abcd     Clinical Study Synopsis for Public Disclosure  This clinical study synopsis is provided in line with Boehringer Ingelheim’s Policy on Transparency and Publication of Clinical Study Data.   The synopsis ‐ which is part of the clinical study report ‐ had been prepared in accordance with best practice and applicable legal and regulatory requirements at the time of study completion.  The synopsis may include approved and non‐approved uses, doses, formulations, treatment regimens and/or age groups; it has not necessarily been submitted to regulatory authorities.  A synopsis is not intended to provide a comprehensive analysis of all data currently available regarding a particular drug.  More current information regarding a drug is available in the approved labeling information which may vary from country to country..  Additional information on this study and the drug concerned may be provided upon request based on Boehringer Ingelheim’s Policy on Transparency and Publication of Clinical Study Data.  The synopsis is supplied for informational purposes only in the interests of scientific disclosure. It must not be used for any commercial purposes and must not be distributed, published, modified, reused, posted in any way, or used for any other purpose without the express written permission of Boehringer Ingelheim.  

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Full Clinical Study Rep01t Protocol A4471008

CLINICAL STUDY REPORT SYNOPSIS

Clinical Study Report Synopsis: Protocol A4471008

Protocol Title: A 24 Week, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of 18 meg of Tiotropium Inhalation Capsules Administered by Handihaler® Once-Daily Plus pm Albuterol (Salbutamol) vs. Placebo Plus pm Albuterol (Salbutamol) in Chronic Obstructive Pulmonmy Disease Subjects Naive to Maintenance Therapy

Study Centers: Overall 70 centers (of which, 11 did not randomize subjects); Belgium 4 centers; Canada 4 centers (of which, 2 did not randomize subjects), Czech Republic 12 centers; Gennany 5 centers; Greece 4 centers; Netherlands 4 centers; Portugal 3 centers; Ukraine 7 centers; United Kingdom 4 centers; (of which, 2 did not randomize subjects); and United States 23 centers (7 did not randomize subjects) .

Publications Based on the Study: None .

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

Phase of Development: Phase 4

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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 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.

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).

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]).

Approximately 436 subjects were to be randomized in a ratio of 1:1 at baseline to receive either tiotropium or matching placebo.

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, 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 betreated previously with maintenance medications for chronic respiratory disease (eg, long acting β-agonists, inhaled anticholinergics, inhaled or systemic corticosteroids, theophylline, leukotriene receptor antagonists) 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:

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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 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).

Pharmacokinetic, Pharmacodynamic, and/or Other Evaluations: No pharmacokinetic, pharmacodynamic, or other evaluations were performed in this study.

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.

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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) 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 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

Healthy lifestyle, defined as 30 minutes >3 METS activity for 70% of eligible days

Active energy expenditure (kcal/day)

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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.

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 S1).

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Table S1. Subject Disposition

No. of Subjects (%) Tiotropium18 μg/capsule

Placebo

Screened, 933Randomized 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) 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 safetyAdverse events 238 (100.0) 219 (100.0)

Discontinuations occurring outside the lag period were attributed to the last study treatment received.a Subject was discontinued due to unblinding of the subject’s data as a result of a serious adverse event; however, because the discontinuation did not result from the adverse event itself; the discontinuation was categorized as due to “Other” .b Subject completed the study but had no Week 24 FEV1 data and was therefore excluded from the Completers Set.

Demographic characteristics are provided in Table S2. The 2 treatment groups were generally comparable with respect to demographics.

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Table S2. Demographic Characteristics

Tiotropium 18 μg/capsule PlaceboNo. of Subjects (%) Male Female Total Male Female Total

166 72 238 147 72 219Age (years)

Mean 61.2 61.1 61.2 62.9 61.0 62.3SD 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 83.2SD 15.8 14.4 16.6 18.6 18.5 20.1

Height (cm)Mean 174.5 164.2 171.4 174.2 162.8 170.5SD 6.9 6.3 8.2 6.2 6.8 8.3

Smoking statusEx 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.

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 S2 and Table S3).

Table S3. Pulmonary Function Test and COPD Characteristics at Screening

Tiotropium 18 μg/capsuleN = 238

PlaceboN = 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 S4 and Figure S1). 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 S4 and Figure S1). This treatment effect for FEV1 AUC0-3h was observed at each of 09

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the 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 S1. Summary (Mean SE) and Analysis of FEV1 AUC0-3h - FAS

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 S4. Change from Baseline in FEV1 AUC0-3h in Liters - FAS

Raw Values Change from BaselineStudy Visit Parameter Tiotropium

N = 227PlaceboN = 207

TiotropiumN = 227

PlaceboN = 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 -0.0695% CI 0.12, 0.20 -0.10, -0.02Versus placebo

LS mean diff 0.2395% CI of diff 0.18, 0.27P-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 S2). This treatment effect for trough FEV1 was observed at all 3 study visits.

Figure S2. Summary (Mean SE) and Analysis of Trough FEV1 in Liters - FAS

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 comparable between treatment groups. At Week 24 for the FAS, a mean increase from baseline in FVCAUC0-3h 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.

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Trends with other FVC parameters (trough and peak FVC), were similar to those of analogous FEV1 parameters and significant differences vs placebo were observed at Week 24 in favor of tiotropium. Treatment effects for were observed at each of the 3 study visits.

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 S3) or in moderate or higher activity (Figure S4) 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.

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Figure S3. Summary (Mean ±SE) and Analysis of Logarithm Minutes/Day in Light 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 S4. Summary (Mean ±SE) and Analysis of Logarithm Minutes/Day in Moderate or Higher 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.

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

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score indicated a significant relationship between less severe COPD symptoms and more 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.

Pharmacokinetic, Pharmacodynamic, and/or Other Results: No pharmacokinetic, pharmacodynamic, or other evaluations were performed in this study.

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 for Subject in the tiotropium group; no SAEs were considered related to the study treatment (see Table S5). 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 S5). The incidence of AEs observed for 1% of subjects in either treatment group, by decreasing cumulative frequency is summarized in Table S6.

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 S5. Treatment-Emergent Adverse Events – All Causality and Treatment Related

All Causality Treatment RelatedNo. of Subjects (%) Tiotropium Placebo Tiotropium PlaceboSubjects evaluable for AEs 238 219 238 219Number of AEs 185 205 11 16Subjects with

AEs 95 (39.9) 98 (44.7) 8 (3.4) 14 (6.4)Serious AEs 10 (4.2) 11 (5.0) 0 0Severe 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 S6. Incidence of Treatment-Emergent AEs (1% in either Treatment Group) –by Decreasing Cumulative Frequency

MedDRA Preferred Term All Causality Treatment RelatedNo. of Subjects (%) Tiotropium Placebo Tiotropium PlaceboSubjects evaluable for AEs 238 219 238 219COPD (ie, exacerbation of COPD) a 11 (4.6) 24 (11.0) 0 2 (0.9)Nasopharyngitis 16 (6.7) 11 (5.0) 0 0Upper 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 0Headache 2 (0.8) 5 (2.3) 1 (0.4) 1 (0.5)Influenza 4 (1.7) 2 (0.9) 0 0Respiratory tract infection 3 (1.3) 3 (1.4) 0 0Rhinitis 2 (0.8) 4 (1.8) 0 0Dry mouth 3 (1.3) 2 (0.9) 3 (1.3) 1 (0.5)Respiratory tract infection viral 3 (1.3) 2 (0.9) 0 0Hypertension 3 (1.3) 2 (0.9) 1 (0.4) 0Arthralgia 2 (0.8) 3 (1.4) 0 0Dyspnea 0 5 (2.3) 0 0Nausea 3 (1.3) 1 (0.5) 0 0Herpes zoster 3 (1.3) 1 (0.5) 0 0Bronchitis chronic 1 (0.4) 3 (1.4) 0 0Back pain 0 4 (1.8) 0 0Hyperglycemia 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 S7).

Table S7. Permanent Discontinuations due to Adverse Events

Subject MedDRA PT Severity Outcome Causality SAE?Tiotropium

Placebo

MedDRA (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.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 andplacebo groups, respectively; 1 additional non-treatment-emergent SAE occurred for Subject in the tiotropium group (see Table S8). No SAEs were considered related to the study drug; subjects recovered from all events.

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Full Clinical Study Rep01t Protocol A4471008

CLINICAL STUDY REPORT SYNOPSIS

Table S8. Serious Adverse Events

Subject M edDRA (v13.0) Prefened Term

are mc:mc1e.a

Action Taken (Drug Level)

Investigator Causality

Clinical Outcome/Seliousness

MedORA = Medical Dictiona1y for Regulatoty Activities; COPD = clu·onic obstmctive puhuonaty disease; perm = petmanent; die = discontinuation; hosp = hospitalization; temp = temporaty; BNP = brain nati-.iuretic peptide; NA = not applicable, because the event onset was subsequent to the end of • Investigator entry · MedDRA term was COPD or no MedORA preferred tenu was frovided (Subj

This event was was due to unblinding after these SAEs and did not result from the AEs

themselves .

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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 meanchange 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.

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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