PFIZER INC.

These results are supplied for informational purposes only.

Prescribing decisions should be made based on the approved package insert.
For publications based on this study, see associated bibliography.

PROPRIETARY DRUG NAME®/GENERIC DRUG NAME: Spiriva® / Tiotropium

THERAPEUTIC AREA AND FDA APPROVED INDICATIONS: See United States

Package Insert (USPI).

NATIONAL CLINICAL TRIAL NO.: NCT00523991

PROTOCOL NO.: A4471008

PROTOCOL TITLE: A 24 Week, Randomized, Double-Blind, Placebo-Controlled,

Multicenter Study to Evaluate the Efficacy and Safety of 18 mcg of Tiotropium Inhalation
Capsules Administered by Handihaler® Once-Daily Plus prn Albuterol (Salbutamol) vs.
Placebo Plus prn Albuterol (Salbutamol) in Chronic Obstructive Pulmonary Disease Subjects
Naïve to Maintenance Therapy
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Study Centers: A total of 59 centers took part in the study, including 4 in Belgium, 2 in
Canada, 12 in Czech Republic, 5 in Germany; 4 in Greece, 4 in Netherlands, 3 in Portugal,
7 in Ukraine, 2 in United Kingdom, and 16 in United States.

Study Initiation Date and Completion Dates: 26 April 2007 to 02 July 2010

Phase of Development: Phase 4

Study Objectives: The objective of this study was to assess the efficacy and safety of
tiotropium in subjects with chronic obstructive pulmonary disease (COPD) (Global Initiative
for Chronic Obstructive Lung Disease [GOLD] Stage 2) who had not previously been treated
with maintenance therapy, ie, the subjects could only have been treated only with
short-acting -agonists on an as-needed basis in the 6 months prior to study enrollment and
who had symptomatic shortness of breath.

The primary objective was to evaluate the difference between treatments with tiotropium plus
prn albuterol (salbutamol) vs placebo plus prn albuterol (salbutamol) on area under the curve
(AUC) normalized over 3 hours (AUC0-3h) forced expiratory volume in 1 second (FEV1).
The effects of tiotropium treatment on other lung function variables and outcomes such as
activity, symptoms, and productivity were also assessed as secondary objectives. The
activity monitor endpoints in this study were considered experimental in nature. The
correlation among health-related quality of life, COPD symptom score, and activity was also
examined at baseline as an exploratory objective.

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METHODS

Study Design: This was a 24-week, randomized, parallel-group, double-blind,

placebo-controlled, multicenter study in subjects with COPD (GOLD Stage 2) who had not
previously been treated with maintenance therapy (ie, who had not been treated with other
than only a short-acting -agonist on an as-needed basis in the 6 months prior to study
enrollment and who had symptomatic shortness of breath). Subjects were to be randomized
in a ratio of 1:1 at baseline to receive either tiotropium or matching placebo.

The study consisted of 9 clinic visits over a period of 28 weeks. There was a 4-week
screening period that included Visit 1/Week -4 with single-blind placebo run-in at
Visit 2/Week -3; and a 24-week double-blind phase (ie, Visit 3/Week 0 [baseline],
Visit 4/Week 4, Visit 5/Week 8, Visit 6/Week 12, Visit 7/Week 16, Visit 8/Week 20, and
Visit 9/Week 24 [end of the study]).

Number of Subjects (Planned and Analyzed): A total of 654 subjects were to be enrolled
in the screening phase of the study at Visit 1, so that 436 subjects would be randomized at the
baseline visit. Overall, 933 subjects were screened and 457 subjects were randomized to
study treatment.

Diagnosis and Main Criteria for Inclusion: Subjects were men and women current or
ex-smokers (smoking history of 10 pack-years) with GOLD Stage 2 COPD,
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postbronchodilator FEV1 50% and <80% of predicted normal, and were from 40 to 80 years
of age. Subjects were required to have postbronchodilator FEV1/FVC ratio <70% (Week -4
[screening]) and a Medical Research Council dyspnea score of 2. Subjects could not be
treated previously with maintenance medications for chronic respiratory disease within
6 months prior to screening.

Study Treatment: During screening, all subjects received single-blinded placebo treatment
from Week -3 (screening) through Week 0 (baseline/randomization). During the active
double-blind treatment phase, subjects were randomized to 1 of the 2 treatment groups:
tiotropium 18 μg or placebo. Albuterol (salbutamol) was provided for prn use by all subjects
(for use as rescue therapy) during the screening and treatment period. Each dose of
tiotropium or placebo consisted of 1 capsule and was self-administered from a HandiHaler
once daily in the morning (between 7 and 10 am) for 24 weeks.

Efficacy Evaluations:

Spirometry: Spirometry was performed at Week -4 (screening), at Week 0

(baseline/randomization), and at Weeks 8, 16, and 24 (end of study). At the Week 0 through
Week 24 (end of study) visits, the predose FEV1 and forced vital capacity (FVC)
measurements were obtained at 10 3 minutes prior to administration of study drug; postdose
measurements were performed at 30, 60, 120, and 180 minutes (5 minutes) postdose.

Activity Monitor: Physical activity and energy expenditure over time were determined by the
activity monitor (SenseWear® Armband), which captured all activity and metabolic
measurements. The activity monitor was dispensed at Week -4 (screening) and compliance

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with the monitor was assessed at Week -3 (screening). When the subject returned to the site
at Weeks -3 through 24 (end of study), the subject’s data from the activity monitor were
downloaded.

Physician’s and Patient’s Global Assessment: Both assessments were performed at Week 0
(baseline) and Weeks 12 and 24 (end of study). The physician’s and patient’s global
assessments were based on the patient’s overall clinical condition with respect to COPD.

Work Productivity and Activity Impairment (WPAI) Questionnaire: The WPAI, administered
at Week 0 (baseline/randomization) and all subsequent visits, is a 6-item self-administered
instrument developed to measure the impact of a specific disease on work productivity.

Subject Diary: The subject recorded the number of rescue albuterol (salbutamol) inhalations
in a subject diary at Week -4 (screening) through Week 24.

Exploratory Endpoint Evaluations - Clinical COPD Questionnaire (CCQ) and Chronic

Respiratory Disease Questionnaire (CRQ): The CCQ is a 10-item, self-administered
instrument developed to systematically assess respiratory symptoms and functional and
mental state. A high score on the CCQ indicates worse COPD symptoms. The CRQ is a
20-item, self-administered instrument developed to systematically assess respiratory-related
quality of life. A high score in the CRQ was favorable (ie, less dyspnea, fatigue, etc). The
CRQ and the CCQ were completed by the subject only at the baseline visit (Week 0).
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Safety Evaluations: Safety evaluations included collection of subject-reported adverse

events (AEs) and assessment of COPD exacerbations (captured as AEs), blood pressure, and
heart rate. Laboratory evaluations were not routinely performed in this study.

Statistical Methods: Analysis sets for this study included: Full Analysis Set (FAS): All
subjects who were randomized, received at least 1 dose of the study drug, and had baseline
and at least 1 postbaseline data measurement available for the primary efficacy variable,
FEV1; Completers Set: All subjects who were included in the FAS and had completed the
study, ie, had baseline and final visit (Week 24) data available for FEV1; Safety Set: All
subjects who were randomized, and received at least 1 dose of the study drug; and Activity
Evaluable Set (ActES): All subjects included in the FAS, who had physical activity and
energy expenditure data available for 12 weeks, and who met the minimum requirements
for use of the monitor.

All efficacy analyses, except analyses for physical activity endpoints, were performed using
the FAS population; physical activity and exploratory endpoints (CRQ and CCQ) and were
assessed using the ActES. All hypotheses were tested using a Type I error rate of 0.05 and
statistical tests were performed as 2-sided tests.

For pulmonary function tests (PFTs), baseline was defined as the time point of the predose
measurement at Week 0.

Primary endpoint: The primary endpoint was the FEV1 AUC0-3h postdose response at
Week 24 (end of study). The null hypothesis for this study was that there is no difference in

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mean FEV1 AUC0-3h response between subjects treated with tiotropium 18 μg vs placebo, and
the alternative hypothesis was that there is a difference between the 2 treatment groups.

A descriptive summary was provided for the primary endpoint at Weeks 0, 4, 8, 12, 16, 20,
and 24 (end of the study). The primary efficacy analysis for the change in FEV1 AUC0-3h
from baseline to Week 24 was performed using an analysis of covariance (ANCOVA) model
with terms for treatment group and investigator site, and baseline value as covariate.

Secondary endpoints: The following secondary endpoints were analyzed using change from
baseline to the final visit in:

 FEV1 parameters (trough, peak, individual measurement at each time point, AUC0-3h at
all timepoints other than Week 24)
 FVC parameters (trough, peak, AUC0-3h, individual measurement at each time point)
 Physical activity and energy expenditure (over time) as determined by the activity
monitor:
 Average time spent per day in light intensity (<3 metabolic equivalents; METS)
and in moderate or higher intensity (3 METS) activity, and with use of
age appropriate predefined activity METS
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 Healthy lifestyle, defined as 30 minutes >3 METS activity for 70% of eligible
days
 Active energy expenditure (kcal/day)
 Number of steps per day
 Physician’s and patient’s global assessments
 Work productivity as assessed by the WPAI questionnaire
 Use of prn albuterol (salbutamol) per week
Descriptive summaries were provided for all secondary endpoints at each of the time points
of Weeks 0, 4, 8, 12, 16, 20, and 24 (end of the study). The following endpoints were
analyzed using change from baseline to the final visit: FEV1 parameters, FVC parameters,
and use of prn albuterol (salbutamol) per week.

WPAI scores were derived according to the algorithms validated by the instrument
developers. For physical activity and energy expenditure endpoints, the analysis was
provided for Weeks 12, 16, 20, and 24 (end of study) based on the activity evaluable analysis
set.

All these secondary endpoints were analyzed by ANCOVA models, with terms for treatment
group and investigator site, and baseline value as covariate.

Physician’s and patient’s global assessment endpoints and the healthy lifestyle endpoint were
treated as categorical and were analyzed by Cochran-Mantel-Haenszel tests with investigator
site as the stratification variable.

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Exploratory endpoints (CCQ and CRQ): The association between health-related quality of
life instruments (CCQ and CRQ) with physical-activity data at baseline was assessed using
correlation analysis.

RESULTS

Subject Disposition and Demography: Of 457 subjects randomized to study treatment,

238 were randomized to the tiotropium group and 219 to the placebo group (see Table 1).

Table 1. Subject Disposition

No. of Subjects (%) Tiotropium Placebo

18 μg/capsule
Screened, 933
Randomized to study treatment, 457
Treated 238 (100.0) 219 (100.0)
Completed 211 (88.7) 198 (90.4)
Discontinued 27 (11.3) 21 (9.6)
Relation to study drug not defined 22 (9.2) 15 (6.8)
Lost to follow-up 1 (0.4) 4 (1.8)
No longer willing to participate in study 17 (7.1) 7 (3.2)
Other 0 3 (1.4)a
Protocol deviation 4 (1.7) 1 (0.5)
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Related to study drug 1 (0.4) 1 (0.5)

Adverse event 1 (0.4) 1 (0.5)
Not related to study drug 4 (1.7) 5 (2.3)
Adverse event 4 (1.7) 5 (2.3)
Analyzed for efficacy
Full Analysis Set 227 (95.4) 207 (94.5)
Completers Set 210b (88.2) 198 (90.4)
Activity Evaluable Set 221 (92.9) 205 (93.6)
Analyzed for safety
Adverse events 238 (100.0) 219 (100.0)
Discontinuations occurring outside the lag period were attributed to the last study treatment received.
a
One subject was discontinued due to unblinding of the subject’s data as a result of a serious adverse event;
however, the because discontinuation did not result from the adverse event itself; the discontinuation was
categorized as due to “Other”.
b
One subject completed the study but was excluded from the Completers Set because the subject had no
Week 24 FEV1 data.

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Demographic characteristics are provided in Table 2. The 2 treatment groups were generally
comparable with respect to demographics.

Table 2. Demographic Characteristics

Tiotropium 18 μg/capsule Placebo

No. of Subjects (%) Male Female Total Male Female Total
166 72 238 147 72 219
Age (years)
Mean 61.2 61.1 61.2 62.9 61.0 62.3
SD 8.2 8.1 8.2 8.8 8.0 8.6
Race
White 163 (98.2) 71 (98.6) 234 (98.3) 143 (97.3) 70 (97.2) 213 (97.3)
Black 3 (1.8) 1 (1.4) 4 (1.7) 4 (2.7) 2 (2.8) 6 (2.7)
Weight (kg)
Mean 83.9 70.0 79.7 88.6 72.2 83.2
SD 15.8 14.4 16.6 18.6 18.5 20.1
Height (cm)
Mean 174.5 164.2 171.4 174.2 162.8 170.5
SD 6.9 6.3 8.2 6.2 6.8 8.3
Smoking status
Ex smoker 66 (39.7) 25 (34.7) 91 (38.2) 74 (50.3) 20 (27.7) 94 (42.9)
Smoker 100 (60.2) 47 (65.2) 147 (61.7) 73 (49.6) 52 (72.2) 125 (57.0)
SD = standard deviation.
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As per the inclusion criteria, subjects were men and women current or ex-smokers (smoking
history of 10 pack-years) with GOLD Stage 2 COPD, postbronchodilator FEV1 50% and
<80% of predicted normal, and were from 40 to 80 years of age (see Table 2 and Table 3).

Table 3. Pulmonary Function Test and COPD Characteristics at Screening

Tiotropium 18 μg/capsule Placebo

N = 238 N = 219
PFT Findings (Postbronchodilator), Mean (SD)
FEV1, liters 1.95 (0.438) 1.90 (0.434)
FVC, liters 3.53 (0.804) 3.41 (0.870)
FEV1 as percent of predicted 65.64 (8.198) 65.84 (8.188)
FEV1/FVC 0.56 (0.080) 0.56 (0.079)
PFT = pulmonary function test; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity;
COPD = chronic obstructive pulmonary disease; SD = standard deviation.

Efficacy Results: The primary objective was to evaluate the difference between tiotropium
plus prn albuterol (salbutamol) vs placebo plus prn albuterol (salbutamol) on FEV1 AUC0-3h
and the primary endpoint was the FEV1 AUC0-3h postdose response at Week 24 (end of
study). The primary endpoint of this study was met.

At baseline, FEV1 AUC0-3h (which is defined as baseline trough FEV1) was comparable
between treatment groups (see Table 4 and Figure 1). At Week 24, mean changes from
baseline FEV1 AUC0-3h were 0.19 L with tiotropium and -0.03 L with placebo; furthermore,
the LS mean difference with tiotropium from placebo was statistically significant (see
Table 4 and Figure 1). This treatment effect for FEV1 AUC0-3h was observed at each of the

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3 study visits, and the treatment effect appeared to be sustained over 3 hours post-treatment.
Results were similar in the Completers Set Population.

Figure 1. Summary (Mean SE) and Analysis of FEV1 AUC0-3h - FAS

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Baseline FEV1 AUC0-3h is defined as trough FEV1; FAS = full analysis set; SE = standard error; FEV1 = forced
expiratory volume in 1 second; AUC = area under the curve; AUC0-3h = AUC normalized over 3 hours;
Diff = difference; LSM = least squares mean; CI = confidence interval.

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Table 4. Change from Baseline in FEV1 AUC0-3h in Liters - FAS

Raw Values Change from Baseline

Study Visit Parameter Tiotropium Placebo Tiotropium Placebo
N = 227 N = 207 N = 227 N = 207
Baseline Mean (SD) 1.74 (0.463) 1.71 (0.448)
Week 24 Mean (SD) 1.93 (0.514) 1.68 (0.474) 0.19 (0.270) -0.03 (0.218)
Statistical Analysis of Change from Baseline to Week 24
LS mean 0.16 -0.06
95% CI 0.12, 0.20 -0.10, -0.02
Versus placebo
LS mean diff 0.23
95% CI of diff 0.18, 0.27
P-value <0.001
Baseline FEV1 AUC0-3h is defined as trough FEV1. P-values are based on analysis of covariance model with
terms for treatment, site number, and FEV1 AUC at baseline as covariates. The p-value for the treatment-by-
site interaction was 0.429.
FAS = full analysis set; SD = standard deviation; LS = least squares; CI = confidence interval; diff = difference;
FEV1 = forced expiratory volume in 1 second; AUC = area under the curve; AUC0-3h = AUC normalized over
3 hours.
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At Week 24, a mean increase from baseline in trough FEV1 of 0.08 L was observed for the
tiotropium group and a mean decrease of 0.05 L was observed for the placebo group.
Furthermore, a significant LS mean difference with tiotropium from placebo was observed
(see Figure 2). This treatment effect for trough FEV1 was observed at all 3 study visits.

Figure 2. Summary (Mean SE) and Analysis of Trough FEV1 in Liters - FAS
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FAS = full analysis set; SE = standard error; FEV1 = forced expiratory volume in 1 second; Diff = difference;
LSM = least squares mean; CI = confidence interval.

At Week 24 for the FAS, the mean increase from baseline in peak FEV1 was significantly
larger for the tiotropium group (0.28 L) vs the placebo group (0.04 L), with an LS mean
difference vs placebo of 0.24 (p <0.001). This treatment effect for peak FEV1 was observed
at all 3 study visits (Weeks 8, 16, and 24).

At baseline, FVC AUC0-3h (which is defined as baseline trough FVC) was between treatment
groups. At Week 24 for the FAS, a mean increase from baseline in FVC AUC0-3h of 0.23 L
was observed for the tiotropium group and a mean decrease of 0.06 L was observed for the
placebo group. A significant difference in the change from baseline to Week 24 was
observed in favor of tiotropium (LS mean difference vs placebo, 0.31 L; p <0.001). This
treatment effect for FVC AUC0-3h was observed at each of the 3 study visits (Weeks 8, 16,
and 24), and at each time point the treatment effect appeared to be sustained over 3 hours.

Trends with other FVC parameters were similar to those of analogous FEV1 parameters and
significant differences vs placebo were observed at Week 24 in favor of tiotropium for trough
FVC (LS mean difference vs placebo, 0.21 L; p <0.001) and for peak FVC (LS mean
difference vs placebo, 0.33; p <0.001). Treatment effects for were observed at each of the
3 study visits.

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Use of albuterol prn was infrequent and was similar between treatment groups throughout the
study.

For the physician’s global assessment, at baseline, approximately 58% of subjects in both
treatment groups received a physician’s global assessment of “good”; in addition, subjects in
the tiotropium group were somewhat less frequently considered to be “excellent” compared
with the placebo group at baseline (7.5% vs 11.1%). At Week 24, subjects in the tiotropium
group were more frequently classified by their physician as “excellent” vs those in the
placebo group (18.1% vs 10.9%) and less frequently classified as “poor/fair” vs those in the
placebo group (19.0% vs 25.4%). This difference between groups in this assessment reached
significance at Week 24 (p = 0.045). For the patient’s global assessment, trends were similar
to those observed with the physician’s global assessment, but with a significant difference
only at Week 12 (p = 0.010), in favor of the tiotropium group.

For all physical activity endpoints, after adjustment for baseline values, no significant
differences were observed between treatment groups in mean logarithmic minutes per day in
light (Figure 3) or in moderate or higher activity (Figure 4) using age-appropriate predefined
activity METs. Since the time spent in physical activity was skewed, logarithmic
transformation was used to get the distribution of time approximately bell shaped.

Figure 3. Summary (Mean ±SE) and Analysis of Logarithm Minutes/Day in Light

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Activity (Using Age-Appropriate Predefined METs) - ActES

ActES = Activity Evaluable Set; SE = standard error; METs = metabolic equivalents; Diff = difference;
LSM = least squares mean; CI = confidence interval.

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Figure 4. Summary (Mean ±SE) and Analysis of Logarithm Minutes/Day in Moderate

or Higher Activity (Using Age-Appropriate Predefined METs) - ActES
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SE = standard error; METs = metabolic equivalents; Diff = difference; LSM = least squares mean; CI =
confidence interval.

For mean number of steps per day, no significant differences were observed between
treatment groups after adjustment for baseline values. However, there was a trend toward a
mean greater number of steps in favor of the tiotropium group at Weeks 8 through 24. No
clear trends between treatment groups were observed in the change from baseline in the
proportion of subjects maintaining a healthy lifestyle or in energy expenditure as determined
by activity monitoring.

Work productivity and activity impairment using the WPAI questionnaire indicated that this
measure was generally similar between the 2 treatment groups for the FAS. For 1 WPAI
endpoint (change from baseline in percent activity impairment due to health) at Week 24
only, a significant difference was observed that favored the tiotropium group (LS mean
difference vs placebo -3.76; p-value = 0.043).

The association between health-related quality of life instruments (CCQ and CRQ) with
physical-activity data was assessed using correlation analysis. A significant positive
correlation was observed between the less fatigue (CRQ domain score) with more frequent
light (p <0.001) and moderate or greater activity (p <0.001). Similarly, less dyspnea and
emotionality (CRQ domain score) were associated with more frequent moderate or greater
activity (p = 0.012 and p = 0.005, respectively). Correlation analysis using the total CCQ
score indicated a significant relationship between less severe COPD symptoms and more

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frequent moderate or greater activity (p = 0.012 and p = 0.005, respectively). Similarly,

lower scores in the functional domain score of CCQ (ie, less severe COPD characteristics)
significantly correlated with more moderate or greater activity (p = 0.018) but not with more
light activity.

Safety Results: No deaths occurred in this study. Treatment-emergent SAEs were reported
for 10 and 11 subjects in the tiotropium and placebo groups, respectively; 1 additional
non-treatment-emergent SAE occurred in the tiotropium group; no SAEs were considered
related to the study treatment (see Table 5). Overall, all-causality and treatment-related AEs
were infrequent and most AEs were not considered treatment related. AEs were experienced
less frequently in the tiotropium vs placebo group (see Table 5). The incidence of AEs
observed for 1% of subjects in either treatment group, by decreasing cumulative frequency
is summarized in Table 6.

The lower incidence of COPD, cough, bronchitis, and dyspnea reported in the tiotropium
group vs the placebo group is consistent with the observed improvements in pulmonary
function.

Table 5. Treatment-Emergent Adverse Events – All Causality and Treatment

Related
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All Causality Treatment Related

No. of Subjects (%) Tiotropium Placebo Tiotropium Placebo
Subjects evaluable for AEs 238 219 238 219
Number of AEs 185 205 11 16
Subjects with
AEs 95 (39.9) 98 (44.7) 8 (3.4) 14 (6.4)
Serious AEs 10 (4.2) 11 (5.0) 0 0
Severe AEs 10 (4.2) 12 (5.5) 1 (0.4) 2 (0.9)
Discontinued due to AEs 4 (1.7) 6 (2.7) 1 (0.4) 1 (0.5)
Temporary discontinuation due to AEsa 4 (1.7) 6 (2.7) 1 (0.4) 2 (0.9)
Includes data 30 days after last dose of study drug. Except for the number of AEs, subjects are counted only
once per treatment in each row. Serious AEs were according to the investigator’s assessment.
Medical Dictionary for Regulatory Activities (v13.0) coding dictionary applied.
AE = adverse event.
a
Dose reduction did not occur for this study.

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Table 6. Incidence of Treatment-Emergent AEs (1% in either Treatment Group) –

by Decreasing Cumulative Frequency

MedDRA Preferred Term All Causality Treatment Related

No. of Subjects (%) Tiotropium Placebo Tiotropium Placebo
Subjects evaluable for AEs 238 219 238 219
COPD (ie, exacerbation of COPD)a 11 (4.6) 24 (11.0) 0 2 (0.9)
Nasopharyngitis 16 (6.7) 11 (5.0) 0 0
Upper respiratory tract infection 7 (2.9) 5 (2.3) 0 1 (0.5)
Cough 4 (1.7) 8 (3.7) 1 (0.4) 3 (1.4)
Bronchitis 2 (0.8) 8 (3.7) 0 2 (0.9)
Diarrhea 6 (2.5) 3 (1.4) 0 0
Headache 2 (0.8) 5 (2.3) 1 (0.4) 1 (0.5)
Influenza 4 (1.7) 2 (0.9) 0 0
Respiratory tract infection 3 (1.3) 3 (1.4) 0 0
Rhinitis 2 (0.8) 4 (1.8) 0 0
Dry mouth 3 (1.3) 2 (0.9) 3 (1.3) 1 (0.5)
Respiratory tract infection viral 3 (1.3) 2 (0.9) 0 0
Hypertension 3 (1.3) 2 (0.9) 1 (0.4) 0
Arthralgia 2 (0.8) 3 (1.4) 0 0
Dyspnea 0 5 (2.3) 0 0
Nausea 3 (1.3) 1 (0.5) 0 0
Herpes zoster 3 (1.3) 1 (0.5) 0 0
Bronchitis chronic 1 (0.4) 3 (1.4) 0 0
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Back pain 0 4 (1.8) 0 0

Hyperglycemia 0 3 (1.4) 0 1 (0.5)
Epistaxis 0 3 (1.4) 0 2 (0.9)
Subjects are counted only once per treatment in each row. Includes data 30 days after last dose of study drug.
Medical Dictionary for Regulatory Activities (v13.0) coding dictionary applied.
AE = adverse event; COPD = chronic obstructive pulmonary disease; MedDRA = Medical Dictionary for
Regulatory Activities.
a
The preferred term was COPD; however, since COPD was an inclusion criterion for the study, the investigator
entry for this term for all subjects was “exacerbation of COPD”, “COPD exacerbation”, or a similar term.

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Permanent discontinuations due to AEs were observed for 5 and 6 subjects in the tiotropium
and placebo groups, respectively (see Table 7).

Table 7. Permanent Discontinuations due to Adverse Events

MedDRA PT Severity Outcome Causality SAE?

Tiotropium
Hip fracture Severe Resolved Other – accident Yes
Urinary tract infection Severe Resolved Other illness – urinary Yes
infection
COPDa Moderate Resolved Disease under study Yes
Cerebral infarction Severe Resolved Other – hypertension Yes
Headache Moderate Still present Study drug No
Placebo
Aphthous stomatitis Mild Resolved Other – smoking No
COPD Severe Resolved Disease under study Yes
Kidney infection Severe Still present Other illness – bacterial infection No
COPD Severe Resolved Disease under study Yes
Cough Mild Resolved Study drug No
Coronary artery disease Severe Resolved Otherb
Medical Dictionary for Regulatory Activities (v13.0) coding dictionary applied.
MedDRA = Medical Dictionary for Regulatory Activities; PT = preferred term; SAE = serious adverse event; COPD
= chronic obstructive pulmonary disease.
a
This event was not treatment emergent.
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b
Previously unknown background of coronary artery disease, which resulted in triple bypass surgery.

Treatment-emergent SAEs were reported for 10 and 11 subjects in the tiotropium and
placebo groups, respectively; 1 additional non-treatment-emergent SAE occurred in the
tiotropium group (see Table 8). No SAEs were considered related to the study drug; subjects
recovered from all events.

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Table 8. Serious Adverse Events

MedDRA Preferred Term Therapy Event Action Investigator Clinical Outcome/
(v13.0) Stop Day Onset Taken Causality Seriousness
Day (Drug
Level)
Tiotropium
Hip fracture 137 134 Perm d/c Unrelated Recovered/hosp
Urinary tract infection 105 105 Perm d/c Unrelated Recovered/hosp
Abdominal abscess 169 49 No action Unrelated Recovered/hosp
Joint abscess 158 9 No action Unrelated Recovered/hosp
Bladder transitional cell 170 133 No action Unrelated Recovered/hosp
carcinoma
Pancreatic cyst 169 141 No action Unrelated Recovered
Pancreatitis chronic 169 64 Unrelated Recovered with
sequelae/disability
COPD exacerbationa,b 45 45 Perm d/c Unrelated Recovered/hosp
Tendon disorder 169 129 No action Unrelated Recovered/hosp
Cerebral artery occlusion 169 24 Temp d/c Unrelated Recovered/hosp
Streptococcal infection 177 110 No action Unrelated Recovered/hosp
Cerebral infarction 137 137 Perm d/c Unrelated Recovered/hosp
Placebo
Acute exacerbation of COPDa 49 49 Perm d/c Unrelated Recovered/hosp
Renal failure acute 148 65 Perm d/c Unrelated Recovered/hosp
Atrial fibrillation 112 37 No actionc Unrelated Recovered/hosp
COPD exacerbationa
Cardiac failure
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Angina pectoris 169 43 No action Unrelated Recovered/hosp

Rectal polyp 169 91 No action Unrelated Recovered/hosp
Myocardial ischemia 142 128 Perm d/c Unrelated Recovered/hosp
Coronary artery stenosis
Acute exacerbation of COPDa 32 37 NA Unrelated Recovered/hosp
Acute on chronic hypoxemic Unrelated Recovered/hosp
respiratory failurea
Acute respiratory failure Unrelated Recovered/hosp
BNP abnormal Unrelated Recovered
Troponin increased Unrelated Recovered
Hyponatriaemia Unrelated Recovered
Sinus tachycardia Unrelated Recovered
Dehydration Unrelated Recovered
Cholelithiasis 165 136 No action Unrelated Recovered
Renal failure chronic Unrelated Recovered
Hepatic cirrhosis Unrelated Recovered
Portal hypertension Unrelated Recovered
Normochromic normocytic 165 93 Unrelated Recovered/hosp
anemia
Acute exacerbation of COPDa 121 122 Perm d/c Unrelated Recovered/hosp
Pancreatitis acute 173 166 No action Unrelated Recovered/hosp
Coronary diseasea 22 22 Perm d/c Unrelated Recovered/hosp
Only enrolled and randomized subjects are included in this in-text table. MedDRA = Medical Dictionary for Regulatory
Activities; COPD = chronic obstructive pulmonary disease; perm = permanent; d/c = discontinuation; hosp =
hospitalization; temp = temporary; BNP = brain natriuretic peptide; NA = not applicable, because the event onset was
subsequent to the end of therapy.
a
Investigator entry term; for the AEs of acute on chronic hypoxemic respiratory failure and coronary disease, no MedDRA
preferred term was provided; for the remaining AEs, either the MedDRA preferred term was COPD or no MedDRA
preferred term was provided.
b
This event was not treatment emergent.
c
This discontinuation was due to unblinding after these SAEs and did not result from the AEs themselves.

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Protocol A4471008 – 01 December 2010 – Final

CONCLUSIONS:

 The primary objective of this study was met. This study demonstrated that tiotropium
plus prn albuterol (salbutamol) was more effective in improving the FEV1 AUC0-3h
postdose response compared with placebo plus prn albuterol (salbutamol) after
24 weeks of treatment in subjects with GOLD Stage 2 COPD when used as
maintenance therapy.

 In subjects with GOLD Stage 2 COPD, tiotropium was more effective than placebo in
increasing pulmonary function test parameters (eg, FVC AUC0-3h, trough FEV1 and
FVC, and peak FEV1 and FVC) from baseline to Week 24.

 Although the average time spent per day in physical activity and the number of steps
taken per day were numerically higher in the tiotropium group, the adjusted mean
change from baseline was similar between treatment groups.

 In general, other endpoints such as rescue use of albuterol, healthy lifestyle, work
productivity, and activity impairment were comparable between the 2 groups.
However, the percent activity impairment due to health at Week 24 was significantly
lower in subjects treated with tiotropium compared with placebo.
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 At Week 24, the physician’s global assessment indicated a significantly more

favorable assessment for subjects in the tiotropium group vs those in the placebo
group. Trends for the patient’s global assessment were similar, but, the differences
between groups were significant only at Week 12.

 Tiotropium was well tolerated and the safety results were consistent with the previous
safety experience for this drug and label.

o The lower incidence of COPD, cough, bronchitis, and dyspnea reported in the
tiotropium group vs the placebo group is consistent with the observed
improvements in pulmonary function.

o Among subjects enrolled in the study, no deaths were reported;

treatment-emergent SAEs were experienced by 10 subjects in the tiotropium
group and 11 subjects in the placebo group; but, none were considered
treatment related.

o One subject in each treatment group experienced a treatment-emergent,

treatment-related AE that resulted in permanent discontinuation from the
study.

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