Clinical trial NCT03118765
Conditions: Mild to Moderate Chronic Obstructive Pulmonary Disease (COPD)
Sponsor: Glenmark Specialty S.A.
Start date: 2017-03-24; Completion date: 2017-07-31
Enrollment: 155 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Pharmacodynamic and Pharmacokinetic Dose Ranging Study of Tiotropium Bromide Administered Via Inhalation Solution in Patients With Chronic Obstructive Pulmonary Disease (COPD).

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None
Interventions: intervention 1: GSP304 (tiotropium bromide) Inhalation Solution intervention 2: GSP304 Placebo Inhalation Solution intervention 3: Spiriva® Respimat® inhalation spray
Intervention descriptions: intervention 1: Once daily (QD) oral inhalation using a nebulizer intervention 2: Once daily (QD) oral inhalation using a nebulizer intervention 3: Once daily (QD) oral inhalation

Protocol documents:
Prot_001.pdf: 
 
         
 
Confidential 
 
 
                      Page 1 of 1 
 
 
 
Tiotropium Bromide Inhalation Solution GSP304-201 A Dose Ranging, Parallel Group, Active 
(Spiriva® Respimat®) And Placebo Controlled Study To Assess Relative Bioavailability, 
Pharmacodynamics And Safety Of Three Doses Of Tiotropium Bromide Inhalation Solution In 
Subjects With Mild To Moderate Chronic Obstructive Pulmonary Disease. 
 
Identifiers  
                 NCT03118765    
 
Date of Document            13 April 2017 


Protocol Number: GSP304-201 
 
Version 3.0 
 
 
Date: 11-Apr-2017 
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1. 
TITLE PAGE 
TIOTROPIUM BROMIDE INHALATION SOLUTION 
GSP304-201 
A DOSE RANGING, PARALLEL GROUP, ACTIVE 
(SPIRIVA
® RESPIMAT®) AND PLACEBO-
CONTROLLED STUDY TO ASSESS RELATIVE 
BIOAVAILABILITY, PHARMACODYNAMICS AND 
SAFETY OF THREE DOSES OF TIOTROPIUM 
BROMIDE INHALATION SOLUTION IN SUBJECTS 
WITH MILD TO MODERATE CHRONIC 
OBSTRUCTIVE PULMONARY DISEASE 
 
Phase of Development 
Phase 2  
Sponsor 
Glenmark Specialty SA 
Avenue Léopold-Robert 37  
2300 La Chaux-de-Fonds 
Switzerland 
Protocol Number 
GSP304-201 
IND Number 
131794 
Approved by 
Fred Grossman, DO, FAPA 
Protocol Version 
Version 3.0 Final 
Date 
11-Apr-2017 
Supersedes 
Version 2.0 
PROTOCOL HISTORY 
Original protocol 
Version 1.0, 11-Oct-2016 
Amendment 1 
Version 2.0, 05-Jan-2017 
Amendment 2 
Version 3.0, 11-Apr-2017 
 
This study must be conducted in accordance with International Conference on Harmonisation 
(ICH) guidelines on Good Clinical Practice (GCP) and with the applicable regulatory 
requirements. 


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INVESTIGATOR’S AGREEMENT 
 
I have received and read the Investigator’s Brochure for GSP304 (tiotropium bromide) Inhalation 
Solution.  I have read the GSP304-201 protocol and agree to conduct the study as outlined.  I 
agree to maintain the confidentiality of all information received or developed in connection with 
this protocol. 
 
 
 
                         
Printed Name of Investigator: 
 
                         
Signature of Investigator 
 
             
Date 
 
 
 




Protocol Number: GSP304-201 
 
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2. 
SYNOPSIS 
Name of Sponsor/Company: 
Glenmark Specialty, SA   
Name of Investigational Product: 
GSP304 (tiotropium bromide) Inhalation Solution  
Name of Active Ingredient: 
Tiotropium Bromide 
Title of Study:  
A Dose Ranging, Parallel Group, Active (Spiriva® Respimat®) and Placebo-controlled Study to Assess 
Relative Bioavailability, Pharmacodynamics and Safety of Three Doses of Tiotropium Bromide 
Inhalation Solution in Subjects With Mild to Moderate Chronic Obstructive Pulmonary Disease 
Phase of development: 2 
Objectives:  
Primary: 
To assess the relative bioavailability of GSP304 (tiotropium bromide) Inhalation Solution at dose 
levels of 10 μg, 20 μg, and 40 μg once daily (QD) compared with Spiriva® Respimat® inhalation spray 
(5 μg QD) in subjects with COPD. 
To characterize the dose response of GSP304 at dose levels of 10 μg, 20 μg, and 40 μg with respect to 
pharmacodynamics (PD).  
Secondary: 
To assess the safety and tolerability of GSP304 at dose levels of 10 μg, 20 μg, and 40 μg QD. 
Methodology:  
This is a phase 2, randomized, parallel group, active- and placebo-controlled, 5-arm study to compare 
the PK profile of 3 blinded doses of GSP304 with open label Spiriva® Respimat®.  The study will also 
evaluate the dose response PD profile of 3 blinded doses of GSP304 compared with blinded GSP304 
placebo, using spirometry in subjects with mild to moderate COPD.  A total of 155 male and female 
subjects will be randomized in a 1:1:1:1:1 ratio to one of 5 treatment arms.  A subject will receive 1 of 
the 3 double-blind doses of GSP304, or double-blind GSP304 placebo, or open-label Spiriva® 
Respimat®.  The study will include a screening period of up to 2 weeks, followed by a 2 week run-in 
period, 3 weeks of treatment, and a 2 week post treatment follow up period.  The total duration of study 
participation will be approximately 9 weeks.  In this study, PK of tiotropium in plasma and urine will 
be assessed on Day 1 and on Day 21 (at steady state). 
Number of subjects (planned):  
A total of 155 subjects will be randomized in this study. 
Study Endpoints 
Primary Endpoints 
• The PK endpoints for tiotropium in plasma to assess the relative bioavailability are: 
- Peak concentrations during the dosing interval at steady-state (C
maxSS) 
- Area under the plasma concentration-time curve over the dosing interval at steady state 
(AUC
0-tauSS) 


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• Change from baseline in trough forced expiratory volume in one second (FEV1) at 24 hours 
after the last dose of treatment on Day 21 in comparison with placebo 
Secondary Endpoints 
• Amount (A
etau) and fraction of dose (F
e) of tiotropium excreted in urine over the dosing 
interval on Day 1 and Day 21 
• Peak concentrations during the dosing interval (Cmax) on Day 1  
• Area under the plasma concentration-time curve over the dosing interval (AUC
0-tau) on Day 1 
• Time of peak drug concentration over the dosing interval (tmax) on Day 1 and Day 21 
• Average concentration during a dosing interval at steady state (C
avSS) on Day 21 
• Accumulation ratio (Rac)  
• Change from baseline in peak FEV1 within 12 hours post-dose  on Day 1 and Day 21 
• Change from baseline in forced vital capacity (FVC) on Day 1 and Day 21  
• Change from baseline in time-normalized area under the curve for FEV1 measured over 
12 hours on Day 1 and Day 21 
Safety Endpoints 
• Vital signs, laboratory parameters, 12-lead electrocardiogram (ECG)  
• Incidence of all adverse events (AEs) 
Diagnosis and main criteria for inclusion:  
Males and females of non-childbearing potential ≥40 and ≤85 years of age with a primary clinical 
diagnosis of mild to moderate COPD, a FEV1/FVC ratio of <70% and a baseline FEV1 of ≥50% of 
predicted normal value as per the NHANES III predicted normal values at screening. 
Investigational product, dosage and mode of administration:  
Name of Investigational Products:  
Test Treatment T1: GSP304 (tiotropium bromide) Inhalation Solution, 10 µg   
Test Treatment T2: GSP304 (tiotropium bromide) Inhalation Solution, 20 µg   
Test Treatment T3: GSP304 (tiotropium bromide) Inhalation Solution, 40 µg   
Dosage Form: Inhalation Solution 
Dosage: Oral inhalation of either T1, T2, or T3  
Dosage Frequency: Once daily (QD) 
Mode of Administration: By oral inhalation using a nebulizer 
Comparator, dosage and mode of administration:  
Placebo to match GSP304   
Dosage Form: Inhalation Solution 
Dosage: Oral inhalation  
Dosage Frequency: QD 
Mode of Administration: By oral inhalation using a nebulizer 
Reference therapy, dosage and mode of administration:  
Name of Comparator: Spiriva® Respimat® inhalation spray 2.5 µg per actuation  


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Name of Sponsor/Company: 
Glenmark Specialty, SA   
Dosage Form: Inhalation Spray 
Dosage: 5 µg (2 actuations of 2.5 µg each) 
Dosage Frequency: Once daily (QD) 
Mode of Administration: By oral inhalation using Respimat® Soft Mist Inhaler 
Duration of treatment:  
3 weeks (21 days) 
Criteria for evaluation: 
Efficacy: 
Spirometry 
FEV1 and FVC  
Refer to ‘Pharmacodynamic Assessments’ sub-section below. 
Pharmacokinetic, Pharmacodynamic, Biomarker, and Pharmacogenomic Assessments: 
Pharmacokinetic Assessments 
Blood samples (approximately 6 mL) will be collected in dipotassium ethylenediaminetetraacetic acid 
(EDTA) coated vacutainers on Day 1 and Day 21 according to the below schedule: Pre-dose (0 hour), 
and 2, 4, 6, 10, 15, 30, 45, 60, 75, and 90 minutes post-dose, as well as 2, 4, 6, 8, 12, 16, 20 and 
24 hours post-dose.  The pre-dose sample on Day 1 should be collected within 30 minutes prior to 
dosing while on Days 7, 14, and 21 the pre-dose sample should be collected within 10 minutes prior to 
the morning dose.  On Day 1 and Day 21, samples will be collected within the following collection 
windows:  
For the 2 minute sample, within a window of ±30 seconds 
For the 4, 6, 10, 15, and 30 minute samples, within a window of ± 1 minute  
For the 45, 60, 75, 90 minute, and 2.0 hour samples, within a window of ± 2 minutes 
For the 4, 6, 8, 12, 16, 20 and 24 hour samples, within a window of ± 5 minutes.   
In addition, urine will be collected into pre-weighed containers at pre-dose (within 1 hour prior to 
dosing), and at the following intervals post-dose from 0-6, 6-12, and 12-24 hours on Day 1 and Day 21.  
Collection time intervals and the accurate weights of containers before and after urine collection at 
each interval will be noted.  In each urine container, approximately 5 mL of 1M citric acid must be 
added prior to start of collection.  Plasma and urine concentrations of tiotropium will be quantified by a 
validated liquid chromatography-mass spectrometry (LC/MS/MS) method.   
Pharmacokinetic Parameters 
Plasma: 
• AUC0-tauSS  
•  C
maxSS, C
minSS, C
avSS  
•  C
max on Day 1 
•  t
max on Day 1 and Day 14 
• AUC0-tau on Day 1 
•  R
ac  
Urine: 
•  A
etau and Fe 


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Additional Pharmacokinetics 
Additional parameters may be evaluated depending on the data obtained during the study. 
Pharmacodynamic, Biomarker, and Pharmacogenomic Assessments 
In addition to screening, pre-dose FEV1 and FVC will be assessed at -45 minutes and -15 minutes prior 
to dosing on Day 1, Day 7, Day 14, and Day 21.  Trough FEV1 will be assessed on Day 22 (ie, 
24 hours after the Day 21 dose). 
On Day 1 and Day 21, FEV1 will be recorded, at the following time points after the morning dose: 
immediately post-dose at 5 minutes (±3 minutes), 15 minutes (±2 minutes), 30 minutes (±5 minutes), 
60 minutes, 90 minutes, and 2 hours (120 minutes); and post-dose at 4, 6, 8, 10, 12, 23 hours 
15 minutes and 23 hours 45 minutes post dose.  The window for 1-hour spirometry and thereafter is 
±5 minutes. 
FEV1 
FEV1 is the volume of air forcibly exhaled in one second as measured by a spirometer.  
Pre- dose trough FEV1  
It is defined as the mean of FEV
1 values obtained -45 minutes and -15 minutes pre-morning dose at 
Day 1.  
Peak FEV1 
It is defined as the maximum FEV
1 over the period of 12 hours post-morning dose.  
Trough FEV1 
It is defined as the mean FEV
1 obtained 23 hours 15 minutes and 23 hours 45 minutes post-morning 
dose of the previous day.  
Baseline FEV1 
It is defined as the average of the pre-dose FEV1 measured at -45 minutes and -15 minutes at Day 1   
FVC 
FVC is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath 
possible. 
Baseline FVC  
It is defined as the average of the pre-dose FVC measured at -45 minutes and -15 minutes at Day 1. 
Safety: 
Safety assessments will consist of monitoring and recording all AEs and serious adverse events 
(SAEs), clinical laboratory measurements, vital signs, 12-lead ECG, and physical examinations. 
Statistical methods: 
Detailed statistical methods will be provided in the Statistical Analysis Plan (SAP). 
Analysis Sets 
Full Analysis Set (FAS) 
This will include all subjects who are randomized, have received at least 1 dose of study medication 
and have at least 1 post-baseline PD assessment.  This analysis set will be the primary analysis set for 
the PD endpoints. 
Safety Analysis Set (SAF) 
This will include all subjects who are randomized and received at least 1 dose of study medication.  All 
safety endpoints will use the SAF unless otherwise specified. 


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Per Protocol Analysis Set (PP) 
This will include all subjects who are randomized, received at least 1 dose of study medication, 
completed the study and do not have exclusionary major protocol deviations.  Major and exclusionary 
protocol deviations will be defined in the SAP and by clinical review prior to unblinding. 
PK Analysis Set (PKAS) 
This will include all subjects who are randomized, received at least 1 dose of study treatment and have 
at least 1 quantifiable PK sample and do not have exclusionary major protocol deviations.  The PKAS 
will be used to analyze the PK endpoints unless otherwise specified in the SAP.  Major and 
exclusionary protocol deviations will be defined in the SAP and by clinical review prior to unblinding. 
Determination of Sample Size  
A sample size of 28 subjects per treatment arm will have 90% power to detect a difference in mean 
change from baseline in trough FEV1 of 150 mL between GSP304 and GSP304 placebo assuming a 
2-sided alpha of 5% and a standard deviation (SD) of 170 mL.  These assumptions are based on 
available literature from similar studies conducted for Spiriva
® Respimat®. 
Given the overall 1:1:1:1:1 study treatment allocation ratio, 140 subjects are required for the analysis of 
the primary endpoint.  Assuming a dropout rate of approximately 10%, a total of 155 subjects 
(31 subjects per treatment arm) will be randomized. 
This sample size is also considered to be sufficient for the relative bioavailability endpoint. 
Pharmacodynamic Analyses 
The PD comparisons will be made between each dose of GSP304 and GSP304 placebo.   
Analysis of Primary Pharmacodynamic Endpoint.  
Change from baseline in trough FEV1 at 24-hours after the last dose of treatment on Day 21 in 
comparison to GSP304 placebo.  
The primary endpoint measures the change from baseline in trough FEV1 at 24 hours after the last dose 
of treatment on Day 21.  This will be analyzed using a Mixed-effect Model Repeated Measure 
(MMRM) model to produce treatment differences for each dose of GSP304 vs GSP304 placebo.  The 
MMRM model will include pre-dose data from all visits (Days 7, 14, and 21) and fixed terms for 
treatment, visit, baseline, center, treatment by visit and baseline by visit interactions.  The adjusted 
means for each treatment and the estimated treatment differences for the treatment comparisons will be 
presented together with 95% confidence intervals (CIs).  Multiple imputation-based methods will be 
considered as a sensitivity analysis for missing data, with further detail provided in the SAP.  
The primary endpoint will be analyzed using the FAS and primary inference will be based at Day 21.  
A sensitivity analysis will be based on the PP Analysis Set. 
Analysis of Secondary Pharmacodynamic Endpoints 
Analysis of secondary PD endpoints will be performed on the FAS. 
Change from baseline in peak FEV1 within 12 hours post dose on Day 1 and Day 21: This endpoint 
measures the peak FEV1 from the serial readings taken through 12 hours post-dose and then calculates 
the change from baseline.  The change from baseline will be analyzed using MMRM in a similar way 
to that of the primary endpoint to produce treatment differences for each dose of GSP304 versus 
GSP304 placebo. 
Change from baseline in FVC on Day 1 and Day 21: The change from baseline will be analyzed using 
MMRM in a similar way to that of the primary endpoint to produce treatment differences for each dose 
of GSP304 versus GSP304 placebo. 
Change from baseline in time-normalized area under the curve for FEV1 measured over 12 hours on 
Day 1 and Day 21: The endpoint measures a series of FEV1 readings taken within 12 hours of dosing.  
The trapezoidal rule will be used to calculate AUC0-12h and then normalized to the length of time.  The 


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change from baseline will be analyzed using MMRM in a similar way to that of the primary endpoint 
to produce treatment differences for each dose of GSP304 versus GSP304 placebo. 
All PD data will also be displayed in summaries and listings. 
Pharmacokinetic, Pharmacogenomic, and Other Biomarker Analyses 
Pharmacokinetic Analyses 
Pharmacokinetic analysis will be performed using the PKAS.  
Plasma: Individual subject plasma PK parameters will be determined from plasma concentrations 
using non-compartmental methods for each subject using appropriate software.  Actual collection times 
will be used for the analyses.  
Urine: Amount and fraction of dose of tiotropium excreted in urine during the collected time interval 
in individual subjects will be estimated.  Actual collection times and urine volumes will be used for the 
estimation.  
Additional parameters may be evaluated depending on the data obtained during the study.  
The derived PK parameters will be listed by subject and summarized by treatment.  Wherever 
appropriate, data will be visualized by means of graphical representations.  For the summaries, 
descriptive statistics for all relevant PK parameters will include: n, mean, SD, coefficient of variation 
(%CV), minimum, median, maximum, geometric mean and geometric mean %CV. 
The plasma concentrations and amount in urine of tiotropium will also be listed by subject, 
summarized by treatment, and presented graphically as mean plots, and individual plots. 
Statistical Analysis of Pharmacokinetic Parameters 
An analysis of variance (ANOVA) will be performed on the ln-transformed PK parameters AUC
0-tauSS, 
and CmaxSS.  The ANOVA model will include treatment as fixed effect.  The results from the model 
will be back-transformed and the adjusted geometrics means for each treatment and the estimated 
treatment ratios for the treatment comparisons will be presented together with 90% CIs. 
The ratios and corresponding 90% CIs will be expressed as a percentage. 
The following comparisons will be made: 
Test Treatment T1 versus Reference Treatment 
Test Treatment T2 versus Reference Treatment 
Test Treatment T3 versus Reference Treatment 
For GSP304, dose-proportionality of tiotropium C
maxSS and AUC
0-tauSS parameters will be assessed 
using a power model (linear regression relating log-transformed C
maxSS and AUC
0-tauSS to the 
log-transformed dose).  Estimates of the mean slopes of log-transformed dose will be reported along 
with corresponding 90% CIs.  Dose proportionality will also be assessed based on amount of 
tiotropium excreted in urine.  More detail will be provided in the SAP. 
Pharmacogenomic, and Other Biomarker Analyses 
Not applicable. 
Safety Analyses 
All safety analyses will be performed on the SAF and will be presented by the study treatment.  Safety 
data will be summarized descriptively.  Data describing quantitative measures will be summarized as 
mean, SD, median and range (minimum and maximum).  Qualitative variables will be presented as 
counts and percentages. 
All safety data will also be displayed in listings. 


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Name of Sponsor/Company: 
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Other Analyses 
Not applicable. 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE 
..............................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES 
...............11
 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................18
 
5. 
INTRODUCTION 
................................
................................
......................................20 
5.1. 
Investigational Product: Mechanism of Action 
..........................................................21
 
5.2. 
Nonclinical Experience 
..............................................................................................21 
5.3. 
Clinical Experience 
...................................................................................................22 
6. 
STUDY OBJECTIVES AND PURPOSE 
................................
..................................24 
6.1. 
Primary Objectives 
................................
................................
.....................................24 
6.2. 
Secondary Objective 
.................................................................................................24 
7. 
INVESTIGATIONAL PLAN 
....................................................................................25 
7.1. 
Overall Study Design 
................................................................................................25 
7.1.1. 
Screening and Run-in .................................................................................................30 
7.1.2. 
Treatment Period ........................................................................................................30 
7.1.3. 
Follow-up 
..................................................................................................................31 
7.1.4. 
Extension Phase 
................................
................................
..........................................31 
7.2. 
Discussion of Study Design, Including Choice of Control Groups 
............................31
 
7.2.1. 
Study Rationale 
.........................................................................................................31 
7.2.2. 
Study Design 
.............................................................................................................32 
7.2.3. 
Dose selection 
...........................................................................................................32 
7.2.4. 
Population 
................................
................................
...................................................33 
7.3. 
Number of Subjects 
................................
................................
....................................33 
7.4. 
Treatment Assignment 
..............................................................................................33 
7.5. 
Dose Adjustment Criteria 
................................
...........................................................33 
7.6. 
Criteria for Study Termination 
................................
...................................................33 
7.7. 
Benefit-Risk Assessment 
................................
............................................................34 
7.7.1. 
Evaluation of Benefit 
................................................................................................34 
7.7.2. 
Assessment of Risk 
...................................................................................................34 


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7.7.3. 
Benefit-Risk Conclusion 
............................................................................................36 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
..............................................37
 
8.1. 
Subject Inclusion Criteria 
................................
...........................................................37 
8.2. 
Subject Exclusion Criteria 
................................
..........................................................37 
8.3. 
Subject Withdrawal Criteria 
................................
.......................................................40 
9. 
TREATMENT OF SUBJECTS 
.................................................................................42 
9.1. 
Description of Study Drug 
.........................................................................................42 
9.2. 
Concomitant Medications 
..........................................................................................43 
9.2.1. 
Rescue Medication(s) 
................................
................................
.................................43 
9.3. 
Lifestyle and/or Dietary Restrictions 
.........................................................................43 
9.4. 
Treatment Compliance 
..............................................................................................44 
9.5. 
Treatment of Investigational Product Overdose 
.........................................................44
 
9.6. 
Randomization and Blinding 
................................
......................................................44 
9.6.1. 
Allocation to Treatment Groups 
................................
.................................................44 
9.6.2. 
Blinding and Unblinding Procedures 
.........................................................................44 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
...........................................46
 
10.1. 
Study Drug 
................................................................................................................46 
10.1.1. 
Blinded GSP304 
................................
................................
.........................................46 
10.1.2. 
Blinded GSP304 Placebo 
...........................................................................................46 
10.1.3. 
Open-label Spiriva® Respimat® 
...............................................................................46 
10.2. 
Study Drug Packaging and Labeling 
................................
..........................................46 
10.3. 
Study Drug Storage 
...................................................................................................46 
10.4. 
Study Drug Preparation 
................................
..............................................................46 
10.5. 
Administration 
................................
................................
............................................46 
10.5.1. 
Rescue Medication 
....................................................................................................47 
10.6. 
Study Drug Accountability 
................................
.........................................................47 
10.7. 
Study Drug Handling and Disposal 
................................
............................................47 
11. 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS ............48
 
11.1. 
Study Endpoints 
........................................................................................................48 
11.1.1. 
Primary Endpoints 
................................
................................
......................................48 
11.1.2. 
Secondary Endpoints 
................................
................................
..................................48 
11.1.3. 
Safety Endpoints 
.......................................................................................................48 
11.1.4. 
Appropriateness of Measurements .............................................................................48 


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11.2. 
Efficacy Assessments 
................................
................................
.................................49 
11.2.1. 
Spirometry 
................................
................................
..................................................49 
11.2.2. 
Pharmacokinetic, Biomarker, and Pharmacogenomic Assessments ..........................49
 
11.2.2.1. Pharmacokinetic Assessments 
................................
....................................................49 
11.2.2.2. Pharmacodynamic Assessments 
................................
.................................................51 
11.2.2.3. Diary Assessments 
....................................................................................................51 
11.2.2.4. Biomarker Assessments 
.............................................................................................51 
11.2.2.5. Pharmacogenomic Assessments 
................................
.................................................52 
12. 
ASSESSMENT OF SAFETY 
....................................................................................53 
12.1. 
Safety Parameters 
................................
................................
.......................................53 
12.1.1. 
Demographic/Medical History 
................................
...................................................53 
12.1.2. 
Vital Signs ..................................................................................................................53 
12.1.3. 
Weight and Height 
....................................................................................................53 
12.1.4. 
Physical Examination 
................................
................................
.................................54 
12.1.5. 
Electrocardiogram (ECG) 
................................
...........................................................54 
12.1.6. 
Laboratory Assessments 
................................
.............................................................54 
12.1.6.1. Laboratory and Other Safety Assessment Abnormalities Reported as AEs 
and SAEs ....................................................................................................................55 
12.1.6.2. Virus Serology 
................................
................................
............................................55 
12.1.6.3. Drug Screen 
................................
................................
................................................55 
12.1.6.4. Pregnancy Testing ......................................................................................................55 
12.1.6.5. Follicle-Stimulating Hormone Screening 
................................
...................................55 
12.2. 
Adverse and Serious Adverse Events 
................................
.........................................55 
12.2.1. 
Assessment of Adverse Events 
..................................................................................55 
12.2.2. 
Adverse Event 
...........................................................................................................55 
12.2.3. 
Assessment of Severity of Adverse Events 
................................
................................56 
12.2.4. 
Assessment of Relationship to Study Medication 
......................................................57
 
12.2.5. 
Serious Adverse Events 
................................
..............................................................57 
12.2.5.1. Regulatory Reporting Requirements for SAEs 
...........................................................58
 
12.2.6. 
Pregnancy ...................................................................................................................59 
12.2.7. 
Collection and Recording of AEs and SAEs 
..............................................................59 
12.2.7.1. Collection of AEs .......................................................................................................59 
12.2.8. 
Recording of AEs .......................................................................................................60 


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13. 
STATISTICS 
................................
................................
..............................................61 
13.1. 
Sample Size ................................................................................................................61 
13.2. 
Analysis Sets 
.............................................................................................................61 
13.2.1. 
Full Analysis Set (FAS) 
.............................................................................................61 
13.2.2. 
Safety Analysis Set (SAF) 
................................
..........................................................61 
13.2.3. 
Per Protocol Analysis Set (PP) 
................................
...................................................61 
13.2.4. 
PK Analysis Set (PKAS) 
................................
............................................................61 
13.3. 
Subject Disposition 
...................................................................................................62 
13.4. 
Demographics, Baseline Characteristics and Concomitant Medications 
...................62
 
13.5. 
Efficacy Analyses 
................................
................................
.......................................62 
13.6. 
Pharmacokinetic, Pharmacodynamic, Biomarker, and Pharmacogenomic/ 
Pharmacogenetic Analyses 
................................
.........................................................62 
13.6.1. 
Pharmacokinetic Analyses 
.........................................................................................62 
13.6.2. 
Pharmacodynamic Analyses 
......................................................................................63 
13.6.3. 
Biomarker Analyses 
..................................................................................................64 
13.6.4. 
Pharmacogenomic/Pharmacogenetic Analyses 
..........................................................64
 
13.7. 
Safety Analyses ..........................................................................................................64 
13.7.1. 
Extent of Exposure .....................................................................................................64 
13.7.2. 
Adverse Events 
................................
................................
...........................................64 
13.7.3. 
Laboratory Values ......................................................................................................64 
13.7.4. 
Vital Signs ..................................................................................................................64 
13.7.5. 
Electrocardiograms 
................................
................................
.....................................65 
13.7.6. 
Other Safety Analyses 
................................
................................
................................65 
13.8. 
Interim Analysis 
........................................................................................................65 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................66
 
14.1. 
Study Monitoring 
......................................................................................................66 
14.2. 
Audits and Inspections 
..............................................................................................66 
14.3. 
Institutional Review Board (IRB) 
..............................................................................67 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................68
 
16. 
ETHICS 
................................
................................
......................................................69 
16.1. 
Ethics Review 
................................
................................
.............................................69 
16.2. 
Ethical Conduct of the Study 
.....................................................................................69 
16.3. 
Written Informed Consent 
................................
..........................................................69 


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17. 
DATA HANDLING AND RECORDKEEPING 
.......................................................70
 
17.1. 
Inspection of Records 
................................
................................
.................................70 
17.2. 
Retention of Records 
................................
................................
..................................70 
17.3. 
Financing and Insurance 
................................
.............................................................70 
18. 
PUBLICATION POLICY 
................................
..........................................................71 
19. 
LIST OF REFERENCES 
...........................................................................................72 
APPENDIX 1.
 LIST OF MEDICATIONS EXCLUDED DURING ACTIVE 
TREATMENT PERIODS ..........................................................................................75 
APPENDIX 2.
 LIST OF CLINICAL LABORATORY TESTS 
.................................................76
 
APPENDIX 3.
 INSTRUCTIONS FOR THE USE OF GSP304 OR GSP304 
PLACEBO NEBULIZER 
..........................................................................................77 
APPENDIX 4.
 INSTRUCTIONS FOR THE USE OF SPIRIVA® RESPIMAT® 
......................78
 
APPENDIX 5.
 GUIDANCE FOR SPIROMETRY 
................................
....................................79 
APPENDIX 6.
 SUMMARY OF CHANGES IN CURRENT PROTOCOL 
AMENDMENT 
................................
................................
..........................................81 
 


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LIST OF TABLES 
Table 1: Abbreviations and Specialist Terms 
................................
...........................................18 
Table 2: Schedule of Assessments 
...........................................................................................27 
Table 3: GSP304 
................................
................................
.......................................................42 
Table 4:
 Other Study Drugs 
................................
................................
......................................43 
 


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LIST OF FIGURES 
Figure 1: Study Design 
.............................................................................................................26 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Table 1: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
AE 
adverse event 
Aetau 
cumulative amount of unchanged drug excreted into the urine 
over the dosing interval 
ANOVA 
analysis of variance 
AUC 
area under the plasma concentration-time curve 
AUC0-tau 
area under the concentration-time profile over the dosing 
interval  
AUC0-tauSS 
area under the concentration-time profile over the dosing 
interval at steady state
  
BMI 
body mass index 
BP 
blood pressure 
CavSS 
average concentration during a dosing interval at steady state 
Cmax 
peak concentrations during the dosing interval  
CmaxSS 
peak concentrations during the dosing interval at steady-state 
CminSS 
minimum of trough concentrations during the dosing 
interval at steady-state 
CI 
confidence interval 
COPD 
chronic obstructive pulmonary disease 
CRF 
case report form 
CT 
computed tomography  
DPI 
dry powder inhaler 
ECG 
electrocardiogram  
eCRF 
electronic case report form 
FAS 
full analysis set 
Fe 
fraction of drug excreted into the urine 
FEV1 
forced expiratory volume over 1 second 
FVC 
forced vital capacity 
GI 
gastrointestinal 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
HBsAg 
hepatitis B antibody 


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Abbreviation or Specialist Term 
Explanation 
HCV 
hepatitis C virus 
ICF 
informed consent form 
IEC 
independent Ethics Committee 
IP 
investigational product 
IRB 
Institutional Review Board 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
LABA 
long-acting beta2-agonist 
LAMA 
long-acting muscarinic antagonist 
LC/MS/MS 
liquid chromatography-mass spectrometry 
MDI 
metered dose inhaler 
MMRM 
Mixed-effect Model Repeated Measure  
MRHDID 
maximum recommended human daily inhaled dose 
PD 
pharmacodynamics 
%CV 
coefficient of variation 
PK 
pharmacokinetics 
PP 
per protocol analysis set 
 
QD 
once daily 
Rac 
accumulation ratio 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAF 
safety analysis set 
SD  
standard deviation 
t
max  
time of peak drug concentration 
US 
United States   
USPI 
United States Prescribing Information 
 


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5. 
INTRODUCTION 
Chronic obstructive pulmonary disease (COPD), a common preventable and treatable disease, is 
characterized by persistent airflow limitation that is usually progressive and associated with an 
enhanced chronic inflammatory response in the airways and the lung to noxious particles or 
gases.  Exacerbations and comorbidities contribute to the overall severity in individual patients.1 
Inhaled cigarette smoke and other noxious particles such as smoke from biomass fuels cause 
lung inflammation, a normal response that appears to be modified in patients who develop 
COPD.  This chronic inflammatory response may induce parenchymal tissue destruction 
(resulting in emphysema), and disrupt normal repair and defense mechanisms (resulting in small 
airway fibrosis).  These pathological changes lead to air trapping and progressive airflow 
limitation, and in turn, results in breathlessness and other characteristic symptoms of COPD.
1 
COPD is the fourth leading cause of death in the world
1 and represents an important public 
health challenge.  It is a major cause of poor health and contributes significantly to healthcare 
costs and comorbidity.
2,3  According to World Health Organization estimates, globally, 
65 million people have moderate to severe COPD.  More than 3 million people died of COPD in 
2012, which corresponded to 6% of all deaths globally that year.
4  Total deaths from COPD are 
projected to increase by more than 30% in the next 10 years and estimates show that COPD 
could become the third leading cause of death worldwide by 2030.
5  It is a major cause of 
chronic morbidity and mortality throughout the world; many people suffer from this disease for 
years, and die prematurely from it or its complications.  Globally, the COPD burden is projected 
to increase in coming decades because of continued exposure to COPD risk factors and the 
changing age structure of the world’s population (with more people living longer and therefore 
expressing the long-term effects of exposure to COPD risk factors).
1    
In the United States (US), COPD affects an estimated 27 million Americans.  Approximately 
12 million adults in the US are diagnosed with COPD, and 120,000 die from it each year.  An 
additional 12 million adults in the US are thought to have undiagnosed COPD.
6  It results in 
1.5 million visits to the emergency room and more than 15 million physician visits every year, 
and 739,000 hospitalizations.
7  Specifically in the US, it is estimated that economic cost of 
COPD in 2010 was close to $50 billion.  This includes $29.5 billion in direct health care 
expenditures and $20.4 billion in indirect costs.
8   
Although there is no cure for COPD, there are many therapeutic options that can help control and 
relieve associated symptoms.  Inhaled pharmacologic therapies for COPD consist of short-acting 
bronchodilators, long-acting beta2-agonists (LABA), long-acting muscarinic antagonists 
(LAMA), combination of LABA plus LAMA, and inhaled corticosteroids in combination with 
LABA.9  The current Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy 
document recommends the use of one or more long-acting bronchodilators for the maintenance 
treatment of COPD.  The use of bronchodilators should be prescribed according to the patient’s 
airflow limitation, history of exacerbations, and symptoms.
9   
There is a pressing need to develop drugs for COPD because the global prevalence of COPD is 
rising, the disease is associated with significant morbidity and mortality, and current treatment 
options are limited.  The Sponsor has developed a tiotropium bromide inhalation solution to be 
used with a nebulizer and plans to conduct this dose ranging study with an objective to evaluate 
pharmacokinetics (PK) and pharmacodynamics (PD) effects of 3 doses of tiotropium bromide 


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inhalation solution in subjects with mild to moderate COPD by comparing with Spiriva
® 
Respimat®. 
5.1. 
Investigational Product: Mechanism of Action 
Tiotropium is a LAMA and has similar affinity to the subtypes of muscarinic receptors, M1 to 
M5. In the airways, it exhibits pharmacological effects through inhibition of M3-receptors in the 
smooth muscle leading to bronchodilation.  Tiotropium is approved in the US, European Union, 
and other countries for the long-term, once-daily, maintenance treatment of bronchospasm 
associated with COPD.
9  Safety and efficacy of tiotropium (ie Spiriva
®) has been 
well-established from many large randomized controlled studies including long-term outcome 
studies.  Extensive use of this class of drugs in a wide range of doses in clinical settings has 
shown them to be well-tolerated without significant safety concerns.
9  Tiotropium is currently 
available as an inhalation spray (Spiriva® Respimat®) administered as a dose of 5 µg once daily 
(QD) or dry powder inhalation (Spiriva
® HandiHaler®) as 18 µg QD.
10,11  However, tiotropium is 
not available as an inhalation solution to be used with a nebulizer.  While metered dose inhalers 
(MDIs) and dry powder inhalers (DPIs) are widely used for different medications by patients 
with COPD, delivery by nebulization provides an effective alternative in patients who do not 
receive an optimal dose from inhalers.  This may be due to poor coordination, an inability to 
inhale rapidly and forcefully, an inability to hold breath for the allotted time (up to 10
 seconds) 
after the dose and exhalation into the device before or after the dose delivery.
12,13   
5.2. 
Nonclinical Experience 
No toxicity, non-clinical PK, or drug metabolism studies have been conducted with GSP304 to 
date.  The preclinical pharmacological and toxicological profiles of tiotropium bromide have 
been well-established in various pre-clinical studies supporting inhalation powder (Spiriva
® 
HandiHaler®) and inhalation spray (Spiriva
® Respimat®).  The clinical steady state PK 
parameters of Respimat® (5 µg tiotropium) and HandiHaler
® (18 µg tiotropium) were 
approximately similar (area under the concentration time curve over 6 hours of dosing [AUC0-6]: 
24.4 and 32.1 ng.h/mL and peak concentration during the dosing interval (Cmax) 12.4 and 
15.4 ng/L, respectively) despite of a 3.6 fold difference in their maximum recommended human 
daily inhalation dose (MRHDID).  Based on the observation that the MRHDID of Respimat® and 
HandiHaler® produce similar systemic exposure to tiotropium, the exposure multiples between 
animals and humans documented in the US Prescribing Information (USPI) for the HandiHaler 
tiotropium dose have been maintained, and are relevant for Spiriva
® Respimat®.
14  Nonclinical 
and clinical data for tiotropium bromide have been extracted from the USPI of Spiriva® 
Respimat®, and US Food and Drug Administration review data for tiotropium bromide, available 
under the Freedom of Information Act of the US, and published literature.  A concise summary 
of the nonclinical data of tiotropium is presented below. 
Tiotropium bromide had no effect on human Ether-à-go-go-Related Gene-mediated potassium 
channel current in human embryonic kidney cells nor did it affect action potential configuration 
in isolated guinea pig papillary muscles in vitro.  Tiotropium at therapeutic plasma 
concentrations may increase heart rate and inhibit salivation and gastrointestinal (GI) motility.  
The inhibition of salivation occurs at concentrations 5 times lower than the bronchodilation in 
guinea pigs, suggesting that the salivation is probably the earliest indicator of tiotropium side 


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effects.  These effects appear to be secondary pharmacological activity typical of muscarinic 
antagonists.
15  
Acute toxicity of tiotropium was studied in mice, rats, and dogs by intravenous, oral and 
inhalation administration.  Signs of toxicity included reduced motility, tremor, dyspnea, 
tachycardia, hunched posture, coprostasis, convulsion, and eventually, deaths.  The approximate 
inhalation lethal dose 50% values in mice, rats and dogs were more than 6.5, 21 and 30 mg/kg, 
respectively (approximately 1756, 11351 and 54054 times the MRHDID on a µg/m
2 basis, 
respectively).  The majority of repeat dose inhalation studies were conducted using aqueous 
aerosols as the formulation, while some studies used lactose powder.  The duration of treatment 
was up to 3 months in mice and 1 year in rats and dogs.  Tiotropium possesses a toxicity profile 
typical of a muscarinic anticholinergic agent.  The target organs of tiotropium toxicity include 
the eye, GI tract, respiratory tract, urinary bladder, salivary glands and heart.  The no observed 
adverse effect level decreased as the treatment duration increased: The no observed adverse 
effect levels in 4-, 13- and 52-week inhalation toxicity studies were 2300, 70 and 13 μg/kg/day 
(estimated pulmonary doses were 161, 4.9 and 0.9 μg/kg/day, respectively) in rats and 287, 12 
and 5.2 μg/kg/day in dogs (estimated pulmonary doses were 28.7, 1.0 and 0.5 μg/kg/day, 
respectively).  In rats, these doses are approximately 1243, 38 and 7 times, respectively the 
MRHDID on a µg/m2 basis and in dogs these doses are approximately 517, 22 and 9 times, 
respectively the MRHDID on a µg/m
2 basis.16   
Tiotropium was not mutagenic in various genotoxicity assays and no evidence of tumorigenicity 
was observed in mouse [83- and 101-week inhalation studies in females and males, respectively) 
and rat (104-week inhalation study) carcinogenicity studies at doses corresponding to 
approximately 30, 40, and 0.5 times the MRHDID on a µg/m
2 basis, respectively.11   
In rats, decreases in the number of corpora lutea and the percentage of implants were noted at 
inhalation doses of 78 µg/kg/day or greater (approximately 40 times the MRHDID on a µg/m
2 
basis).  No such effects were observed at 9 µg/kg/day (approximately 5 times the MRHDID on a 
µg/m2 basis).  However, the fertility index was not affected at inhalation doses up to 
1689 µg/kg/day (approximately 910 times the MRHDID on a µg/m2 basis.11   
Tiotropium was not teratogenic in rats and rabbits at maternal inhalation doses of 1471 and 
7 µg/kg/day, respectively (approximately 790 and 8 times the MRHDID, respectively on a µg/m
2 
basis).  However, in rats, tiotropium caused fetal resorption, litter loss, decreases in the number 
of live pups at birth and the mean pup weights, and a delay in pup sexual maturation at a 
maternal inhalation dose of 78 µg/kg/day (approximately 40 times the MRHDID, on a µg/m2 
basis).  In rabbits, tiotropium caused an increase in post-implantation loss at a maternal 
inhalation dose of 400µg/kg/day (approximately 430 times the MRHDID on a µg/m
2 basis).  
Such effects were not observed at maternal inhalation doses of 9 and 88 µg/kg/day in rats and 
rabbits, respectively (approximately 5 and 95 times the MRHDID, respectively on a µg/m
2 
basis).
11  
5.3. 
Clinical Experience 
The safety, efficacy, and PK profile for tiotropium bromide is well-established when inhaled as 
an inhalation powder
11 or inhalation spray.
10  Spiriva
® has been approved in the US for the 
long-term, once-daily, maintenance treatment of bronchospasm associated with COPD, and for 


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reducing COPD exacerbations.  Spiriva
® HandiHaler® was approved on January 30, 2004 
(NDA 21-395) and Respimat
® was approved on September 24, 2014 (NDA 21-936).  
However, there is no approved tiotropium bromide product such as GSP304 for use as a 
nebulized solution. 
 


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6. 
STUDY OBJECTIVES AND PURPOSE 
6.1. 
Primary Objectives 
The primary objectives are: 
• To assess the relative bioavailability of GSP304 (tiotropium bromide) Inhalation 
Solution at dose levels of 10 µg, 20 µg, and 40 µg QD compared with Spiriva
® 
Respimat® inhalation spray (5 µg QD) in subjects with COPD. 
• To characterize the dose response of GSP304 at dose levels of 10 µg, 20 µg, and 
40 µg QD with respect to PD.  
6.2. 
Secondary Objective 
The secondary objective is to assess the safety and tolerability of GSP304 at dose levels of 
10 µg, 20 µg, and 40 µg QD. 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a phase 2, randomized, parallel group, active- and placebo-controlled, 5-arm study to 
compare the PK profile of 3 blinded doses of GSP304 with open label Spiriva® Respimat®.  The 
study will also evaluate the dose response PD profile of 3 blinded doses of GSP304 compared 
with blinded GSP304 placebo, using spirometry in subjects with mild to moderate COPD.  A 
total of 155 male and female subjects will be randomized in a 1:1:1:1:1 ratio to 1 of 5 treatment 
arms.  A subject will receive 1 of the 3 double-blind doses of GSP304, or double-blind GSP304 
placebo, or open-label Spiriva® Respimat®.  The study will include a screening period of up to 
2 weeks, followed by a 2-week run-in period, 3 weeks of treatment, and a 2-week post treatment 
follow-up period.  The total duration of study participation will be approximately 9 weeks.  In 
this study, PK of tiotropium in plasma and urine will be assessed on Day 1 and on Day 21 (at 
steady state). 
The study consists of the following periods, as depicted in Figure 1 and described below: 
Screening (Day -28 to Day -15): Up to 2 weeks (14 days), during which the Screening visit 
(Visit 1) will occur. 
Run-in Period (Day -14 to Day -2): 2 weeks (14 days), during which Visit 2 will occur. 
Treatment Period (Day -1 to Day 22): 3 weeks during which Visits 3, 4, 5, and 6 will occur. 
Treatment (GSP304/GSP304 placebo/Spiriva® Respimat®) will be administered QD on Days 1 
through 21.  
Post treatment Follow-up (Day 35 ± 2 days): 14 days after the last dose, the Follow-up visit, 
Visit 7, will occur on Day 35 ± 2.  In the event of early withdrawal, Visit 7 procedures will be 
performed as soon as possible after a subject withdraws from the study (See Section 8.3 for 
details).  
The total duration of study participation will be approximately 9 weeks for each subject. Subjects 
will be required to attend the clinic for all scheduled study visits (Visit 1-7).  
The end of the study will be the date of the last study visit for the last randomized subject in the 
study. 


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Figure 1: 
Study Design  
 
 
QD = once daily


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Table 2: 
Schedule of Assessments 
Activity/Observation Screening Run-
In 
Study Treatment 
End of 
Study 
(Follow Up) 
Day  
D-28 to 
D-15 
D-14 
to 
D -2 
D-1 
(clinic 
check-
in) 
D1 
D2 
(clinic 
check-
out) 
D7 
(ambulatory 
visit) 
D14 
(ambulatory 
visit) 
D20 
(clinic 
check-in) 
D21 D22 
(clinic 
check-
out) 
D35 (±2) 
Visit ID 
1 
2 
3 
3 
3 
4 
5 
6 
6 
6 
7 
Informed consent 
× 
 
 
 
 
 
 
 
 
 
 
Demographic data 
× 
 
 
 
 
 
 
 
 
 
 
Medical and 
treatment history 
× 
 
 
 
 
 
 
 
 
 
 
Vital signs
1 
× 
 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Physical 
examination
2 
× 
 
× 
 
 
× 
× 
× 
 
 
 
Inclusion/Exclusion 
criteria 
× 
 
× 
 
 
 
 
 
 
 
 
Chest x-ray (if 
applicable) 
× 
 
 
 
 
 
 
 
 
 
 
Device training  
× 
×
3 
 
 
 
 
 
 
 
 
 
12 lead ECG 
×
4 
 
 
× 
 
 
 
 
× 
 
 
Laboratory 
investigations 
(hematology 
biochemistry, 
and 
urine analysis)
5 
× 
 
 
 
 
× 
× 
 
× 
 
× 


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Activity/Observation Screening Run-
In 
Study Treatment 
End of 
Study 
(Follow Up) 
Day  
D-28 to 
D-15 
D-14 
to 
D -2 
D-1 
(clinic 
check-
in) 
D1 
D2 
(clinic 
check-
out) 
D7 
(ambulatory 
visit) 
D14 
(ambulatory 
visit) 
D20 
(clinic 
check-in) 
D21 D22 
(clinic 
check-
out) 
D35 (±2) 
Visit ID 
1 
2 
3 
3 
3 
4 
5 
6 
6 
6 
7 
Urine analysis for 
drugs of abuse and 
urine cotinine 
× 
 
× 
 
 
 
 
× 
 
 
 
Blood alcohol test 
× 
 
× 
 
 
 
 
× 
 
 
 
FSH screening (if 
applicable)
6 
× 
 
 
 
 
 
 
 
 
 
 
Pregnancy testing
7  
× 
 
× 
 
 
 
 
 
 
 
× 
In-clinic stay 
 
 
× 
× 
× 
 
 
x 
× 
× 
 
Randomization and 
IP assignment  
 
 
 
x 
 
 
 
 
 
 
 
Administration of 
study medication
8 
 
 
 
× 
× 
× 
× 
× 
× 
 
 
PK sampling (blood 
and urine)
9 
 
 
 
× 
× 
× 
× 
 
× 
× 
 
 
Spirometry
10 
× 
 
 
× 
× 
× 
× 
 
× 
× 
 
Adverse events 
monitoring 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
Concomitant 
medication 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
× 
 
1 Heart rate, blood pressure (systolic and diastolic), respiratory rate and body temperature.  Blood pressure can be taken in the same manner (ie, seated or supine 
position) at every study visit.  On Day 1 and 14: Vital signs will be measured within 1 hour before study drug administration in the morning (prior to pre-dose 
spirometry and PK procedures) and 1 hour after the morning dose. 


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2 Comprehensive physical examination will be performed at screening; a targeted examination will be done if an adverse event occurs at the discretion of the 
Investigator. 
3 Additional training may be provided on Day-1 if required, at the Investigator
's discretion. 
4 Triplicate ECG will be performed at the screening visit. 
5 Refer to Appendix 2. 
6 FSH (follicle stimulating hormone) screening will be performed at Screening for all females to confirm non-childbearing potential (FSH>40 IU/L). 
7 Females only; serum pregnancy testing at Screening, urine pregnancy testing at Day -1 (clinic check in) and End of Study (Follow-up). 
8 On days on which subject visits are scheduled, subjects will take the study drug at the Investigator site (ie, after any required pre-dose blood samples and 
pre-dose PD measures have been collected), EXCEPT on Day 20 when subjects will be requested to take the study medication at home as instructed by the 
study staff.  On all other days, subjects will be requested to take the study medication at home as instructed by the study staff. 
9 Blood samples (approximately 6 mL) will be collected in dipotassium EDTA coated vacutainers on Day 1 and Day 21 according to the below schedule: 
Pre-dose (0 hour), and post morning-dose at 2 minutes, 4, 6, 10, 15, 30, and 45, 60, 75, and 90 minutes post-dose, as well as 2, 4, 6, 8, 12, 16, 20 and 24 hours 
post-dose.  Blood samples for PK should not be drawn or processed in the same room that the subject was dosed with study medication.  The pre-dose sample 
on Day 1 should be collected within 30 minutes prior to dosing while on Days 7, 14, and 21 the pre-dose sample should be collected within 10 minutes prior to 
the morning dose. On Day 1 and Day 21, samples will be collected at 2 minute with a window period of ±30 seconds, a window period of ± 1 minute for other 
samples up to 30 minutes; ± 2 minutes up to 2 hours and ± 5 minutes up to 12 hours.  In addition, urine will be collected at pre-dose (within 1 hour prior to 
dosing), 0-6, 6-12, 12-24 hours on Day 1 and Day 21 in pre-weighed containers with approximately 5 mL of 1M citric acid added prior to start of collection in 
each container.  All post-dose timings are relative to the end of dosing (ie, end of nebulization of GSP304/GSP304 placebo or after the second actuation of 
Spiriva® Respimat
®). 
10 
Pre-dose forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) will be assessed on at -45 minutes and 15 minutes prior to dosing on 
Day 1, Day 7, Day 14, and Day 21.  Trough FEV1 will be assessed on Day 22 (ie, 24 hours after Day 21 dose).  On Day 1 and Day 21, FEV1 will be recorded, 
at the following time points after the morning dose: immediately post-dose at 5 minutes (±3 minutes), 15 minutes (±2 minutes), 30 minutes (±5 minutes), 
60 minutes, 90 minutes, and 2 hours (120 minutes); and post-dose at 4, 6, 8, 10, 12, 23 hours 15 minutes and 23 hours 45 minutes post-dose.  All post-dose 
timings are relative to the end of dosing (ie, end of nebulization of GSP304/GSP304 placebo or after the second actuation of Spiriva® Respimat®).  The window 
for 1-hour spirometry and thereafter is ±5 minutes.   
 


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7.1.1. 
Screening and Run-in 
Screening will occur between Day -28 and Day -15.  The purpose of screening is to obtain 
informed consent and to establish protocol eligibility.  Written informed consent will be obtained 
after the study has been fully explained to each subject and before the conduct of any screening 
procedures or assessments.  Procedures to be followed when obtaining informed consent are 
detailed in Section 16.3.  
After informed consent is obtained, subjects will be evaluated for eligibility based on the 
inclusion and exclusion criteria (see Section 8), which will require review of medical history 
(including smoking history) and concomitant medications, vital signs, physical examination, 
assessment of subject’s current COPD severity by spirometry, 12-lead electrocardiogram (ECG), 
chest X-ray (if no chest x-ray or computed tomography (CT) scan was taken within 6 months 
prior to study start, or if recent results are unavailable for review), clinical laboratory evaluations 
(hematology, blood chemistry, urinalysis), serum alcohol test, urinalysis for drugs of abuse and 
cotinine, serology testing for hepatitis B surface antigen (HBsAg) and hepatitis C virus (HCV) 
antibody, serum pregnancy testing for all female subjects, and follicle stimulating hormone 
(FSH) screening for all females to confirm non-childbearing potential.  Adverse event (AE) 
monitoring will begin after informed consent is obtained.  
If the subject is taking any prohibited medication/s at the time of screening, then washout should 
be performed for appropriate duration (Refer to Appendix 1) before the screening spirometry.  
Appropriate Screening electronic case report form (eCRF) must be completed to indicate 
whether the subject is eligible to participate in the study and to provide reasons for screen failure, 
if applicable. 
After the Screening visit, subjects meeting the eligibility criteria and the safety laboratory test 
results, HbsAg and HCV antibody test results, will undergo a Run-in period of 14 days.  Subjects 
will be instructed not to use the prohibited medications during this run-in period and only rescue 
medication (Section 9.2.1) will be allowed as required.  Device training (for GSP304 and 
Spiriva® Respimat®) will be provided to all subjects once during screening, and once during the 
run-in period at Visit 2.  Additional device training may be provided to the subjects at 
Investigator’s discretion at other visits eg, at Visit 3 before dosing.  Subjects will be provided 
with a diary to record the symptoms of exacerbation, AEs if experienced, and rescue medications 
including other new medication if used during the Screening or Run-in periods. 
Repeat of screening evaluations are allowed in cases where abnormal result(s) are noted during 
the Screening Period that are believed to be related to an error or a transient and/or reversible 
condition.  Results of the repeated assessment must be available during the screening period. 
Subjects who fail to satisfy inclusion/exclusion criteria may rescreen once for the study.  
7.1.2. 
Treatment Period 
Following the run-in period, subjects will attend the study clinic in the evening on Day -1 
(Visit 3) for clinic check-in.  The subjects’ eligibility will be confirmed by the Investigator. 
Following confirmation of eligibility, subjects will be randomized (1:1:1:1:1) in the morning on 
Day 1 to receive treatments with either one of 3 dose levels of blinded GSP304 (10, 20, or 40 μg 


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QD), blinded GSP304 placebo QD, or open-label Spiriva® Respimat® (2.5 μg, 2 actuations, QD).  
On days on which subject visits are scheduled, subjects will take the study drug at the 
Investigator site (ie, after any required pre-dose blood samples and pre-dose PD measures have 
been collected).  On all other days, subjects will be requested to take the study medication at 
home as instructed by the study staff, at approximately the same time the study medication was 
dosed on Day 1.  Subjects will receive the first dose of the allocated study medication in the 
morning on Day 1 (during Visit 3) at the clinic.  During the Treatment period there are 4 
scheduled visits; Visit 3 (Day -1 to Day 2), Visit 4 (Day 7), Visit 5 (Day 14), and Visit 6 (Day 20 
to Day 22).  Subjects will stay in the clinic as in-patients for about 36 to 48 hours at Visit 3 and 
Visit 6. Visit 4 and Visit 5 will be out-patient ambulatory visits.  At each scheduled visit, the 
Investigator and site staff will perform various assessments as described in Table 2.  Subjects 
will record in the diary any symptoms of exacerbation, use of study drug, rescue and other new 
concomitant medication and any AEs if experienced during the treatment period.  Subjects will 
bring their study medication (and nebulizer, if required for treatment administration, per 
randomization group) and the diary to the clinic at each scheduled visit for supervised self–
administration of the morning dose at the clinic, and for the Investigator and site staff to assess 
each subject’s compliance with the dosing regimen. 
Blood (approximately 6 mL, or a little more than a teaspoon of blood) and urine samples will be 
collected for PK at the time points noted in Table 2.  The accurate volume of urine will be noted.  
7.1.3. 
Follow-up 
At the Follow-up visit on Day 35 ± 2 days (Visit 7), subjects will undergo safety assessments as 
described in Table 2. 
7.1.4. 
Extension Phase 
An extension phase is not planned for this study. 
7.2. 
Discussion of Study Design, Including Choice of Control Groups 
7.2.1. 
Study Rationale  
Tiotropium bromide is a long-acting anticholinergic with specificity for muscarinic receptors.  It 
is currently approved as Spiriva
® HandiHaler® (tiotropium bromide inhalation powder) and 
Spiriva® Respimat® (tiotropium bromide inhalation spray) for the long-term, once-daily, 
maintenance treatment of bronchospasm associated with COPD, and for reducing COPD 
exacerbations.  
The choice of inhaler device depends on several factors, including availability, cost, the 
prescribing physician, and the patient’s skills and ability.9  The effectiveness of the product will 
depend on the delivery device used and the patient’s ability to use the device correctly.  If a 
patient cannot or does not use the delivery device as intended, the intended dose may not be 
delivered to the lung, resulting in the potential for reduced efficacy.  Patient errors are common 
with all devices17, and the Sponsor has not identified additional risks described in published 
literature associated with the use of a nebulizer.  


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A set of clinical practice guidelines for aerosol delivery device selection have been established 
by the Grading of Recommendations Assessment, Development, and Evaluation criteria.18  
These criteria recommend the use of a nebulizer for adults who cannot coordinate the use of 
other devices, such as an MDI or a DPI.  In particular, patients with COPD may have problems 
with coordination and may experience difficulties when using an MDI when actuation needs to 
be synchronized with the start of inhalation.  Nebulizer use might also be more practical for 
patients with COPD, who may have severely overinflated lungs, when a slow flow and breath 
hold are required for MDI use and cannot be maintained, or for patients who cannot generate 
enough inspiratory flow required for DPI use.
9,17  In addition, nebulizer therapy (or MDI) is 
recommended for drug delivery during noninvasive ventilation.  
The Sponsor has developed a tiotropium bromide inhalation solution (GSP304) for 
administration by nebulization.  This dose-ranging study aims to provide insight on the 
appropriate dose of tiotropium bromide inhalation solution to be delivered to the lungs via a 
nebulizer.  The proposed indication of this product will be for the long-term, once-daily, 
maintenance treatment of bronchospasm associated with COPD. 
7.2.2. 
Study Design  
This is a phase 2, randomized, parallel group, active- and placebo-controlled, 5-arm study to 
compare the PK profile of 3 blinded doses of GSP304 with open-label Spiriva
® Respimat®.  A 
parallel-group design has been selected over a cross-over design to prevent any potential 
“carry-over effect,” and significantly extended study duration due to multiple cross-over 
treatment with long washout periods (at least 1-2 weeks for each washout).     
The planned treatment duration of the study is 3 weeks because the plateau of effect of FEV1 for 
tiotropium delivered by inhalation aerosol is reached within 2 weeks.
19, 20  Furthermore, it is 
estimated that tiotropium will reach steady state for systemic exposure within 1 week.  
Therefore, the treatment duration of 3 weeks in this study is expected to be sufficient to reach PK 
and PD steady state and confirm the dose-response of tiotropium bromide inhalation solution.  
Spiriva® Respimat
® is selected as the active comparator for the present study (versus Spiriva
® 
HandiHaler®) because both GSP304 and Spiriva® Respimat
® are formulated as a tiotropium 
bromide inhalation solution, whereas Spiriva® HandiHaler® is a tiotropium bromide inhalation 
powder for inhalation.   
This design would enable determination of a dose of GSP304 that would have a comparable PK 
profile with Spiriva
® Respimat® in patients with COPD. 
7.2.3. 
Dose selection 
This is the first-in-human study with GSP304 (tiotropium bromide) Inhalation Solution.  In the 
absence of reported PK or clinical data comparing tiotropium delivered via a nebulizer or 
Spiriva® HandiHaler® or Spiriva® Respimat®, a range of dose strengths 10 μg, 20 μg, and 40 μg 
QD (with respect to tiotropium) will be tested to identify an appropriate dose of GSP304 to be 
delivered to the lungs via a nebulizer in subjects with COPD.  During the preliminary 
development of inhaled tiotropium bromide (Spiriva® HandiHaler®) tiotropium delivered via a 
nebulizer was tested at doses of 0.8, 4, 8, 20, 40, 80, or 160 µg in healthy subjects.
21  Based on 
preliminary in vitro study data, a dose of approximately 16 μg GSP304 delivered via an Omron® 


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NE-U22V MICROAir® nebulizer results in a similar Fine Particle Dose (FPD <5 μm) as 5 μg 
Spiriva® Respimat. 
The following dose strengths of GSP304 (tiotropium bromide) Inhalation Solution will be used 
in this study: 10 µg, 20µg, and 40 µg QD.  The dose strengths to be used in this study for 
delivery via a nebulizer are higher than the approved Spiriva® Respimat® dose strength, because 
the Respimat
® Soft Mist Inhaler uses mechanical energy to increase efficiency of the device, 
therefore reducing the nominal dose of tiotropium required to produce equivalent clinical 
efficacy of either a nebulizer or DPI.  The Sponsor has not identified any study in published 
literature that directly compares a nebulizer and the Respimat
® Soft Mist Inhaler.22,23  The PK of 
GSP304 at these doses will be compared with the approved dose of Spiriva
® Respimat® (5 µg 
QD), which is supplied for this study as an open-label marketed product. 
7.2.4. 
Population 
To be considered for inclusion in this study, a subject must have a primary diagnosis of mild or 
moderate COPD (defined as post bronchodilator FEV
1/FVC ratio of <70% and FEV
1 of ≥50% 
of predicted normal value as per the NHANES III predicted normal values at screening). 
The PD dose response of GSP304 and the marketed comparator will be compared by 
measurement of FEV1.  For this reason, the Sponsor proposes that subjects with mild (GOLD 1) 
to moderate (GOLD 2) COPD will participate in this phase 2 study.  The frequency of treatment 
of GSP304 used in this phase 2 study is the same as the approved Spiriva® Respimat® that is 
indicated for use in patients with mild, moderate and severe symptoms of COPD.
10    
7.3. 
Number of Subjects 
A total of 155 male and female subjects of non-childbearing potential, ≥40 but ≤85 years of age 
will be randomized in this study. 
7.4. 
Treatment Assignment 
Each subject will be randomized to 1 of 5 treatment arms in a 1:1:1:1:1 ratio, to receive 1 of 
3 doses of double-blinded GSP304, or double-blinded GSP304 placebo, or open-label Spiriva 
Respimat®.   
7.5. 
Dose Adjustment Criteria 
Not applicable. 
7.6. 
Criteria for Study Termination 
If the Investigator, or the Sponsor’s Medical Monitor becomes aware of conditions or events that 
suggest a possible hazard to subjects if the study continues, the study may be terminated after 
appropriate consultation between the relevant parties. The study may also be terminated early at 
the Sponsor’s discretion in the absence of such a finding. 
Conditions that may warrant termination include, but are not limited to: 
• The discovery of an unexpected, significant, or unacceptable risk to the subjects 
enrolled in the study; 


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• Failure to enroll subjects at an acceptable rate; 
• A decision on the part of the Sponsor to suspend or discontinue development of the 
drug product. 
The Sponsor reserves the right to discontinue the study for medical reasons or any other reason at 
any time.  If a study is prematurely terminated or suspended, the Sponsor will promptly inform 
the Investigators/Institutions and regulatory authorities of the termination or suspension and the 
reason(s) for the termination or suspension.  The Institutional Review Board (IRB)/independent 
Ethics Committee (IEC) will also be informed promptly and provided the reason(s) for the 
termination or suspension by the Sponsor or by the Investigator/Institution, as specified by the 
applicable regulatory requirement(s). 
The Investigator reserves the right to discontinue the study should his/her judgment so dictate.  If 
the Investigator terminates or suspends a study without prior agreement of the Sponsor, the 
Investigator should inform the Institution where applicable, and the Investigator/Institution 
should promptly inform the Sponsor and the IRB/IEC and provide the Sponsor and the IRB/IEC 
with a detailed written explanation of the termination or suspension.  Study records must be 
retained as noted above. 
7.7. 
Benefit-Risk Assessment 
7.7.1. 
Evaluation of Benefit 
A total of 6614 subjects with COPD (2801 receiving Spiriva
® Respimat® 5 μg and 
2798 receiving placebo) were studied in 5 confirmatory studies of Spiriva
® Respimat®.
10  These 
studies enrolled subjects who had a clinical diagnosis of COPD, were 40 years of age or older, 
had a history of smoking greater than 10 pack-years, had an FEV1 less than or equal to 60% of 
predicted and a ratio of FEV1/FVC of less than or equal to 0.7.  All treatments were administered 
once-daily in the morning.  Change from baseline in trough FEV1 was a primary endpoint in all 
studies.  Three studies included COPD exacerbations as primary endpoints.  Spiriva
® Respimat® 
5 μg demonstrated significant improvement in trough FEV
1 compared with placebo in all 
5 confirmatory studies. 
Pooled analysis of 2 studies showed a significant reduction (0.78 exacerbations/patient year), 
compared with placebo (1.0 exacerbations/patient year, rate ratio 0.78, 95% confidence interval 
[CI] 0.67, 0.92), of COPD exacerbations (defined as a complex of respiratory events/symptoms 
with a duration of ≥3 days with 2 or more of the following AEs [increase of symptoms or new 
onset]: shortness of breath/dyspnea/shallow, rapid breathing; sputum production [volume]; 
occurrence of purulent sputum; cough; wheezing; chest tightness).  In a third study, exacerbation 
was lower in subjects taking Spiriva
® Respimat® 5 μg compared with subjects on placebo and 
the risk of COPD exacerbation-related hospitalization was reduced compared with placebo 
(hazard ratio = 0.73, 95% CI, 0.59, 0.90). 
7.7.2. 
Assessment of Risk  
Immediate hypersensitivity reactions, including urticaria, angioedema (including swelling of the 
lips, tongue, or throat), rash, bronchospasm, anaphylaxis, or itching, may occur after 
administration of tiotropium bromide.  Subjects with a history of allergic reaction to the 


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anti-cholinergic or any components of the study medications will be excluded from study 
participation.  
Inhaled medicines, including tiotropium bromide, may cause paradoxical bronchospasm.  If this 
occurs, it should be treated immediately with an inhaled short-acting beta2-agonist such as 
albuterol.  Albuterol/salbutamol MDI will be permitted throughout the study as rescue 
medication (Section 9.2.1).   
Tiotropium bromide should be used with caution in patients with narrow-angle glaucoma or 
urinary retention.  Investigators and subjects should be alert for signs and symptoms of acute 
narrow-angle glaucoma (eg, eye pain or discomfort, blurred vision, visual halos or colored 
images in association with red eyes from conjunctival congestion and corneal edema) or urinary 
retention (eg, difficulty passing urine, painful urination).  Subjects with clinically significant 
unstable medical abnormalities will be excluded from study participation.  
As a predominantly renally-excreted drug, subjects with moderate to severe renal impairment 
(creatinine clearance of <60 mL/min) treated with tiotropium bromide should be monitored 
closely for anticholinergic side effects.  Subjects with clinically relevant laboratory results will 
be excluded from study participation.  
There are no adequate and well-controlled studies in pregnant women.  Tiotropium bromide 
should be used during pregnancy only if the potential benefit justifies the potential risk to the 
fetus.  Because the risk to a fetus is unknown, only women of non-childbearing potential (as 
defined in Section 8) will eligible for study participation.   
The most common adverse reactions of tiotropium bromide inhalation powder (>5% incidence in 
Spiriva® HandiHaler® 1-year placebo controlled studies) were upper respiratory tract infection, 
dry mouth, sinusitis, pharyngitis, non-specific chest pain, urinary tract infection, dyspepsia, and 
rhinitis.
11  The most commonly reported adverse reactions of tiotropium bromide inhalation 
spray (>3% and higher than placebo) were pharyngitis, cough, dry mouth, and sinusitis.
10  
Pooled analysis of safety data from 29 clinical studies conducted with Spiriva® suggested that 
there is an increased risk of stroke (2 cases per 1000) with tiotropium bromide treatment,
24 that 
raised safety concerns and prompted further long-term safety studies to evaluate risk.  A 
long-term safety study (UPLIFT) followed approximately 6000 subjects over 4 years and 
concluded that the long-term use of tiotropium bromide does not increase the risk of stroke, heart 
attack, or death due to a cardiovascular cause.  These findings support the cardiac safety of 
tiotropium bromide in patients with COPD.
25   In the UPLIFT study, rate ratios for overall AEs, 
SAEs, and fatal AEs favored Spiriva
® HandiHaler® versus placebo treatment.  However, data 
from additional studies has been interpreted to indicate that an increased risk of mortality 
associated with the use of Spiriva
® Respimat® is
 possible.26  
A long-term, randomized, double-blind study (TIOSPIR) was conducted to prospectively 
evaluate safety and exacerbation efficacy of Spiriva
® Respimat® versus Spiriva
® Handihaler®.
27  
The results of the TIOSPIR study demonstrated that the safety profile and exacerbation 
efficiency of Spiriva
® Respimat® 5 μg or 2.5 μg was similar to that of Spiriva
® HandiHaler® 
18 μg for subjects with COPD.  The mortality risk for Spiriva
® Respimat® 5 μg or 2.5 μg was 
similar to that of Spiriva
® HandiHaler® 18 μg, with hazard ratios of 0.96 and 1.00 for Spiriva
® 


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Respimat® 5 μg and 2.5 μg versus Spiriva
® HandiHaler® 18 μg, respectively.  The risks of 
exacerbations and major adverse cardiovascular events were similar in all 3 treatment groups.
28 
7.7.3. 
Benefit-Risk Conclusion 
The safety, efficacy, and PK profile for tiotropium bromide is well-established when inhaled as 
an inhalation powder (Spiriva
® HandiHaler®)
11 or inhalation spray (Spiriva
® Respimat®).
10   
Tiotropium bromide has been approved in the US for the long-term, once-daily, maintenance 
treatment of bronchospasm associated with COPD, and for reducing COPD exacerbations. 
GSP304 (tiotropium bromide) Inhalation Solution is being developed with the expectation that 
the selected dose will result in systemic exposure to tiotropium that is comparable to the 
approved dose of Spiriva
®.  Since the safety of tiotropium bromide at its therapeutic dose is 
well-established in large long-term clinical studies, the Sponsor considers it reasonable to expect 
that the safety profile of GSP304 will be similar to the approved products (Spiriva® HandiHaler® 
and Spiriva
® Respimat®).  In addition, a nebulizer has been selected for the delivery of GSP304 
because this type of device may offer benefit for patients with COPD who have difficulty with 
coordination or have low inspiratory rates. 
 


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
Subjects eligible for enrolment in the study must meet all of the following criteria: 
1. Provide written informed consent. 
2. Willing and able to comply with all aspects of the protocol and able to appropriately use 
the inhalation device. 
3. Male and female subjects ≥40 years and ≤85 years of age at the time of consent. 
4. Subject must have a primary diagnosis of mild or moderate COPD defined as 
post-bronchodilator FEV1/FVC ratio of <70% and FEV
1 of ≥50% of predicted normal 
value as per the NHANES III predicted normal values at screening. 
5. Willing to stop all other COPD medications or other medications which will interfere 
with the study results for the entire duration of the study, except albuterol/salbutamol as 
needed. 
6. Female subjects must have a negative serum pregnancy test at Screening and a negative 
urine pregnancy test at Day-1, and must be of non-childbearing potential, defined as: 
a. Postmenopausal, defined as no menses for 12 months without an alternative medical 
cause.  A high FSH level (>40 IU/L) in the postmenopausal range may be used to 
confirm a postmenopausal woman not using hormonal contraception or hormonal 
replacement therapy; however, in the absence of 12 months of amenorrhea, a single 
FSH measurement is insufficient.  
b. Permanently sterile, including surgical sterilization by hysterectomy, bilateral tubal 
ligation/salpingectomy, and bilateral oophorectomy.      
7. Men with partners of childbearing potential must be willing to use condoms in 
combination with a second effective method of contraception during the study.  Each man 
will be considered as potent unless surgically sterilized (with appropriate post vasectomy 
documentation of the absence of sperm in the ejaculate). 
8. Current or ex-smoker with ≥10 pack-year smoking history.   
9. Subjects must have a body mass index (BMI) of at least 16 kg/m
2 but no more than 
30 kg/m2. 
10. Subjects must be willing to remain in the residential facility for 2 separate periods of 
36 to 48 hours (Day -1 through Day 2 and Day 20 through Day 22) and to visit the 
facility for 3 separate ambulatory sample visits. 
11. Subjects must agree to refrain from strenuous activities, throughout the study, from the 
screening visit until after the end of study/early termination visit. 
8.2. 
Subject Exclusion Criteria 
Subjects meeting any of the following criteria must not be enrolled in the study:    


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1. Any history of or concomitant medical condition that in the opinion of the Investigator 
would compromise the subject’s ability to safely complete the study. 
2. Currently enrolled in another clinical study or have used any investigational product, 
study drug, or device within 30 days or 5 half-lives, whichever is longer, preceding 
informed consent or scheduled to participate in another clinical study involving an 
investigational product or investigational drug during the course of this study. 
3. Subject has had a febrile illness within 3 days before screening. 
4. Subject has any clinically significant unstable medical abnormality, chronic disease, or a 
history of a clinically significant abnormality of the cardiovascular, respiratory, GI, 
hepatic, or renal systems, which, in the opinion of the Investigator, may affect the safety 
of the subject. 
5. Subject has a history of malignancy or currently has malignancy other than non 
melanomatous skin cancer. (Subjects who have been cancer-free for 5 years or more 
[prior to randomization] may be enrolled.) 
6. Subjects with a chest x-ray/CT scan that suggests a diagnosis other than COPD (eg, 
pneumonia, other infection, atelectasis, or pneumothorax or other active/ongoing 
pulmonary conditions) and taken within 6 months prior to study start.  If there is no chest 
x-ray or CT scan taken within 6 months prior to study start, or if recent results are 
unavailable for review, a chest x-ray must be performed. 
7. An abnormal and, in the judgment of the Investigator, clinically significant 12-lead ECG.  
For the purposes of this study, an abnormal ECG will be defined as a 12-lead tracing 
which is interpreted with (but not limited to) any of the following:  
• Clinically significant conduction abnormalities (eg, left bundle branch block, 
Wolff-Parkinson-White syndrome)  
• Myocardial ischemia  
• Clinically significant arrhythmias (eg, atrial fibrillation, ventricular tachycardia)  
• A mean QTcB value at screening ≥450 msec (for males) / ≥470 msec (for females) 
and, the QTcB of all 3 screening ECGs are not within 10% of the mean, or an ECG 
that is not suitable for QT measurements (eg poorly defined termination of the 
T wave)  
8. Has a clinically relevant laboratory abnormality or a clinically significant condition, in 
the judgment of the Investigator, such as (but not limited to):  
• Unstable ischemic heart disease, left ventricular failure (New York Heart Association 
Class III and IV), history of myocardial infarction, arrhythmia (excluding chronic 
stable atrial fibrillation).  Subjects with such events not considered clinically 
significant by the Investigator will be considered for inclusion in the study.  
• Uncontrolled hypo- or hyperthyroidism, hypokalaemia or hyperadrenergic state or 
any condition, which might compromise subject’s safety or compliance, interfere with 
evaluation, or preclude completion of the study. 


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• Tiotropium bromide should be used with caution in patients with narrow-angle 
glaucoma or urinary retention. 
9. Subjects with a screening serum creatinine value >1.5 mg/dL.  
10. Use of oral/parenteral corticosteroids or antibiotics for COPD within 6 weeks or depot 
corticosteroids within 3 months prior to screening or subject has had a change in dose or 
type of any medications for COPD within 14 days before screening. 
11. Hospitalization for COPD exacerbation or pneumonia within 3 months prior to screening. 
12. Subjects with a history of asthma, with the exception of outgrown childhood asthma, 
defined as transient wheezers outgrown by 5 years of age.29  
13. Subject has a known history of alpha 1 antitrypsin deficiency-related emphysema. 
14. Subject has a history of lung resection of more than one full lobe or being a recipient of a 
lung or major organ transplant. 
15. Subject requires nocturnal oxygen or continuous supplemental oxygen therapy. 
16. Subject with history of a positive result for HBsAg or HCV antibody. 
17. Subject is known to be seropositive for human immunodeficiency virus. 
18. Female subject is pregnant or lactating. 
19. Female subject who (a) is of childbearing potential, or (b) is post-menopausal and is 
taking any form of hormone replacement therapy. 
20. Subject has a disorder or history of a condition that may interfere with drug absorption, 
distribution, metabolism, or excretion (eg, malabsorption, GI surgery). 
21. Subject is a staff member or relative of a staff member. 
22. Subject has a positive serum alcohol test during screening.  Subjects with a known 
history of alcohol use may be enrolled in the study if the alcohol use is not indicative of 
abuse, as considered by the Investigator. 
23. Subject has a history or suspected history of abuse of a barbiturate, amphetamine, or 
narcotic and/or has a positive screening result for any of these substances at study start.  
Note: Positive drug screening results are not exclusionary for prescription narcotics, 
amphetamines, or barbiturates, if taken only as prescribed under the supervision of a 
physician for a well-documented medical indication, without any evidence or suspicion 
of abuse.  However, methadone and cannabinoids are exclusionary for this study even 
when taken by prescription. 
24. Subject has a history of allergic reaction to the anti-cholinergic or any components of the 
study medications. 
25. Subject is unable to stop the medications at the defined times prior to screening 
spirometry as defined in Appendix 1. 
26. Subject has received oral anticoagulant therapy within 90 days before screening except 
use of low dose aspirin (up to 325 mg daily) to prevent heart attack or a stroke.  Certain 


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types of anticoagulant therapy (eg, clopidogrel, prasugrel) may be permitted, but all must 
be reviewed on a case-by-case basis with the Medical Monitor. 
27. Subject has had significant blood loss (>500 mL) or donated blood within 60 days 
preceding screening or plans to donate blood during or within 60 days after completing 
the study. 
28. Subject has had an acute illness within 10 days of Day 1. 
29. Intake of grapefruit, Seville oranges, or pomelo containing food or beverages within 
7 days prior to receiving the first dose of study treatment until collection of the final PK 
blood sample. 
30. Subject is not willing to comply with dietary restrictions specified in the protocol. 
8.3. 
Subject Withdrawal Criteria 
A subject may voluntarily discontinue study participation at any time after giving informed 
consent and before the completion of the study.  The Investigator may also discontinue the 
subject’s study participation at any time at his/her discretion and for any reason. 
The reasons for subject withdrawal will be recorded and may include, but are not limited to: 
1. Withdrawal of consent by the subject to continue in the study. 
2. Development of a serious or intolerable AE that necessitates discontinuation at the 
discretion of the Investigator (AE section of case report form [CRF] must be completed; 
includes serious adverse event [SAE], any death). 
3. In the opinion of the Investigator, continued participation is not in the best interest of the 
subject. 
4. In the opinion of the Investigator, the subject does not adhere to the study procedures. 
5. Protocol deviation that, in the opinion of the Sponsor and Investigator, warrants 
discontinuation from the study. 
6. The Investigator may withdraw the subject from the study for any of the following: 
a. The subject suffers from significant inter-current illness or undergoes surgery during 
the course of the study. 
b. The subject requires concomitant medication, which may interfere with the PK 
properties of the study medication. 
7. Subject is unable to comply with spirometry washout criteria. 
8. Experienced a COPD exacerbation defined as worsening of the following 2 or more 
major symptoms for at least 2 consecutive days: 
a. Dyspnea 
b. Sputum volume 
c. Sputum purulence 
OR    


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A worsening of any 1 major symptom together with an increase in any 1 of the following 
minor symptoms for at least 2 consecutive days: 
a. Sore throat 
b. Colds (nasal discharge and/or nasal congestion) 
c. Fever without other cause 
d. Cough 
Note: A COPD exacerbation is considered of moderate severity if treatment with 
systemic glucocorticosteroids or antibiotics or both is required.  A COPD exacerbation is 
considered to be severe if hospitalization will be required.  An emergency room visit of 
longer than 24 hours will be considered a hospitalization.  A COPD exacerbation shall be 
reported as an AE and may be considered serious if it meets the serious criteria for SAE 
reporting (see Section 12.2.5). 
9. Demonstrated clinically significant changes in laboratory parameters or ECG recordings. 
 
Any subject withdrawal during the study, along with the reason for withdrawal, must be 
documented in the source documents and eCRFs. 
All follow-up assessments should be conducted at the Early Withdrawal visit (Visit 7 
procedures).  The follow-up visit should be performed as soon as possible after a subject 
withdraws from the study.  If a subject is lost to follow up (fails to return for study visits), 
reasonable efforts should be made to determine why the subject failed to return.  This 
information should be documented in source documents and in eCRFs. 
Subjects discontinued from the study at any stage after the first dose of study drug will be 
included in the safety analysis.  Discontinued subjects will not be replaced. 


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Description of Study Drug 
Table 3 and Table 4 provide a description of the double-blind GSP304, double-blind GSP304 
placebo, and the open label Spiriva® Respimat® comparator to be used in the study. 
Table 3:  
GSP304 
Product Name: 
GSP304 
GSP304 
GSP304 
Dosage Form: 
inhalation solution 
inhalation solution 
inhalation solution  
Unit Dose 
10 μg 
20 μg 
40 μg 
Route of 
Administration 
oral inhalation  
oral inhalation 
oral inhalation 
Method of 
Administration 
nebulization 
nebulization 
nebulization 
Physical 
Description 
a clear solution in a 
semi-transparent, soft 
plastic ampule 
a clear solution in a 
semi-transparent, soft 
plastic ampule 
a clear solution in a 
semi-transparent, soft 
plastic ampule 


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Table 4: 
Other Study Drugs  
 
Comparator Product 
GSP304 Placebo 
Product Name: 
Spiriva® Respimat® 
Matching placebo for GSP304 
Dosage Form: 
inhalation spray for oral 
inhalation 
inhalation solution 
Unit Dose 
2.5 μg 
0 μg 
Route of 
Administration  
oral inhalation 
oral inhalation 
Method of 
Administration 
metered spray for inhalation 
nebulization 
Physical Description 
a clear solution in a green/grey 
plastic Respimat® inhaler 
a clear solution in a semi-
transparent, soft plastic ampule 
Manufacturer 
Boehringer Ingelheim Pharma 
GmbH & Co 
Glenmark or designee 
9.2. 
Concomitant Medications 
The details of the prohibited prior medications and their washout period are provided 
in Appendix 1.  Any medication (including over-the-counter medications) or therapy 
administered to the subject during the study (other than study drug/treatment, starting at the date 
of informed consent, will be recorded on the Prior & Concomitant Medication eCRF or 
Concomitant Non-Drug Treatment eCRF.  The Investigator will record on the Adverse Event 
eCRF any AE for which the concomitant medication/therapy was administered.  If the 
concomitant medication/therapy is being administered for a medical condition present at the time 
of entry into the study, the Investigator will record the medical condition on the Medical & 
Surgical History eCRF. 
9.2.1. 
Rescue Medication(s) 
Albuterol/salbutamol MDI will be permitted throughout the study as rescue medication.  
Subjects will be trained to abstain from using albuterol/salbutamol MDI, 6 hours prior to start of 
each visit.  If this is not possible, the visit will need to be rescheduled.  Albuterol/salbutamol will 
be sourced from local commercial stock.  Any rescue medication(s) taken will be recorded in the 
subject diary and appropriate eCRFs. 
9.3. 
Lifestyle and/or Dietary Restrictions 
Subjects will not be allowed to consume the following foods or drinks: 


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Intake of grapefruit, Seville oranges, or pomelo-containing foods or beverages within 7 days 
prior to the first dose of study treatment until after collection of the final PK blood sample. 
Foods containing poppy seeds for 48 hours prior to first dosing until the final PK blood sample. 
Alcohol for 48 hours prior to dosing until study completion. 
For additional restrictions on spirometry day, refer to Section 11.2.2.2 and Appendix 5. 
9.4. 
Treatment Compliance 
Records of treatment compliance for each subject will be assessed by reviewing the subject 
diary, the dose indicator of Spiriva® Respimat® (as applicable), or counting of study drug 
ampules (as applicable), and will be documented.  Clinical Research Associates will review 
treatment compliance during site visits and at the completion of the study. 
9.5. 
Treatment of Investigational Product Overdose  
Treatment of overdosage consists of discontinuation of GSP304 together with institution of 
appropriate symptomatic and/or supportive therapy. 
9.6. 
Randomization and Blinding 
9.6.1. 
Allocation to Treatment Groups 
At Screening (Visit 1), each potential subject will be assigned a screening number.  Following 
confirmation of the eligibility criteria as applicable, the subject will enter the Run-in period 
(Visit 2).  After completion of the Run-in period, if the subject is conforming to the applicable 
eligibility criteria, then he/she will be randomized and allocated a subject randomization number 
(Visit 3).  Subjects who drop out of the study before randomization/run-in period will retain their 
screening number.  
Randomization and investigational product (IP) assignment will occur in the morning of Day 1 
after all Screening procedures have been performed, run-in has been completed and eligibility of 
the subject for the study confirmed.  Randomization numbers will be issued centrally using 
interactive voice response system (IVRS)/interactive web response system (IWRS).  
Randomized subjects who terminate their study participation for any reason, regardless of 
whether study drug has been taken or not, will retain their randomization number. 
Subjects will be assigned in the ratio of 1:1:1:1:1 to receive treatments with either of 
double-blind GSP304 at 1 of 3 dose levels, open-label Spiriva® Respimat®, or double-blind 
GSP304 placebo based on a computer-generated randomization scheme that will be reviewed 
and approved by a statistician.  The randomization scheme will be stored within the IVRS/IWRS 
database until unblinding of this study is requested.  The randomization scheme and 
identification for each subject will be included in the final clinical study report for this study. 
9.6.2. 
Blinding and Unblinding Procedures 
The active GSP304 and GSP304 placebo are double-blind; Spiriva® Respimat® is open-label.  
Double-blind study drugs (GSP304 and GSP304 placebo) will be supplied in identical 
packaging, and will be similar in color, smell, and appearance.  


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The study blind should not be broken except in a medical emergency (where knowledge of the 
study drug received would affect the treatment of the emergency) or regulatory requirement.  
The blind should preferably be broken following discussion, on a case-by-case basis, with the 
Sponsor Medical Monitor and Pharmacovigilance group.  
In the event of a medical emergency, unblinding for a given subject can be performed through 
the IVRS/IWRS directly by the Investigator or designee.  The reason for unblinding, date and 
time will be required to be entered the appropriate form in the TMF.   
If the breaking of the blind was due to an AE, the subject should be followed up until the AE has 
resolved or stabilized 
To enable bioanalysis of tiotropium in plasma and urine samples only from active treatment 
groups, randomization codes of GSP304 placebo allocated subjects will be shared with a 
designated person at the bioanalytical site and it will be ensured that this will not unblind the 
clinical Investigator or Sponsor personnel involved in direct conduct of the study.  This process 
will be documented and filed. 
The overall study randomization code will be broken only for study reporting purposes.  This 
will occur once all final clinical data have been entered into the database, all data queries have 
been resolved, all PK samples have been analyzed, and the database is locked. 


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Study Drug 
The following treatments will be administered during the treatment period depending on the 
subject’s randomization. 
10.1.1. Blinded GSP304 
Test Treatment T1: GSP304 (tiotropium bromide) Inhalation Solution, 10 μg   
Test Treatment T2: GSP304 (tiotropium bromide) Inhalation Solution, 20 μg   
Test Treatment T3: GSP304 (tiotropium bromide) Inhalation Solution, 40 μg   
GSP304 will be administered by oral inhalation QD using a nebulizer (provided by the Sponsor). 
10.1.2. Blinded GSP304 Placebo 
Test Treatment T4: Placebo to match GSP304. 
GSP304 placebo will be administered by oral inhalation QD using a nebulizer (provided by the 
Sponsor). 
10.1.3. Open-label Spiriva® Respimat® 
Test Treatment T5 (Reference Treatment): Marketed Spiriva
® Respimat® (see Appendix 4 for 
further details). 
10.2. 
Study Drug Packaging and Labeling 
The investigational product will be labeled in accordance with text that is in full regulatory 
compliance with each participating country and is translated into the required language(s) for 
each of those countries.   
10.3. 
Study Drug Storage 
The investigational product (GSP304/GSP304 placebo) should be stored at 25°C (77°F); 
excursions permitted to 15°C to 30°C (59°F to 86°F, see USP Controlled Room Temperature).  
Avoid freezing.  
Spiriva® Respimat® should be stored at 25°C (77°F); excursions permitted to 15°C to 30°C 
(59°F to 86°F, see USP Controlled Room Temperature).  Avoid freezing. 
10.4. 
Study Drug Preparation 
Not applicable. 
10.5. 
Administration 
On days where subject visits are scheduled, subjects will bring all used and unused study drug 
(GSP304/GSP304 placebo or Spiriva® Respimat®) and rescue medication containers to each 
study visit, along with the nebulizer, if required for treatment administration, per randomization 


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group, EXCEPT on Day 20 when subjects will be requested to take the study medication at home 
as instructed by the study staff.   
On all other days, subjects will be requested to take the study medication at home as instructed 
by the study staff.   
Subjects will receive the first dose of the allocated study medication in the morning on Day 1 
(Visit 3) at the clinic.  Study medication (GSP304/GSP304 placebo or Spiriva® Respimat®) will 
be dispensed to the subjects at Visit 3 (at first dose on Day 1) to support the treatment for 
3 weeks.  At clinic check-in on Day 20, subjects will also be requested to bring any remaining 
full ampules of study medication and all empty ampules of study medication to the study site. 
GSP304 and GSP304 placebo will be administered QD (morning) by oral inhalation via a 
nebulizer.  Refer to Appendix 3 for detailed instructions for use of the nebulizer.  
Spiriva® Respimat® will be administered QD (morning) by oral inhalation.  For the instructions 
for use, refer to Appendix 4. 
The time interval between daily doses should be approximately 24 hours. 
10.5.1. Rescue Medication 
Open-label rescue medication (albuterol/salbutamol MDI) will be dispensed to the subjects at 
Visit 2 or at the start of washout (if the subject requires washout) and at subsequent scheduled 
visits as required, for self-administration as needed, at home.  Albuterol/salbutamol MDI will be 
sourced from local commercial stock. 
10.6. 
Study Drug Accountability 
The Principal Investigator (or designee) is responsible for IP accountability at the site and its 
documentation.  The Principal Investigator must also ensure that the dispensing and recording of 
IP is done only by authorized personnel.  The IP records must be readily available for inspection 
by the study monitor and/or auditor/regulatory agency personnel. 
10.7. 
Study Drug Handling and Disposal 
No medication (used or unused) can be returned to the Sponsor or disposed of at the 
investigational site until the Sponsor’s clinical monitor has verified/reconciled the accuracy of 
the study medication records at the site and indicated whether the medication should be 
destroyed at the site or returned to the Sponsor.  The clinical monitor must indicate the name and 
address of the individual to whom the returned materials should be shipped. 


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11. 
PHARMACOKINETIC AND PHARMACODYNAMIC 
ASSESSMENTS 
11.1. 
Study Endpoints 
11.1.1. Primary Endpoints 
• The PK endpoints for tiotropium in plasma to assess the relative bioavailability are: 
− Peak concentrations during the dosing interval at steady-state (C
maxSS) 
− Area under the plasma concentration-time curve over the dosing interval at steady 
state (AUC
0-tauSS) 
• Change from baseline in trough FEV1 at 24 hours after the last dose of treatment on 
Day 21 in comparison to GSP304 placebo 
11.1.2. Secondary Endpoints 
• Amount (A
etau) and fraction of dose of tiotropium (F
e) excreted in urine over the 
dosing interval on Day 1 and Day 21 
• Peak concentrations during the dosing interval (Cmax) on Day 1  
• Area under the plasma concentration-time curve over the dosing interval (AUC
0-tau) 
on Day 1 
• Time of peak drug concentration over the dosing interval (tmax) on Day 1 and Day 21 
• Average concentration during a dosing interval at steady state (C
avSS) on Day 21  
• Accumulation ratio (Rac)  
• Change from baseline in peak FEV1 within 12 hours post-dose on Day 1 and Day 21 
• Change from baseline in FVC on Day 1 and Day 21  
• Change from baseline in time-normalized area under the curve for FEV1 measured 
over 12 hours on Day 1 and Day 21 
11.1.3. Safety Endpoints 
• Vital signs, laboratory parameters, 12-lead ECG  
• Incidence of all AEs 
11.1.4. Appropriateness of Measurements 
All clinical assessments described in the proposed study are standard measurements commonly 
used in studies of subjects with COPD. 
Collection of blood and urine samples pre-dose and at scheduled time points post-dose for 
determination of individual subject plasma tiotropium concentrations is appropriate to assess the 
co-primary objective of this study, which is to compare the relative bioavailability of GSP304 


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(tiotropium bromide) Inhalation Solution at dose levels of 10 µg, 20 µg, and 40 µg QD compared 
with Spiriva
® Respimat® inhalation (5 µg QD) in subjects with COPD.  
Pre-dose FEV1 and FVC will be assessed, in addition to serial spirometry to record FEV
1 on 
Day 1 and Day 21.  These PD assessments are appropriate to assess the co-primary objective of 
this study, which is to characterize the dose response of GSP304 at dose levels of 10 µg, 20 µg, 
and 40 µg, QD with respect to PD. 
The safety assessments to be performed in this study, including hematology analyses, blood 
chemistry tests, urinalysis, and assessment of AEs, are standard evaluations to ensure subject 
safety. 
11.2. 
Efficacy Assessments  
11.2.1. Spirometry  
The following assessments will be performed in this study:  
FEV1 
FEV1 is the volume of air forcibly exhaled in one second as measured by a spirometer.  
Pre- dose trough FEV
1  
It is defined as the mean of FEV
1 values obtained -45 minutes and -15 minutes pre-morning dose 
at Day 1.  
Peak FEV1 
It is defined as the maximum FEV
1 over the period of 12 hours post-morning dose.  
Trough FEV1 
It is defined as the mean FEV
1 obtained 23 hours 15 minutes and 23 hours 45 minutes 
post-morning dose of the previous day.  
Baseline FEV1 
It is defined as the average of the pre-dose FEV1 measured at -45 minutes and -15 minutes at 
Day 1   
FVC 
FVC is the amount of air which can be forcibly exhaled from the lungs after taking the deepest 
breath possible. 
Baseline FVC  
It is defined as the average of the pre-dose FVC measured at -45 minutes and -15 minutes at 
Day 1. 
For a description of FEV1 and FVC procedures, refer to Section 11.2.2.2 Pharmacodynamic 
Assessments. 
11.2.2. Pharmacokinetic, Biomarker, and Pharmacogenomic Assessments 
11.2.2.1. Pharmacokinetic Assessments  
The following PK parameters of tiotropium bromide will be evaluated:  


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Plasma: AUC0-tauSS;C
maxSS; C
minSS; C
avSS; C
max on Day 1; t
max on Day 1 and Day 14; AUC0-tau 
on Day 1; Rac 
Urine: Aetau and Fe 
Additional parameters may be evaluated depending on the data obtained during the study. 
11.2.2.1.1. Blood Sample Collection  
Blood samples (approximately 6 mL) will be collected in dipotassium ethylenediaminetetraacetic 
acid (EDTA) coated vacutainers on Day 1 and Day 21 according to the below schedule: Pre-dose 
(0 hour), and at 2, 4, 6, 10, 15, 30, and 45, 60, 75, and 90 minutes post-dose, as well as 2, 4, 6, 8, 
12, 16, 20 and 24 hours post-dose.  Blood samples for PK should not be drawn or processed in 
the same room that the subject was dosed with study medication.  All post-dose timings are 
relative to the end of dosing (ie, end of nebulization of GSP304/GSP304 placebo or after the 
second actuation of Spiriva
® Respimat®).  The pre-dose sample on Day 1 should be collected 
within 30 minutes prior to dosing while on Days 7, 14, and 21 the pre-dose sample should be 
collected within 10 minutes prior to the morning dose.  On Day 1 and Day 21, blood samples 
collected within the following collection windows: 
• For the 2 minute sample, within a window of ±30 seconds  
• For the 4, 6, 10, 15, and 30 minute samples, within a window of ± 1 minute  
• For the 45, 60, 75, 90 minute, and 2.0 hour samples, within a window of ± 2 minutes 
• For the 4, 6, 8, 12, 16, 20, and 24 hour samples, within a window of ± 5 minutes.   
The collected PK blood samples should be placed immediately on an ice bath and centrifuged 
under refrigeration at 2°C to 8°C within 30 minutes to separate the plasma.  The entire plasma 
(approximately 3 mL) will be transferred into 2 approximately equal aliquots (approximately 
1.5 mL each) and stored at -20°C or below and then sent to the bioanalytical site as specified in a 
separate instruction manual.  
Plasma concentrations of tiotropium will be quantified by a validated liquid 
chromatography-mass spectrometry (LC/MS/MS) method.  Only samples from active treatment 
groups will be analyzed.  Details of bioanalysis will be described in a separate bioanalytical plan.  
A PK blood sample will also be drawn where possible at the first report of an SAE or severe 
unexpected AE and at its resolution. 
11.2.2.1.2. Urine Sample Collection  
Urine will be collected into pre-weighed containers at pre-dose (within 1 hour prior to dosing), 
and at the following intervals post-dose from 0-6, 6-12, and 12–24 hours on Day 1 and Day 21.  
In each urine container, approximately 5 mL of 1M citric acid must be added prior to the start of 
collection.  During each collection period, the containers will be stored in refrigerators at 2°C to 
8°C.  Collection time intervals and the accurate weights of containers before and after collection 
of urine for each interval will be noted.  Weight of urine (weight of container with urine – weight 
of empty container) will be converted to volume using a nominal specific gravity of 1.018.  Two 
representative aliquots of equal volume (approximately 20 mL each, estimated) will be taken 
from each collection interval and shipped to the bioanalytical laboratory as specified in a 


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separate instruction manual.  The remaining volume will be discarded upon confirmation by the 
Sponsor PK representative.  
Urine concentrations of tiotropium will be quantified by a validated LC/MS/MS method.  Only 
samples from active treatment groups will be analyzed for tiotropium concentrations.  Details of 
bioanalysis will be described in a separate bioanalytical plan.  
11.2.2.2. Pharmacodynamic Assessments  
In addition to screening, pre-dose FEV1 and FVC will be assessed at -45 minutes 
and -15 minutes prior to dosing on Day 1, Day 7, Day 14, and Day 21.  Trough FEV
1 will be 
assessed on Day 22 (ie, 24-hours after the Day 21 dose).  
On Day 1 and Day 21, FEV1 will be recorded, at the following time points after the morning 
dose: immediately post-dose at 5 minutes (±3 minutes), 15 minutes (±2 minutes), 30 minutes 
(±5 minutes), 60 minutes, 90 minutes, and 2 hours (120 minutes); and post-dose at 4, 6, 8, 10, 12, 
23 hours 15 minutes and 23 hours 45 minutes.  All post-dose timings are relative to the end of 
dosing (ie, end of nebulization of GSP304/GSP304 placebo or after the second actuation of 
Spiriva® Respimat®).  The window for 1-hour spirometry and thereafter is ±5 minutes.  When 
multiple procedures (eg, PK, spirometry, ECG) conflict at a point of time, PK should be 
performed first, followed by spirometry, then ECG. 
Centralized spirometry will be conducted using equipment meeting or exceeding American 
Thoracic Society (ATS)/European Respiratory Society (ERS) minimal performance 
recommendations, with all sites using standardized equipment provided by a vendor.  Spirometry 
testing is to be performed according to the procedure detailed in Appendix 5.  The start time of 
the first spirometry effort will be used for all spirometry time points recorded.  For FEV1 and 
FVC, at least 3 (and no more than 8) acceptable efforts will be obtained; the largest FEV1 and 
FVC from the 3 acceptable efforts will be recorded, regardless of whether the FEV1 and FVC are 
from the same effort.  Repeatable FEV1 and FVC will be obtained according to the ATS/ERS 
recommendations in Appendix 5.  Albuterol/salbutamol rescue medication is to be withheld for 
at least 6 hours.  For screening spirometry at Visit 1, COPD medications must be withheld as 
specified in the exclusion criteria/Appendix 1.  At Visit 3 through Visit 6, dosing of the study 
drug must be withheld until baseline or trough spirometry, as applicable, has been conducted. 
11.2.2.3. Diary Assessments  
Subjects will be provided a diary at Visit 1 and trained to record symptoms of exacerbation, 
frequency and time of rescue medication and/or other new concomitant medications and any AE 
experienced.  In addition, frequency and time of administration of study drug at home will be 
recorded in the diary by the subject during the treatment period.  Investigator or responsible 
study staff will review the diary at scheduled visits for compliance check, exacerbation reporting 
and/or AE reporting. 
11.2.2.4. Biomarker Assessments 
Not applicable.  


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11.2.2.5. Pharmacogenomic Assessments  
Not applicable.  


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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
Safety assessments will consist of monitoring and recording all AEs and SAEs; regular 
monitoring of hematology, blood chemistry, and urine values; periodic measurement of vital 
signs and ECGs; and performance of physical examinations as detailed in the Schedule of 
Procedures and Assessments (Table 2). 
Stopping/discontinuation/withdrawal criteria are listed in Section 7.6 and Section 8.3. 
In case of premature discontinuation, the reason and their cause must be documented.  All 
appropriate assessments applicable for Visit 7 should be conducted at the Early Withdrawal visit 
and should be scheduled as soon as possible after a subject withdraws from the study (See 
Section 8.3 for details).  If the withdrawal is due to an AE, the AE should be monitored until it is 
resolved or it has returned to a status that was prior to the AE. 
12.1.1. Demographic/Medical History 
Subject demography information will be collected at the Screening visit.  Demography 
information includes date of birth (or age), sex and race/ethnicity.  Other study-specific 
demography information may be included. 
Medical and surgical history, current medical conditions and smoking status will be recorded at 
the Screening visit.  All relevant medical and surgical history must be noted in source documents 
and in the Medical & Surgical History form of the eCRF. 
12.1.2. Vital Signs 
Examination of vital signs will be performed as designated on the Schedule of Procedures and 
Assessments (Table 2).  
Vital sign measurements (ie, systolic and diastolic blood pressure [BP] [mmHg], pulse rate 
[beats per minute], respiratory rate [per minute] and temperature [degrees in Centigrade]) will be 
obtained at the visits designated on the Schedule of Procedures and Assessments (Table 2) by 
standard methods.  Blood pressure and pulse will be measured after the subject has been sitting 
or lying down for 5 minutes.  Blood pressure can be taken in the same manner (ie, seated or 
supine position) at every study visit.  All BP measurements should be performed on the same 
arm, and preferably performed by the same person at the study site. 
Documentation of the vital signs will be included in the source documentation at the site. 
Significant findings at the Screening visit will be recorded in the Medical & Surgical History 
form of the eCRF.  Changes from screening/baseline examination findings that meet the 
definition of an AE will be recorded on the Adverse Events eCRF. 
12.1.3. Weight and Height 
Bodyweight, height and BMI will be assessed at screening visit only.  


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12.1.4. Physical Examination 
Physical examinations (comprehensive or symptom directed/targeted examination) will be 
performed as designated on the Schedule of Procedures and Assessments (Table 2).  A 
comprehensive physical examination will include general appearance, skin/subcutaneous tissue, 
head and neck (including thyroid gland), eyes, ears, nose and throat, mouth, abdomen, lymph 
nodes, musculoskeletal, thorax, lungs/respiratory, heart/cardiovascular, urogenital, anal/rectal, 
extremities and a brief neurological/psychiatric examination.  Urogenital and anal/rectal 
examinations are optional and sign/symptom-directed examination might be performed as per the 
Investigator’s discretion.  
Documentation of the physical examination will be included in the physical examination section 
of the eCRF and source documentation at the site if applicable.  Significant findings at the 
Screening visit will be recorded on the Medical & Surgical History eCRF. Changes from 
screening/baseline examination findings that meet the definition of an AE will be recorded on the 
Adverse Events eCRF. 
12.1.5. Electrocardiogram (ECG) 
Electrocardiograms will be obtained as designated on the Schedule of Procedures and 
Assessments (Table 2).  Subjects must be in the recumbent position for a period of 5 minutes 
prior to the ECG. 
An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Section 12.2) and the eCRF Completion Guidelines.  In these instances, the AE corresponding to 
the ECG abnormality will be recorded on the Adverse Events eCRF. 
For ECG abnormalities meeting criteria of an SAE (see Section 12.2.5), the site must fax or 
email the SAE report including the ECG report (with Subject ID only, and subject’s name 
masked) to the Sponsor using the SAE form (see Regulatory Reporting Requirements for SAEs 
[Section 12.2.5.1]). 
12.1.6. Laboratory Assessments 
Clinical laboratory tests to be performed, including hematology, blood chemistry and urinalysis, 
are summarized in Appendix 2. 
Subjects should be in a seated or supine position during blood collection.  The Schedule of 
Procedures and Assessments (Table 2) shows the visits and time points at which blood for 
clinical laboratory tests and urine for urinalysis will be collected in the study. 
A central laboratory should usually be used to measure laboratory parameters that are to be 
assessed as part of the safety analyses for the clinical study report.  Local laboratories may be 
used in cases of a safety concern during the study, in which case the blood sample would be split 
(or 2 samples collected) to allow both a local laboratory and a central laboratory analysis.  In 
such cases, the local laboratory result(s) will be considered part of the source documentation 
only and the central laboratory result will be entered into the clinical database.  Local laboratory 
reports from non-split samples generated to follow safety concerns will be contained in the 
source documentation. 


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12.1.6.1. Laboratory and Other Safety Assessment Abnormalities Reported as AEs and 
SAEs  
Any abnormal laboratory test results (hematology, blood chemistry or urinalysis) or other safety 
assessments (eg, ECGs, vital signs measurements), including those that worsen from baseline, 
and considered to be clinically significant in the medical and scientific judgment of the 
Investigator are to be recorded as AEs or SAEs. 
12.1.6.2. Virus Serology 
Virus serology to be performed at Screening are summarized in Appendix 2.  
12.1.6.3. Drug Screen 
A standard urine drug screening for drugs of abuse and urine cotinine will be performed at 
Screening and at each clinic check-in (Day-1, Day 20).  
12.1.6.4. Pregnancy Testing 
For all female subjects, serum pregnancy testing will be performed at Screening and urine 
pregnancy testing will be performed at Day -1 (clinic check in) and End of Study (Follow-up). 
12.1.6.5. Follicle-Stimulating Hormone Screening 
For all female subjects, FSH screening will be performed at screening to confirm 
non-childbearing potential (FSH >40 IU/L).  
12.2. 
Adverse and Serious Adverse Events 
The Investigator or site staff will be responsible for detecting, documenting, and reporting events 
that meet the definition of an AE or SAE. 
12.2.1. Assessment of Adverse Events 
The Reference Safety Information for this study is the Investigator’s Brochure section on 
Guidance for Investigators, Undesirable Effects.  
The Reference Safety Information for the comparator product will be the comparator product 
(Spiriva
® Respimat®) USPI sections on Warnings and Precautions and Contraindications.
10  
12.2.2.  Adverse Event  
An AE is defined as any untoward medical occurrence in a subject administered study drug that 
does not necessarily have a causal relationship with the treatment.  An AE can, therefore, be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease 
(new or exacerbated) temporally associated with the use of the study drug, whether or not related 
to the study drug.  An AE includes any event, regardless of the presumed causality between the 
event and the study drug.  
Events that, while not necessarily meeting the definition of AEs, should be treated as such 
because they may be reportable to Regulatory Authorities according to AE reporting regulations, 
whether or not considered causally associated with IP, include the following: 


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• Study drug overdose, whether accidental or intentional 
• Study drug abuse 
• An event occurring from study drug withdrawal 
• Any failure of expected pharmacological action 
• Inadvertent or accidental study drug exposure (eg, product leaking or being spilled 
onto a subject or care-giver) 
• Unexpected therapeutic or clinical benefit from the study drug 
• Medication errors (ie, incorrect route of administration, incorrect dosage, use of 
incorrect product).  
Events that do not meet the definition of an AE include: 
• Medical or surgical procedure (eg, endoscopy, appendectomy); the condition that 
leads to the procedure is an AE 
• Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition.  Note that significant worsening (ie, requiring systemic steroids, 
antibiotics, or hospitalization, as described in Section 8.3) will be reported as an AE. 
12.2.3. Assessment of Severity of Adverse Events 
The severity of AEs is classified as follows: 
• Mild: 
− The AE is a transient discomfort and does not interfere in a significant manner 
with the subject.  
− The AE resolves spontaneously or may require minimal therapeutic intervention. 
• Moderate:  
 
− The AE produces limited impairment of function and may require therapeutic 
intervention. 
− The AE produces no sequelae. 
• Severe:  
− The AE results in a marked impairment of function and may lead to temporary 
inability to resume usual life pattern. 
• The AE produces sequelae, which require (prolonged) therapeutic intervention. 


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The criteria for assessing severity are different from those used for seriousness (see 
Section 12.2.5 for the definition of an SAE). 
12.2.4. Assessment of Relationship to Study Medication 
The relationship of AEs to study medication is classified as follows: 
• Not Related: A causal relationship between the study treatment and the AE is not a 
reasonable possibility 
• Related: A causal relationship between the study treatment and the AE is a reasonable 
possibility  
Items to be considered when assessing the relationship of an AE to the study treatment are: 
• Temporal relationship of the onset of the event to the initiation of the study treatment 
• The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable 
• Whether the event is known to be associated with the study treatment or with other 
similar treatments 
• The presence of risk factors in the study subject known to increase the occurrence of 
the event 
• The presence of non-study treatment-related factors that are known to be associated 
with the occurrence of the event. 
For each AE, the Investigator should answer the following question with Yes or No: 
• Was there a reasonable possibility (evidence) that the drug caused the AE?  
A reasonable possibility means that there are facts (evidence) or arguments to suggest a causal 
relationship. 
NOTE: For subjects that have not started receiving study medication, or run-in phase 
medications the answer must be no. 
12.2.5. Serious Adverse Events  
A SAE is any untoward medical occurrence that, at any dose: 
• Results in death 
• Is life-threatening 
NOTE: The term 
'life-threatening
' in the definition of 
'serious
' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
• Requires hospitalization or prolongation of existing hospitalization 
NOTE: In general, hospitalization signifies that the subject has been detained (usually involving 
at least an overnight stay) at the hospital or emergency ward for observation and/or treatment 
that would not have been appropriate in the physician’s office or outpatient setting. 


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Complications that occur during hospitalization are AEs.  If a complication prolongs 
hospitalization or fulfills any other serious criteria, the event is serious.  When in doubt as to 
whether “hospitalization” occurred or was necessary, the AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
• Results in disability/incapacity 
NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions.  This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) that may interfere or prevent everyday life functions but 
do not constitute a substantial disruption. 
• Is a congenital anomaly/birth defect 
• Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition.  These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
12.2.5.1. Regulatory Reporting Requirements for SAEs 
Prompt notification of SAEs by the Investigator to GLENMARK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met. 
GLENMARK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GLENMARK will 
comply with country-specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC and Investigators. 
All SAEs must be reported to the Sponsor immediately or within 24 hours of the Investigator or 
their staff becoming aware of them.  Reporting should be performed by recording as much 
information as is available at the time on the SAE Form and sending it to the contact information 
provided below:  
Fax:   + 44 1923 251137 
Email:  GlobalClinicalSAE@glenmarkpharma.com 
When further information becomes available, the SAE Form should be updated with the new 
information and reported immediately via the same contact information.  Follow-up reports must 
be submitted to the Sponsor until the event resolves, the event stabilizes or the event returns to 
baseline if a baseline value is available. 
Additional information will be requested by the Sponsor as necessary. 


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12.2.6. Pregnancy 
The Investigator will attempt to collect pregnancy information on any female partner of a male 
study subject who becomes pregnant while participating in this study.  The Investigator will 
record pregnancy information on the appropriate form and submit it to the Sponsor within 
2 weeks of learning of the partner’s pregnancy.  The partner will also be followed to determine 
the outcome of the pregnancy.  Information on the status of the mother and child will be 
forwarded to the Sponsor.  Generally, follow-up will be no longer than 6 to 8 weeks following 
the estimated delivery date.  Any premature termination of the pregnancy will be reported. 
Any pregnancy that occurs during study participation must be reported to the Sponsor, using a 
clinical trial pregnancy form, immediately or within 24 hours of the Investigator learning of its 
occurrence. The report should contain as much information as possible and should be sent to:  
Fax:   + 44 1923 251137 
Email:  
GlobalClinicalSAE@glenmarkpharma.com 
When further information becomes available, the Pregnancy Report Form should be updated 
with all new information and reported immediately via the same contact information above. The 
Pregnancy must be followed up to determine outcome (including premature termination) and 
status of mother and child, and this information must be sent to the Sponsor as above.  Pregnancy 
complications and elective terminations for medical reasons must be reported as an AE or SAE. 
Spontaneous abortions must be reported as an SAE. 
Additional information will be requested by the Sponsor as necessary. 
Any SAE occurring in association with a pregnancy brought to the Investigator’s attention after 
the subject has completed the study and considered by the Investigator as possibly related to the 
study drug, must be promptly reported to the Sponsor. 
12.2.7. Collection and Recording of AEs and SAEs 
12.2.7.1. Collection of AEs 
The Investigator or site staff is responsible for detecting, documenting and reporting events that 
meet the definition of an AE or SAE. 
AEs will be collected from the time of signing the informed consent form (ICF) until the follow 
up contact. 
SAEs will be collected over the same time period as stated above for AEs. However, any SAEs 
assessed as related to study participation (eg, study drug, protocol mandated procedures, invasive 
tests, or change in existing therapy) or related to a concomitant medication that is a Glenmark 
product, will be recorded from the time a subject consents to participate in the study up to and 
including any follow up contact.  All SAEs will be reported to the Sponsor within 24 hours, as 
indicated in Section 12.2.5.1.  
The Investigator will enquire about the occurrence of AEs/SAEs at every visit throughout the 
study (including Follow-up and Early Withdrawal visits where applicable), by asking the 
following non-leading verbal question of the subject (or care-giver, where appropriate): 
• “Have you had any medical problems since your last visit?” 


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All AEs not resolved by the end of the study or that have not resolved upon the subject’s 
discontinuation in the study must be followed until the event resolves, the event stabilizes or the 
event returns to baseline if a baseline value is available. 
12.2.8. Recording of AEs 
All AEs, regardless of the seriousness, severity or relationship to the study medication must be 
recorded on the AE CRF.  
Adverse events that meet the definition of a SAE must be reported on the SAE Form provided 
for this study. 
Adverse events must be documented in clear, unambiguous medical language.  Do not use 
abbreviations or acronyms.  
For each AE record only the diagnosis, do not report the characteristic signs and symptoms of 
the diagnosis as additional AEs.  
If a diagnosis is not available record each sign and symptom as an AE, when a diagnosis 
becomes available, update the AE CRF, to record the relevant diagnosis only. 
In general abnormal findings at screening should be recorded in the subject’s Medical History or 
in the Concurrent Conditions section in the CRF.  However if, in the Investigators opinion, the 
finding is clinically significant and represents a condition that was not present at signing of 
informed consent, then the finding must be reported as an AE. 
 


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13. 
STATISTICS 
A Statistical Analysis Plan (SAP) will be written to provide details of the analysis, along with 
specifications for tables, listings, and figures to be produced.  The SAP will be finalized before 
the database lock at the latest.  Any changes from the analyses planned in the SAP will be 
justified in the clinical study report. 
All analyses will be performed using SAS®. PK analyses will be performed using appropriate 
software.  
In general, all data will be summarized with descriptive statistics (number of subjects, mean, 
standard deviation (SD), minimum, median and maximum) for continuous endpoints, and 
frequency and percentage for categorical endpoints. 
13.1. 
Sample Size  
A sample size of 28 subjects per treatment arm will have 90% power to detect a difference in 
mean change from baseline in trough FEV1 of 150 mL between GSP304 and GSP304 placebo 
assuming a 2-sided alpha of 5% and a SD of 170 mL.  These assumptions are based on available 
literature from similar studies conducted for Spiriva
® Respimat®.
30  
Given the overall 1:1:1:1:1 study treatment allocation ratio, 140 subjects are required for the 
analysis of the primary endpoint.  Assuming a dropout rate of approximately 10%, a total of 
155 subjects (31 subjects per treatment arm) will be randomized. 
This sample size is also considered to be sufficient for the relative bioavailability endpoint. 
13.2. 
Analysis Sets 
13.2.1. Full Analysis Set (FAS) 
This will include all subjects who are randomized, have received at least 1 dose of study 
medication and have at least 1 post-baseline PD assessment.  This analysis set will be the 
primary analysis set for the PD endpoints. 
13.2.2. Safety Analysis Set (SAF) 
This will include all subjects who are randomized and received at least 1 dose of study 
medication.  All safety endpoints will use the SAF unless otherwise specified. 
13.2.3. Per Protocol Analysis Set (PP) 
This will include all subjects who are randomized, received at least 1 dose of study medication, 
completed the study and do not have exclusionary major protocol deviations.  Major and 
exclusionary protocol deviations will be defined in the SAP and by clinical review prior to 
unblinding. 
13.2.4. PK Analysis Set (PKAS) 
This will include all subjects who are randomized, received at least 1 dose of study treatment and 
have at least 1 quantifiable PK sample and do not have exclusionary major protocol deviations.  
The PKAS will be used to analyze the PK endpoints unless otherwise specified in the SAP.  


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Major and exclusionary protocol deviations will be defined in the SAP and by clinical review 
prior to unblinding. 
13.3. 
Subject Disposition 
Number and percentage of subjects who were screened for the study (enrolled subjects, ie, those 
who signed informed consent) and reasons for screen failure will be summarized.  The number of 
subjects randomized per treatment arm and the numbers and percentages of subjects in each of 
the FAS, SAF, PP, and PKAS will be summarized.  In addition, the number and percentage of 
subjects who completed study treatment and discontinued study treatment before Day 21 will be 
summarized, along with the reason. 
13.4. 
Demographics, Baseline Characteristics and Concomitant 
Medications 
13.5. 
Efficacy Analyses  
Refer to Section 13.6 below.  
13.6. 
Pharmacokinetic, Pharmacodynamic, Biomarker, and 
Pharmacogenomic/ Pharmacogenetic Analyses 
13.6.1. Pharmacokinetic Analyses 
Pharmacokinetic analysis will be performed using the PKAS.  
Individual subject plasma PK parameters will be determined from plasma concentrations using 
non-compartmental methods for each subject using appropriate software.  Actual collection times 
will be used for the analyses.   
The amount and fraction of dose of tiotropium excreted in urine during the collected time 
interval in individual subjects will be estimated.  Actual collection times and urine volumes will 
be used for the estimation. 
Additional parameters may be evaluated depending on the data obtained during the study.  
The derived PK parameters will be listed by subject and summarized by treatment.  Wherever 
appropriate, data will be visualized by means of graphical representations.  For the summaries, 
descriptive statistics for all relevant PK parameters will include: n, mean, SD, coefficient of 
variation (%CV), minimum, median, maximum, geometric mean and geometric mean %CV. 
The plasma concentrations and amount in urine of tiotropium will also be listed by subject, 
summarized by treatment, and presented graphically as mean plots, and individual plots. 
Statistical Analysis of Pharmacokinetic Parameters 
An analysis of variance (ANOVA) will be performed on the ln-transformed PK parameters 
AUC0-tauSS, and C
maxSS.  The ANOVA model will include treatment as fixed effect. The results 
from the model will be back-transformed and the adjusted geometrics means for each treatment 
and the estimated treatment ratios for the treatment comparisons will be presented together with 
90% CIs. 


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The ratios and corresponding 90% CIs will be expressed as a percentage. 
The following comparisons will be made: 
• Test Treatment T1 versus Reference Treatment 
• Test Treatment T2 versus Reference Treatment 
• Test Treatment T3 versus Reference Treatment 
More detail will be provided in the SAP. 
For GSP304, dose-proportionality of tiotropium CmaxSS and AUC0-tauSS parameters will be 
assessed using a power model (linear regression relating log-transformed C
maxSS and AUC0-tauSS 
to the log transformed dose).  Estimates of the mean slopes of log-transformed dose will be 
reported along with corresponding 90% CIs.  Dose proportionality will also be assessed based on 
amount of tiotropium excreted in urine.  More detail will be provided in the SAP. 
13.6.2. Pharmacodynamic Analyses 
The PD comparisons will be made between each dose of GSP304 and GSP304 placebo.   
Analysis of Primary Pharmacodynamic Endpoint 
Change from baseline in trough FEV1at 24-hours after the last dose of treatment on Day 21 in 
comparison to GSP304 placebo.  
The primary endpoint measures the change from baseline in trough FEV1 at 24 hours after the 
last dose of treatment on Day 21.  This will be analyzed using a Mixed-effect Model Repeated 
Measure (MMRM) model to produce treatment differences for each dose of GSP304 vs GSP304 
placebo.  The MMRM model will include pre-dose data from all visits (Days 7, 14, 21 and 22) 
and fixed terms for treatment, visit, baseline, center, treatment by visit and baseline by visit 
interactions. The adjusted means for each treatment and the estimated treatment differences for 
the treatment comparisons will be presented together with 95% CIs.  Multiple imputation-based 
methods will be considered as a sensitivity analysis for missing data, with further detail provided 
in the SAP.  
The primary endpoint will be analyzed using the FAS and primary inference will be based at 
Day 21.  A sensitivity analysis will be based on the PP Analysis Set. 
Analyses of Secondary Pharmacodynamic Endpoints  
Analyses of secondary PD endpoints will be performed on the FAS. 
• Change from baseline in peak FEV1within 12 hours post dose on Day 1 and Day 21: 
This endpoint measures the peak FEV1from the serial readings taken through 
12 hours post-dose and then calculates the change from baseline.  The change from 
baseline will be analyzed using MMRM in a similar way to that of the primary 
endpoint to produce treatment differences for each dose of GSP304 vs GSP304 
placebo. 
• Change from baseline in FVC on Day 1 and Day 21: The change from baseline will 
be analyzed using MMRM in a similar way to that of the primary endpoint to produce 
treatment differences for each dose of GSP304 vs GSP304 placebo. 


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• Change from baseline in time-normalized area under the curve for FEV1 measured 
over 12 hours on Day 1 and Day 21: The endpoint measures a series of FEV1 
readings taken within 12 hours of dosing.  The trapezoidal rule will be used to 
calculate AUC
0-12h and then normalized to the length of time.  The change from 
baseline will be analyzed using MMRM in a similar way to that of the primary 
endpoint to produce treatment differences for each dose of GSP304 vs GSP304 
placebo. 
All PD data will also be displayed in summaries and listings. 
13.6.3. Biomarker Analyses 
Not applicable.  
13.6.4. Pharmacogenomic/Pharmacogenetic Analyses 
13.7. 
Safety Analyses  
All safety analyses will be performed on the SAF and will be presented by the study treatment.  
Safety data will be summarized descriptively.  Data describing quantitative measures will be 
summarized as mean, SD, median and range (minimum and maximum).  Qualitative variables 
will be presented as counts and percentages. 
All safety data will also be displayed in listings. 
13.7.1. Extent of Exposure 
The extent of exposure in each treatment group will be characterized according to the number of 
subjects exposed, the duration of exposure, and the dose to which they were exposed. 
13.7.2. Adverse Events  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities.  The 
number and percentage of AEs, SAEs, AEs leading to discontinuation, and AEs related to study 
drug will be summarized by system organ class, preferred term and treatment group.  The 
number and percentage of AEs by severity will also be summarized.  All AEs will be displayed 
in listings. 
13.7.3. Laboratory Values  
For quantitative laboratory measurements descriptive statistics will be used to summarize results 
and change from baseline by treatment group and time point.  Shifts in laboratory tests relative to 
normal ranges from baseline to each time point during treatment will also be tabulated.  All 
laboratory data will be displayed in listings. 
13.7.4. Vital Signs  
Descriptive statistics will be used to summarize vital sign results and changes from baseline by 
treatment group and time.  All vital signs data will be displayed in listings. 


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13.7.5. Electrocardiograms 
ECG assessments are to be performed at visits as described in Schedule of Procedures and 
Assessments (Table 2).  Descriptive statistics for ECG parameters and changes from baseline 
will be presented by treatment group and time point. 
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) by visit. 
13.7.6. Other Safety Analyses 
Physical examination results including baseline bodyweight, height and BMI will be summarized 
and will be displayed in listings.  
13.8. 
Interim Analysis  
No interim analysis is planned for this study. 


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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Study Monitoring 
Before an investigational site can enter a subject into the study, a representative of the Sponsor 
will visit the investigational study site to: 
• Determine the adequacy of the facilities 
• Discuss with the Investigator(s) and other personnel their responsibilities with regard to 
protocol adherence, and the responsibilities of the Sponsor or its representatives.  This 
will be documented in a Clinical Study Agreement between the Sponsor and the 
Investigator. 
During the study, a monitor from the Sponsor or representative will have regular contacts with 
the investigational site, for the following: 
• Provide information and support to the Investigator(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the CRF, and that investigational product accountability checks are 
being performed 
• Perform source data verification.  This includes a comparison of the data in the CRFs 
with the subject’s medical records at the hospital or practice, and other records relevant to 
the study.  This will require direct access to all original records for each subject (eg, 
clinic charts). 
• Record and report any protocol deviations not previously sent to the Sponsor.  
• Confirm AEs and SAEs have been properly documented on CRFs and confirm any SAEs 
have been forwarded to the Sponsor and those SAEs that met criteria for reporting have 
been forwarded to the IRB. 
The monitor will be available between visits if the Investigator(s) or other staff needs 
information or advice. 
14.2. 
Audits and Inspections 
Authorized representatives of the Sponsor, a regulatory authority, an IEC or an IRB may visit the 
site to perform audits or inspections, including source data verification.  The purpose of a 
Sponsor audit or inspection is to systematically and independently examine all study-related 
activities and documents to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the protocol, Good Clinical Practice 
guidelines of the International Conference on Harmonization, and any applicable regulatory 
requirements.  The Investigator should contact the Sponsor immediately if contacted by a 
regulatory agency about an inspection. 


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14.3. 
Institutional Review Board (IRB) 
The Principal Investigator must obtain IRB approval for the investigation.  Initial IRB approval, 
and all materials approved by the IRB for this study including the subject consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 


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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, 
The Sponsor may conduct a quality assurance audit.  Please see Section 14.2 for more details 
regarding the audit process. 


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16. 
ETHICS 
16.1. 
Ethics Review 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC as appropriate.  The Investigator must submit 
written approval to the Sponsor before he or she can enroll any subject into the study. 
The Principal Investigator is responsible for informing the IRB or IEC of any amendment to the 
protocol in accordance with local requirements.  In addition, the IRB or IEC must approve all 
advertising used to recruit subjects for the study.  The protocol must be re-approved by the IRB 
or IEC upon receipt of amendments and annually, as local regulations require. 
The Principal Investigator is also responsible for providing the IRB with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product.  The Sponsor will provide this information to the Principal Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
16.2. 
Ethical Conduct of the Study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on Harmonisation/Good 
Clinical Practice, applicable regulatory requirements and the Sponsor’s policy on Bioethics. 
16.3. 
Written Informed Consent 
The Principal Investigator(s) at each center will ensure that the subject is given full and adequate 
oral and written information about the nature, purpose, possible risk and benefit of the study.  
Patients must also be notified that they are free to discontinue from the study at any time.  The 
subject should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
The subject’s signed and dated informed consent must be obtained before conducting any study 
procedures. 
The Principal Investigator(s) must maintain the original, signed ICF.  A copy of the signed ICF 
must be given to the subject. 
 


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17. 
DATA HANDLING AND RECORDKEEPING 
17.1. 
Inspection of Records 
The Sponsor will be allowed to conduct site visits to the investigation facilities for the purpose of 
monitoring any aspect of the study.  The Investigator agrees to allow the monitor to inspect the 
drug storage area, study drug stocks, drug accountability records, subject charts and study source 
documents, and other records relative to study conduct. 
17.2. 
Retention of Records 
The Principal Investigator must maintain all documentation relating to the study for a period of 
2 years after the last marketing application approval, or if not approved 2 years following the 
discontinuance of the test article for investigation.  If it becomes necessary for the Sponsor or the 
Regulatory Authority to review any documentation relating to the study, the Investigator must 
permit access to such records. 
17.3. 
Financing and Insurance 
The Sponsor will provide clinical study insurance for any subjects participating in the study in 
accordance with all applicable laws and regulations. 


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18. 
PUBLICATION POLICY 
The Sponsor recognizes and supports the publication and dissemination of scientific information 
as a means of furthering knowledge.  The general strategy regarding publication of the study 
(what, when, where, etc.) will be mutually agreed upon by the Investigator and Sponsor. 
However, in order to protect its commercial interests, the Sponsor reserves the right to manage 
the publication of all study results.  The Investigator agrees that oral and written communication 
to third parties of any procedures or results from the study is subject to prior written consent of 
the Sponsor.  Presentation material and/or manuscript(s) for publication will be reviewed by 
Sponsor prior to submission for publication.  This review will be completed within 30 days of 
receiving presentation material and 60 days of receiving the manuscript from the Investigator.  
Alterations in the material will only be made in agreement between the Investigator and the 
Sponsor.  
In the event of inconsistency between the above and the study contract, the terms of the study 
contract would prevail to the extent of such inconsistency. 


Protocol Number: GSP304-201 
 
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19. 
LIST OF REFERENCES 
1. Global Health Estimates, 2013. Global health estimates 2013: Projections of mortality 
and causes of death, 2015 and 2030. Available from 
URL http://www.who.int/healthinfo/global_burden_disease/projections/en/. 
2. Blasi et al, 2014. Blasi F, Cesana G, Conti S, et al. The clinical and economic impact of 
exacerbations of chronic obstructive pulmonary disease: a cohort of hospitalized patients. 
PLoS One. 2014;9:e101228. 
3. Miravitlles et al, 2013. Miravitlles M, Sicras A, Crespo C, et al. Costs of chronic 
obstructive pulmonary disease in relation to compliance with guidelines: a study in the 
primary care setting. Ther Adv Respir Dis. 2013;7:139-50. 
4. World Health Organization (WHO). Chronic obstructive pulmonary disease (COPD) Fact 
Sheet. 2015. Available at: http://www.who.int/mediacentre/factsheets/fs315/en/. 
5. WHO. WHO: Chronic respiratory diseases – COPD. [Accessed 2016 May 2] Available at 
URL http://www.who.int/respiratory/copd/burden/en/. 
6. NIH, 2010. FACT SHEET – Chronic Obstructive Pulmonary Disease (COPD), NIH 
2010. 
7. NIH, 2012. National Institutes of Health. COPD: the more you know, the better for you; 
National Institutes of Health. Morbidity & mortality: 2012 chart book. 
8. American Lung Association, 2010. American Lung Association. State of lung disease in 
diverse communities 2010. 
9. The Global Strategy for the Diagnosis, Management, and Prevention of Chronic 
Obstructive Pulmonary Disease (Updated 2016) 
10. Prescribing information of SPIRIVA® RESPIMAT® (tiotropium bromide) Inhalation 
Spray, for oral inhalation, Reference ID: 3633537,  Boehringer Ingelheim International 
GmbH, Revised 09/2014 
11. Prescribing information SPIRIVA® HandiHaler® (tiotropium bromide inhalation 
powder) Capsules for Respiratory Inhalation ,Boehringer Ingelheim International GmbH, 
Revised 2011 
12. Sestini P, Cappiello V, Aliani M et al. Group AIPOE. Prescription bias and factors 
associated with improper use of inhalers. J Aerosol Med.2006;19:127-136.  
13. Rau JL. Practical problems with aerosol therapy in COPD. Respir Care. 2006;51:158-
172. 
14. Center for Drug Evaluation and Research (CDER), Food and Drug Administration. 
Pharmacology and Toxicology Review(s). NDA Application Number 21-936, 
Submission date 10-Sept 2014. Generic name: Tiotropium bromide inhalation dry 
powder [Spiriva® Respimat]. Available from 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/021936Orig1s000PharmR.pdf 
15. Clinical pharmacology and biopharmaceutics review(s), Spiriva® Inhalation Powder, 
Retrieved May 27, 2015, from U.S. Food and Drug Administration 


Protocol Number: GSP304-201 
 
Version 3.0 
 
Date: 11-Apr-2017 
 
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16. Center for Drug Evaluation and Research (CDER), Food and Drug Administration. 
Pharmacology and Toxicology Review(s). NDA Application Number 021-395, 
Submission date 30-Jan 2009. Generic name: Tiotropium bromide inhalation powder 
[Spiriva® HandiHaler]. Available 
from http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/dr
ugs/pulmonary-allergydrugsadvisorycommittee/ucm190463.pdf 
17. Hess, D. Metered-dose inhalers and dry powder inhalers in aerosol therapy. Respir Care. 
2005 Oct;50(10):1376-83. 
18. Ari A. Aerosol delivery device selection for spontaneously breathing patients: 2012. 
AARC Clinical Practice Guideline. Respir Care. 2012;57(4):613– 26. 
19. Durham MC. Tiotropium (Spiriva): a once-daily inhaled anticholinergic medication for 
chronic obstructive pulmonary disease. Proc (Bayl Univ Med Cent). 2004 Jul;17(3):366-
73. 
20. van Noord JA, Smeets JJ, Custers FL, Korducki L, Cornelissen PJ. Pharmacodynamic 
steady state of tiotropium in patients with chronic obstructive pulmonary disease. Eur 
Respir J. 2002;19(4):639–44 
21. Center for Drug Evaluation and Research (CDER), Food and Drug Administration. 
Pharmacology and Toxicology Review(s). NDA Application Number 21-395, 
Submission date 12-Dec 2001. Generic name: Tiotropium bromide inhalation powder 
[Spiriva® HandiHaler®]. Available from 
http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21-
395.pdf_Spiriva_BioPharmr_P1.pdf 
22. Gross NJ, Kerwin E, Levin B, et al. Nebulized formoterol fumarate: Dose selection and 
pharmacokinetics. Pulm Pharmacol Ther. 2008;21(5):818-23. 
23. Van Noord JA, Cornelissen PJ, Aumann JL, Platz J, Meller A, Fogarty C. The efficacy of 
tiotropium administered via Respimat Soft Mist Inhaler or HandiHaler in COPD patients. 
Respir Med. 2009;103(1):22-9 
24. United States Food and Drug Administration. FDA Early Communication about an 
Ongoing Safety Review of 
Tiotropium. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationfor
PatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm070651.htm. 
Accessed June 20, 2016. 
25. Tashkin DP, Leimer, I, Metzdorf, N, Decramer M. Cardiac safety of tiotropium in 
patients with cardiac events: a retrospective analysis of the UPLIFT® trial. Respir Res 
2015; 6:65. 
26. Verhamme KM, Afonso A, Romio S, Stricker BC, Brusselle GG, Sturkenboom MC. Use 
of tiotropium Respimat Soft Mist Inhaler versus HandiHaler and mortality in patients 
with COPD. Eur Respir J. 2013;42(3):606-15. 
27. Wise RA, Anzueto A, Calverley P, et al. The Tiotropium Safety and Performance in 
Respimat Trial (TIOSPIR), a large scale, randomized, controlled, parallel-group trial-
design and rationale. Respir Res. 2013(2);14:40. 


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Date: 11-Apr-2017 
 
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28. Wise RA, Anzueto A, Cotton MS, et al. Tiotropium Respimat inhaler and the risk of 
death in COPD. N Engl J Med. 2013;369(16):1491:501. 
29. Stein RT, Martinez FD. Asthma phenotypes in childhood: lessons from an 
epidemiological approach. Paediatr Respir Rev. 2004 Jun;5(2):155-61. 
30. Caillaud D, Le Merre C, Martinat Y et al. A dose-ranging study of tiotropium delivered 
via Respimat Soft Mist Inhaler or HandiHaler in COPD patients. Int J Chron Obstruct 
Pulmon Dis. 2007;2(4):559-65. 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol Number: GSP304-201 
 
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APPENDIX 1. LIST OF MEDICATIONS EXCLUDED DURING ACTIVE 
TREATMENT PERIODS  
Medication 
No use within the following 
time intervals prior to 
Screening (Visit 1) 
Spirometry and thereafter at 
any time during the study 
Inhaled short acting muscarinic antagonist (ipratropium or 
ipratropium/salbutamol combination product) 
6 hours 
Inhaled short acting beta2-agonists  
6 hours 
Oral beta2-agonists 
48 hours 
Inhaled long-acting beta2-agonists (salmeterol, formoterol, etc.)  
48 hours 
Xanthines preparations 
48 hours 
Cromolyn and nedocromil inhalers 
24 hours 
Zafirlukast, montelukast, zileuton 
48 hours 
Inhaled LAMA (tiotropium etc.) 
7 days 
Inhaled corticosteroid or inhaled corticosteroids/LABA combination 
7 days 
Oral PDE-4 inhibitors 
7 days 
Oral or parenteral corticosteroids 
6 weeks 
Any other investigational medication 
30 days or 5 drug half-lives of 
the investigational drug 
(whichever is longer) 
Depot corticosteroids 
3 months 
Antibiotics (for lower respiratory tract infection) 
6 weeks 
Systemic cytochrome P450 3A4 strong inhibitors including but not limited to 
antiretrovirals (protease inhibitors) (eg, indinavir, nelfinavir, ritonavir, 
saquinavir, atazanavir); imidazole and triazole anti-fungals (eg, ketoconazole, 
itraconazole, voriconazole); clarithromycin, telithromycin, troleandomycin, 
mibefradil,  cyclosporin, nefazodone 
6 weeks 
LABA = long-acting beta2-agonist; LAMA = long-acting muscarinic antagonist; PDE-4 = phosphodiesterase 4 


Protocol Number: GSP304-201 
 
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APPENDIX 2. LIST OF CLINICAL LABORATORY TESTS 
Blood Chemistry Parameters 
Hematology Parameters 
Blood glucose 
Erythrocyte count 
Total protein 
Hemoglobin 
Albumin 
Packed cell volume 
Albumin to globulin ratio 
Activated partial thromboplastin time and 
prothrombin time 
Serum cholesterol (total) 
Mean corpuscular volume 
Serum triglycerides 
Mean corpuscular hemoglobin 
Serum creatinine 
Mean corpuscular hemoglobin concentration 
Blood urea nitrogen 
Red cell distribution width 
Sodium 
Total and differential leucocyte count (absolute 
and percents) 
Potassium 
Platelet count 
Bicarbonate 
 
Glomerular filtration rate (GFR); GFR will 
be estimated by the Cockcroft-Gault formula 
utilizing serum creatinine values, age, 
weight, and gender, from the screening visit. 
 
Liver Function Parameters 
Urinalysis 
Serum glutamic oxaloacetic transaminase 
(SGOT)/aspartate aminotransferase (AST) 
Color, appearance, pH 
Serum glutamic-pyruvic transaminase 
(SGPT)/alanine aminotransferase (ALT) 
Microscopy 
Gamma-glutamyl transferase 
Specific gravity 
Alkaline phosphatase 
Glucose 
Bilirubin (total, direct and indirect) 
Protein 
 
Ketones 
Screening for 
Blood 
HBsAg and HCV antibody 
Billirubin 
Thyroid stimulating hormone 
Leukocyte Esterase 
Follicle stimulating hormone 
Nitrite 


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APPENDIX 3. INSTRUCTIONS FOR THE USE OF GSP304 OR GSP304 
PLACEBO NEBULIZER 


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2
Before Using the Device
Introduction.............................................................................. 3
Safety Information .................................................................... 4
Know Your Unit  ...................................................................... 7
Accessories and Replacement Parts................................................ 8
Unit Assembly............................................................................ 9
Operating Instructions
Battery Installation .................................................................... 11
Using the AC Adapter ................................................................ 12
Filling the Medication Bottle ........................................................ 13
Selecting the Nebulization Mode .................................................. 14
Using the Device  ...................................................................... 15
Care and Maintenance
Cleaning after Each Use 
.......................................................................... 16
Daily Disinfecting ...................................................................... 17
Caring for the Device.................................................................. 18
Troubleshooting
Troubleshooting Guide 
................................................................ 20
Warranty  
Infor mation ................................................................ 22
FCC Statement ........................................................................ 23
Specifications ............................................................................ 24
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3
Thank you for purchasing the Omron®NE-U22V MICROAir®Vibrating Mesh Nebulizer
.
Omron Healthcare has moved forward in the development of electronic nebulizer technology with
the introduction of the NE-U22V MICROAir
® Vibrating Mesh Nebulizer.  Focusing on patient
convenience and compliance as its goal, this device offers ultimate portability for wherever you go
and revolutionary vibrating mesh technology that provides a precise, powerful and effective
treatment every time. 
The MICROAir® is a vibrating mesh nebulizer system designed to aerosolize liquid medications for
inhalation by the patient. The device may be used with pediatric and adult patients in the home,
hospital, and sub-acute care settings.     
Yo u 
r
  N E
 
- U 2 2 V
  M 
I C ROA
 
i 
r® comes with the following components:
• Main Unit
• Unit Cover
• Medication Bottle
• Mesh Cap
• Mask and Mouthpiece Adapter
• Mouthpiece
• Storage Case
• Instruction Manual
• Instructional DVD
The following are optional accessories sold separately:
• AC Adapter
• Child Mask
The MICROAir
® is a prescription medical device. Operate this device only as
instructed by your physician and/or licensed healthcare practitioner
.
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4
To
  a 
s 
s u 
re
  
t h 
e
  
c o 
r 
re 
c 
t
  u 
s 
e
  o 
f t h 
e
  p 
ro d u 
c 
t
  b 
a 
s
 
i 
c
  
s 
a 
f 
e 
t 
y
  m 
e 
a 
s u 
re 
s
  
s h o u
 
l d
  a
 
lway 
s
  b 
e
followed including the warnings and cautions listed in this instruction manual.
OPERATING THE DEVICE
Read all the information in the instruction book and any other literature 
included in the box before using the unit.
For  
type,  dose,  and  
regimen  of medication  
follow  
the 
 
instructions  of your
physician and/or licenced healthcare practitioner.
Pentamidine is not an approved medication for use with this device.
Do not use tap or mineral water in the nebulizer for nebulizing purposes.
Clean and disinfect the Medication Bottle, Mesh Cap, Mask, Mouthpiece 
and Mask and Mouthpiece Adapter before using the device for the first time 
after purchase.
If the device has not been used for a long period of time, clean and disinfect
the Medication Bottle, Mesh Cap, Mask, Mouthpiece, and Mask and
Mouthpiece Adapter before using them.
Always dispose of any remaining medication in the medication cup after each
use. Use fresh medication each time you use the device.
Do not leave the device or its parts where it will be exposed to extreme
temperatures or changes in humidity
, such as leaving the device in a vehicle
during warm or hot months, or where it will be exposed to direct sunlight.
Indicates a potentially hazardous situation which, if
not avoided, could result in death or serious injury
Indicates a potentially hazardous situation which, if
not avoided, may result in minor or moderate injury
to the user or patient or damage to the equipment or
other property
.
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5
OPERATING THE DEVICE (continued)
Provide close supervision when this device is used by
, on, or near infants,
children or compromised individuals.
Inspect the main unit and the nebulizer parts each time before using the device.
Make sure no parts are damaged, the device is assembled properly
, and the
device operates normally
.
To prevent damage to the device, add the medication slowly
. Do not allow the
medication to overflow the Medication Port.
Do not add more than 7 mL of medication to the medication cup.
To
  p 
reve n 
t
  d 
a m 
ag 
e
  
t o
  
t h 
e
  d 
ev
 
i 
c 
e,
  m a ke
  
s u 
re
  
t h at
  
t h 
e
  M 
e 
s h
  C ap
  
i 
s
  
c o 
r 
re 
c 
t
 
ly
  
i n
place. If the Mesh Cap is not properly closed, medication will leak.
Do not operate the device at temperatures greater than +104º F (+40º C).
Do not subject the device or any of the components to strong shocks, such as
dropping on the floor.
This device is approved for human use only
.
Do not disassemble or attempt to repair the device or components.
Operate the device only as intended. Do not use the device for any other purpose
.
Dispose of the device, components and optional accessories according to
applicable local regulations
. Unlawful disposal may cause environmental pollution.
Use only Omron authorized parts and accessories. Parts and accessories not
approved for use with the device may damage the unit.
Changes or modifications not approved by Omron Healthcare will void the
user warranty
.  
RISK OF ELECTRICAL SHOCK WHEN USING THE AC ADAPTER
Do not plug or unplug the power cord into the electrical outlet with wet hands.
Use only the AC adapter designed by Omron for this device. Use of any other
AC adapter may damage the device.
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6
RISK OF ELECTRICAL SHOCK WHEN USING THE AC ADAPTER
(continued)
Do not overload power outlets
. Plug the device into the appropriate voltage outlet.
Do not use extension cords
. Plug the power cord directly into the electrical outlet.
Unplug the power cord from the electrical outlet after using the device.
Unplug the power cord from the electrical outlet before cleaning the device.
MAINTENANCE AND STORAGE
Keep the device out of the reach of unsupervised infants and children. The
device may contain small parts that can be swallowed.
Do not immerse the main unit in water or other liquid.
Do not use or store the device in humid locations, such as a bathroom. Use the
device within the operating temperature and humidity
.
Do not leave the cleaning solution in the nebulizer parts. Rinse the nebulizer
parts with distilled water after disinfecting.
Rinse the nebulizer parts after each use. Dry the parts immediately after washing.
Store the device and the components in a clean, safe location.
To prevent damage to the device, do not carry or leave the Medication Bottle
filled with medication or distilled water.
Do not place or attempt to dry the device or any of its parts in a microwave oven.
To prevent damage to the device, do not rinse or immerse the Main Unit in any
liquid, do not wash or rinse any of the parts under strong running water
, and do
not touch the mesh with your hand or any object.
Do not use household bleach. The mesh will rust and the Mesh Cap cannot be used.
To prevent damage to the device, do not clean the Main Unit using abrasive
cleaners or any type of chemical, and do not allow any moisture to contact the
electrodes or the AC Adapter jack on the Main Unit.
Do not put the AC Adapter in the Storage Case.  The Storage Case is not
intended to carry the AC Adapter.
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7
ON/OFF Button
Turns the power for the 
Main Unit on and off
Bottle Cap Locking Lever
Opens the Medication Bottle for cleaning  
Medication Bottle
Holds maximum capacity of 7mL for treatment
Medication Port
Add the medicine to the bottle 
Electrode
Power conductor from the Main Unit
to the vibrator on the Medication
Bottle
Battery Low Indicator
An orange light blinks when the
batteries 
are worn
Power Indicator
The green light shows the power is on
Main Unit
Bottom of Main Unit
Battery Cover
Push lever to 
remove cover
Medicine Bottle
Mesh Cap
Metal Alloy Mesh creates
high efficiency aerosol
Mask and Mouthpiece Adapter
Mouthpiece
Main Unit Cover 
Protects the Main
Unit with the
attached
Medication Bottle
and 
Mesh Cap
during storage
Holds the Mouthpiece or Mask
securely on the device
Patient Interface
Electrode
Power conductor from the Main
Unit to the AC Adapter
Connection Stand
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8
Instruction Manual
Storage Case
Instructional DVD
Power Plug
Cord Band
AC Adapter Connection Stand
Case holds the Main Unit,
Medication Bottle, Mask and
Mouthpiece Adapter
AC Adapter Model No. U22-5
Model No.
BATTERY COVER
U22-8
MAIN UNIT COVER
U22-9
MASK AND MOUTHPIECE
ADAPTER
U22-2
MEDICATION BOTTLE
U22-3
MESH CAP
U22-4
MOUTHPIECE
U22-1
STORAGE CASE 
U22-7
Child Mask
Model No. C922
Patient Interface 
for pediatric use
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9
Insert the
Mesh Cap
vertically
.
Do not open
the Bottle Cap. 
Close it
securely
.
You have finished
installation.
Read all the information in the instruction book and any other literature included
in the box before using the unit.
Clean and disinfect the Medication Bottle, Mesh Cap, Mask, Mouthpiece and Mask
and Mouthpiece Adapter before using the device for the first time after purchase.
If the device has not been used for a long period of time, clean and disinfect the
Medication Bottle, Mesh Cap, Mask, Mouthpiece, and Mask and Mouthpiece
Adapter before using them.
For directions on cleaning and disinfecting go to page 16 and 17 under Care and Maintenance. 
The device must be assembled before it is used.
General Information
• Components may fit tightly since they are made to prevent the medication
from leaking.
• Hold the device securely with both hands.
• Install the parts securely
.  You may hear a click sound as you install some of the parts
.
1. Attach the Mesh Cap to the Medication Bottle.
Click
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10
You have finished
installation.
You have finished
assembly
.
You have finished
assembly
.
Align both 
electrodes with 
each other.
You have finished
installation.
Click
2.Attach the Medication Bottle to the Main Unit.
3.Attach the Mask and Mouthpiece Adapter to the Main Unit.
4.Attach the Mouthpiece or the Child Mask to the Mask and Mouthpiece Adapter.
• How to attach the Child Mask
• How to attach the Mouthpiece
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11
Bottom of the
Main Unit
Alkaline Batteries 
• The device can be used for approximately
8 days if operating for 30 minutes a day
.
• The Battery Low Indicator (orange light) flashes to
signal the batteries are low
.  Replace both batteries
with new ones.
• The Battery Low Indicator (orange light) turns on
to signal the batteries are worn  out. The device
will not nebulize. 
Immediately replace both batteries with new ones.
NiMH Rechargeable Batteries
• The device can be used for approximately 8 days if
operating for 30 minutes a day when the batteries are
fully charged.   
• The Battery Low Indicator (orange light)  flashes to
signal the rechargeable batteries have little or no
residual power remaining. If the device will not
nebulize immediately echarge the batteries.
• Recharge the batteries using a commercially available
battery charger suitable for the  batteries used in the
device.
• The AC Adapter does not function as a battery
charger. 
Battery Life and Battery Replacement
Click
This device operates using two (2) AA alkaline batteries or two (2) NiMH AA rechargeable batteries. 
Do not install worn and new batteries together.
Do not use different types of batteries together. 
Remove the batteries if the device will not be used
for three months or longer.   
1.  Remove the Battery Cover.
( Rotate  
the  Battery  Cover 
 
lever 
 
in  
the  direction  of the  arrow  as  
shown 
 
in  
the
illustration.
( Remove the Battery Cover. The Battery Cover may appear to be tight
fitting since it was designed to prevent fluids from getting into the device.  
2. Insert the batteries.
Correctly align the polarities (+ and -) with the batteryindication marks on the
device.
3. Replace the Battery Cover.
Use your thumbs to push on both ends of the Battery Cover Press down firmly
until you hear both tabs click into place.
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12
The device is designed not to draw power from the batteries when the AC Adapter is used. The AC
Adapter is not a battery charger.
Use only the AC adapter designed by Omron for this device. Use of any other
AC adapter may damage the device.
To connect the AC Adapter to the Main Unit
(1)  Place the Main Unit on the AC Adapter
Connection Stand as shown in the
illustration below
.
It will click and lock to the stand.
(2)  Insert the AC Adapter Power Plug into
a 120V electrical outlet.   
Do not plug or unplug the power cord into the electrical outlet with wet hands.
Do not overload power outlets. Plug the device into the appropriate voltage outlet.
Do not use extension cords.  Plug the power cord directly into the electrical outlet.
Unplug the power cord from the electrical outlet before cleaning the device.
To remove the AC Adapter from the Main Unit
(1) Disconnect the AC Adapter Power Plug from the electrical outlet.
(2) Push on both sides of the Connection Stand  to unlock the Main Unit.
(3) Remove the Main Unit
Unplug the power cord from the electrical
outlet after using the device.
(1) Unplug
(3) Remove
(2) Push both ends
Connection is completed.
(1)
(2)
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13
Remove the Mouthpiece or Mask and the Mask and Mouthpiece Adapter from the Main Unit.
1. Open the Mesh Cap.
Hold the device securely 
in your hand.
2. Fill the Medication Bottle.
Pentamidine is not an approved medication for use
with this device.
Do not use tap or mineral water in the nebulizer
for nebulizing purposes.
Be careful to prevent the Mesh Cap from closing
as shown in the illustration.
The maximum capacity of the Medication Bottle is 7mL.
Do not add more than 7 mL of medication to the
medication cup. 
To prevent damage to the device, add the medication
slowly
. Do not allow the medication to overflow the
medication port.
3.  Close the Mesh Cap.
To
  p 
reve n 
t
  d 
a m 
ag 
e
  
t o
  
t h 
e
  d 
ev
 
i 
c 
e,
  m a ke
  
s u 
re
  
t h at
  
t h 
e
  M 
e 
s h
  C ap
  
i 
s
 
correctly in place.  If the Mesh Cap is not properly closed, 
medication will leak.
4. Attach the Mask and Mouthpiece Adapter to the Main Unit
Attach the Mouthpiece or the Child Mask to the Mask and Mouthpiece Adapter.
For instructions on attaching the Mask and Mouthpiece Adapter 
return to Unit Assembly on Page 10.
Do not open the
Bottle Cap. 
Lift up the mesh 
cap while pressing
your thumb upward
on the brim.
Check that the 
Mesh Cap is
closed.
Click
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14
This device operates in the Continuous Nebulization Mode or in the Manual Nebulization Mode.
• Continuous Nebulization Mode
To start the device using the continuous
nebulization mode press and hold the ON/OFF
Button down for 1 second.
Press the ON/OFF Button again to stop nebulization.
• Manual Nebulization Mode
In the Manual Nebulization Mode the
device will nebulize only when you press
and hold the ON/OFF Button down.
You can inhale on demand using this mode.
To start the device using manual nebulization
press and hold the ON/OFF Button down
for at least 2 seconds.
Press and hold the ON/OFF Button to
start nebulization.
The power indicator (green light) illuminates during nebulization.   
Press and hold the ON/OFF 
Button down with your 
finger for 1 second.
Press and hold the ON/OFF
Button down with your 
finger for 2 seconds.
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15
For  
type,  dose,  and  
regimen  of medication  
follow  
the 
 
instructions  of your
healthcare provider.
Always dispose of any remaining medication in the medication cup after each
use. Use fresh medication each time you use the device.
Provide close supervision when this device is used by
, on, or near infants,
children or compromised individuals.
Inspect the Main Unit and the nebulizer parts each time before using the device. 
Make sure no parts are damaged, the device is assembled properly
, and the
device operates normally
.
Do not operate the device at temperatures greater than +104ºF (+40ºC).
This device is approved for human use only
.
1.Slightly tilt the Main Unit toward yourself to immerse the Vibrating Mesh Cap
in the medication.
If the vibrator is not immersed in the medication, the device will not nebulize.
2.Start inhalation in a relaxed position.
3.Place your lips lightly around the mouthpiece.  If using the Child Mask position the
mask lightly against the face. 
4.Start the treatment as directed by your healthcare provider.
5.Press the ON/OFF Button to turn off the device when finished with your treatment.
The device has a built-in timer to turn off the power approximately 30 minutes 
after the power is turned on.
When the AC Adapter is used, remove the power plug from the electrical outlet.
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page 15


16
Following the cleaning instructions after each use will prevent any remaining medication in the
bottle from drying, adhering to the mesh cap, and resulting in the device not nebulizing effectively
.  
Wash the Medication Bottle, Mesh Cap, Mask, Mouthpiece, and Mask and Mouthpiece
Adapter after each use.
Rinse the nebulizer parts after each use. Dry the parts immediately after washing.
To prevent damage to the device:
•   Do not rinse or immerse the Main Unit in any liquid.
•   Do not wash or rinse any of the parts under strong running water.
•   Do not touch the mesh with your hand or any other object.  
1. Remove the Mouthpiece or Mask and the Mask and Mouthpiece Adapter
from the Main Unit.
2. Remove the Medication Bottle from the Main Unit.
3. Open the Medication Bottle and discard any remaining medication.
4. Attach the Medication Bottle to the Main Unit.  Open the Mesh Cap.
5. Pour a small amount of distilled water into the Medication Bottle and
close the Mesh Cap.
6. Turn on the device to nebulize the distilled water for 1 to 2 minutes to 
remove residual medication from the mesh holes.
7. Turn off the device and remove the Medication Bottle from the Main Unit.
8. Remove the Mesh Cap from the Medication Bottle and discard any remaining
distilled water from the Medication bottle. 
9. Rinse the Medication Bottle, Mesh Cap, Mask, Mouthpiece, and Mask
and Mouthpiece Adapter with distilled water.  
10.Gently wipe off excess water with a soft clean cloth or allow the parts to air
dry in a clean environment.
11.Assemble the device.  Store the device in the Storage Case or in a
clean environment.     
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page 16


17
Disinfect the Medication Bottle, Mesh Cap, Mask, Mouthpiece, and Mask
and Mouthpiece Adapter after the last treatment of each day
. 
To prevent damage to the device:
• Do not rinse or immerse the Main Unit in any liquid.
• Do not wash or rinse any of the parts under strong running water.
• Do not touch the mesh with your hand or any other object.  
1. Make a solution using one of the following solutions:  Vinegar (1 part white vinegar 
and 3 parts distilled water), OR mild detergent soap (dishwashing soap in distilled water).
Do not use household bleach. The mesh will rust and the Mesh Cap cannot be used.
2. Lift open the Mesh Cap and pour a small amount of disinfecting solution into the
Medication Bottle.
3. Turn on the device to nebulize the disinfecting solution for 1 to 2 minutes.
4. Turn off the device and remove the Medication Bottle from the Main Unit.
5. Remove the Mesh Cap from the Medication Bottle and discard any remaining
disinfecting solution from the Medication Bottle.
6. Soak the Medication Bottle, Mesh Cap, Mask, Mouthpiece, and Mask and 
Mouthpiece Adapter in the disinfecting solution for 10 to 15 minutes.
7. Rinse the Medication Bottle, Mesh Cap, Mask, Mouthpiece, and Mask and 
Mouthpiece Adapter in distilled water.
Do not leave the cleaning solution in the nebulizer parts
. Rinse the nebulizer
parts with distilled water after disinfecting.
8. Gently wipe off excess water with a soft clean cloth or allow the parts to air dry in 
a clean environment.
9. Assemble the device. Store the device in the Storage Case or in a clean environment.
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page 17


18
To keep your device in the best condition and protect the unit from damage
follow these directions:
Keep the device out of the reach of unsupervised infants and children. The device may 
contain small parts that can be swallowed.
Store the device and the components in a clean, safe location.
Do not use or store the device in humid locations, such as a bathroom. Use the device 
within the operating temperature and humidity
.
Do not leave the device or its parts where it will be exposed to extreme temperatures or  
changes in humidity
, such as leaving the device in a vehicle during warm or 
hot months, or where it will be exposed to direct sunlight.
Do not subject the device or any of the components to strong shocks, such as dropping
on the floor.
Do not disassemble or attempt to repair the device or components.
Use only Omron authorized parts and accessories. Parts and accessories not approved for
use with the device may damage the unit.
Operate the device only as intended. Do not use the device for any other purpose.
Changes or modifications not approved by Omron Healthcare will void the user 
warranty
.
Dispose of the device, components, and optional accessories according to applicable local
regulations. Unlawful disposal may case environmental pollution.
Remove the batteries if the device will not be used for three months or longer. Always 
replace all the batteries with new ones at the same time. Do not use different types of
batteries together.
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page 18


19
Cord band
Cleaning the Main Unit 
To
  
c
 
l 
e 
a n
  
t h 
e
  
c 
a 
s
 
i n 
g
  o 
f t h 
e
  m 
a
 
i n
  u n
 
i 
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  m o
 
i 
s 
t 
e n
  a
  
s o 
f 
t
  
c
 
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t h
  w
 
i 
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  wat 
e 
r
  o 
r
  a
  m
 
i
 
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rg 
e n 
t
 
.
  Wi p 
e
  
t h 
e
  
c a 
s
 
i n g
and immediately dry using a soft clean cloth. 
Do not place or attempt to dry the device or any of its parts in a microwave oven.
To prevent damage to the device:
• Do not rinse or immerse the Main Unit in any liquid.
• Do not clean the Main Unit using abrasive cleaners or any type of chemical. 
• Do not allow any moisture to contact the electrodes or the AC Adapter Jack 
on the Main Unit or AC Adapter connection stand. 
Carrying the device in the Storage Case 
Assemble the device by attaching the Mesh Cap and the Medication Bottle to the Main Unit. Place the
Main Unit Cover on the device.
Position the device in the Storage Case as shown in the illustration.  
The Mouthpiece and Mask Adapter can be easily placed in the Storage Case to carry with the Main
Unit.
To prevent damage to the device
• Do not carry or leave the nebulizer with
medication or distilled water in the Medicine Bottle.
• Do not put the AC Adapter in the Storage Case.
The Storage Case is not intended to carry the
optional AC Adapter.  
To
  
c 
a 
r 
r 
y
  
t h 
e
  AC
  A d 
ap 
t 
e 
r
  bu n d
 
l 
e
  
t h 
e
  p owe 
r
  
c o 
rd
  o 
f t h 
e
AC Adapter and fasten it to the Main Unit of the AC
Adapter with the cord band as shown in the illustration.
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page 19


20
PROBLEM
CAUSE
SOLUTION
The power indicator
does not illuminate. 
The AC Adapter is not plugged
into an electrical outlet. 
The connection stand is not
attached to the Main Unit. 
The batteries have not been
inserted properly
. The batteries
are low in charge.
Turn the power switch off. Plug the power
plug into an electrical outlet. Turn the device on.
Make sure Main Unit has been clicked onto
the Connection Stand.
Reinsert the batteries.
Replace both worn batteries immediately
.
Recharge NiMH batteries with a
commercially available charger.
Residual medication has
dried on the components
and accessories.
Clean and disinfect the components
and accessories.
The mesh cap needs to be replaced. 
Replace the Mesh Cap.
The power indicator
is illuminated but the
unit does not nebulize.
The batteries are low
in charge.
Replace same type batteries with new
alkaline or charged NiMH batteries.
The Medication Bottle has
too much medication in it.
Fill the Medication Bottle with the
proper amount of prescribed
medication.  Max is 7 mL. 
Liquid may have collected around
the electrodes of the Main Unit.
Absorb any moisture with a soft cloth.
There is liquid on top of the
Mesh Cap.
Remove visible liquid with a soft cloth
and a very light touch so as not to
damage the mesh. 
The medication has not
come in contact with the
nebulizing parts.
Slightly slant the Main Unit towards you
with the ON/OFF button pointing down.
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page 20


21
PROBLEM
CAUSE
SOLUTION
The unit is on;
however
, it
nebulizes weakly
,
or is taking too long
for treatment.
The Medication Bottle is not
properly installed.
Make sure the Medication Bottle is
properly installed.  
The unit needs to be cleaned.
Follow  directions  
for  
cleaning  after
each use.
The unit needs to be disinfected.
Follow  directions  
for  disinfecting.
The batteries are low in charge.
Replace the batteries per installation
instructions.
Nebulization rates vary based on
the medication used.
Treatment  
times  may  vary  among
medications and patients.
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page 21


22
LIMITED WARRANTIES
Yo u 
r
  N E
 
- U 2 2 V
  N 
e b u
 
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e 
r
,
  e 
x 
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t h 
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  m 
e 
s h
  c a p
  a n d
  a 
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s 
s o 
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i 
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s,
  
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s
  w 
a 
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r a n
 
t 
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t o
  b 
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e
  
f 
r o m
  d 
e
 
f 
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c
 
t 
s
in materials and workmanship appearing within 2 years from date of purchase, when used in
accordance with the instructions provided with your device. The above warranty extends only to the
original retail purchaser.
We  will,  at  our  option,  
repair  or  
replace  without  
charge  your  Omron  Nebuliz 
er
.  Repair  or  
replacement
is our only responsibility and your only remedy under the above warranties.
To
  o b 
t 
a
 
i n
  wa 
r 
ra n 
t 
y
  
s 
e 
r 
v
 
i 
c 
e,
  
c o n 
t 
a 
c 
t
  O m 
ro n
  H 
e 
a
 
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c 
a 
re
 
' 
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  C u 
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t o m 
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  by
  
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  1 
- 
8 
0 
0 
- 
6 
3 
4 
- 
4 
3 
5 
0
for the address of the repair location and the return shipping and handling fee.  Information for
warranty service is available on our website at www
.omronhealthcare.com.  
Enclose the Proof of Purchase. Include a letter
, with your name, address, phone number
, and
description of the specific problem. Pack the product carefully to prevent damage in transit.
Because of possible loss in transit, we recommend insuring the product with return receipt requested.
ALL IMPLIED WARRANTIES, INCLUDING BUT NOT LIMITED TO THE IMPLIED
WARRANTIES OF MERCHANTABILITY AND FITNESS FOR PARTICULAR PURPOSE,
ARE LIMITED TO THE DURATION OF THE APPLICABLE WRITTEN WARRANTY
ABOVE.Some states do not allow limitations on how long an implied warranty lasts, so the above
limitation may not apply to you.
OMRON SHALL NOT BE LIABLE FOR LOSS OF USE OR ANY OTHER INCIDENTAL,
CONSEQUENTIAL OR INDIRECT COSTS, EXPENSES OR DAMAGES.Some states do not
allow the exclusion or limitation of incidental or consequential damages, so the above exclusions may
not apply to you.
This warranty gives you specific legal rights, and you may also have other rights, which may vary
from state to state.
FOR CUSTOMER SERVICE (US and CANADA)
Visit our web site at:                        www
.omronhealthcare.com
Call toll free:                                                      1-800-634-4350
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page 22


23
Note:
POTENTIAL FOR RADIO/TELEVISION INTERFERENCE (for U
.S.A. only)
This product has been tested and found to comply with the limits for a Class B
digital device, pursuant to part 15 of the FCC rules.
These limits are designed to provide reasonable protection against harmful
interference in a residential installation. The product generates, uses, and can
radiate radio frequency energy and, if not installed and used in accordance with
the instructions, may cause harmful interference to radio communications.  However
, there
is no guarantee that interference will not occur in a particular
installation. If the product does cause harmful interference to radio or television reception,
which can be determined by turning the product on and off, the user
is encouraged to try to correct the interference by one or more of the following measures:
• Reorient or relocate the receiving antenna.
• Increase the separation between the product and the receiver.
• Connect the product into an outlet on a circuit different from that to
which the receiver is connected.
• Consult the dealer or an experienced radio/TV technician for help.
POTENTIAL FOR RADIO/TELEVISION INTERFERENCE (for Canada only)
This digital apparatus does not exceed the Class B limits for radio noise emissions from
digital apparatus as set out in the interference-causing equipment standard entitled “
Digital Apparatus”, ICES-003 of the Canadian Department of Communications.
Cet appareil numérique respecte les limites de bruits radioeléctriques applicables aux
appareils numériques de Clase B prescrites dans la norme sur le materiel brouilleur:
“Ap p a 
r 
e
 
i
 
l 
s
  N u m 
é 
r
 
i q u 
e 
s ”
 
,
  
I C E S 
- 0 0 3
  é d
 
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t 
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  p a 
r
  
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e
  m
 
i n
 
i 
s 
t 
e 
r
  d 
e 
s
communications.
Changes or modifications not expressly approved by the party responsible for
compliance could void the user
's authority to operate the equipment.
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page 23


24
Model:
Omron NE-U22V Nebulizer with V
.M.T
.®
Power Source:
DC 3V AC 120V 60 Hz (with AC adapter)
Power Consumption: 
1.5 W
Nebulization Rate:
0.25 mL/min minimum
Particle Size Range: 
MMD approximately 5µm
Medication Capacity: 
7 mL maximum
Operating
Temperature/Humidity:
+50ºF to +104ºF (+10ºC to +40ºC) / 
30% to 85% RH
Storage
Temperature/Humidity/
Air Pressure:
-4ºF to +140ºF (-20ºC to +60ºC) /
10% to 95% RH / 700hPa to 1060 hPa
Vibration Frequency: 
180 kHz
Dimensions:
1.5” (l) x 2.1” (w) x 4.1” (h)
(38mm x 51mm x 104mm)
Weight:
3.4 oz. (97 g)
Battery:
2 “AA” Alkaline or NiMH Rechargeable 
(not included)
Contents:
Main unit, medication bottle, carrying case, mouthpiece, mesh cap, mask
and mouthpiece adapter
, video and instruction manual
UPC Code:
0 73796 45122 6
Pulmicort®
Intal
®
Salubutamol®
MMD (micron)
6.76µ
6.43µ
5.79µ
GSD
 (geometr
ic
standard
 dev
iat
ion)
2.08
2.56
2.75
Resp
irab
le
 fract
ion
(%mass
 0
.52
 to
 6
 µ)
65.0%
66.0%
73.4%
• Subject to technical modification without prior notice
Cascade Impactor Testing at 13 lpm:
Treatment time 5 minutes for 2ml.
• Please note that specifications may vary with medication type used.
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/19/09  1:35 PM  Page 24


25
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page 25


Made in Japan
Distributed by:
OMRON HEALTHCARE, INC.
1200 Lakeside Drive
Bannockburn, Illinois 60015
www.omronhealthcare.com
Copyright © 2007 Omron Healthcare
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page 26


NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page f1


F2
TABLE
 DES
 MATIÈRES
Avant d’utiliser l’appareil
Introduction....................................................................................F3
Renseignements sur la sécurité ............................................................F4
Familiarisez-vous avec l’appareil  ...................................................... F7
Accessoires et pièces de rechange ...................................................... F8
Assemblage de l’appareil..................................................................F9
Mode d’emploi
Installation des piles ......................................................................F11
Utilisation de l’adaptateur c.a. .......................................................... F12
Remplissage du réservoir de médicament ............................................ F13
Sélection du mode de nébulisation .................................................... F14
Utilisation de l’appareil ..................................................................F15
Entretien et nettoyage
Nettoyage après chaque usage ...................................................................... F16
Désinfection quotidienne..................................................................F17
Entretien de l’appareil......................................................................F18
Dépannage
Guide de dépannage........................................................................F20
Renseignements sur la garantie 
.......................................................... F22
Conformité FCC ............................................................................F23
Spécifications................................................................................F24
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page F2


INTRODUCTION
Nous vous remercions d’avoir acheté le nébuliseur à filtre vibrant MICROAir® modèle NE-U22V
d’Omron
®.
Omron Healthcare va de l’avant dans le développement de la technologie des nébuliseurs
électroniques avec son nouveau nébuliseur à filtre vibrant MICROAir® modèle NE-U22V
. Ayant pour
objectifs la commodité pour le patient et la conformité, cet appareil offre une portabilité unique où que
vous alliez ainsi que la technologie révolutionnaire des filtres vibrants qui procure un traitement précis,
puissant et efficace en tout temps. 
Le système MICROAir® est un nébuliseur à filtre vibrant conçu pour transformer en aérosol les
médicaments liquides pour permettre au patient de les inhaler 
. L’appareil peut être utilisé par les enfants
et les adultes à la maison, à l’hôpital et dans les établissements de soins subaigus.
Votre MICROAir® modèle NE-U22V est livré avec les composants suivants :
• Unité principale
• Couvercle de l’appareil
• Réservoir de médicament
• Bouchon-filtre
• Adaptateur pour masque et embout buccal
• Embout buccal
• Étui de rangement
• Guide de l’utilisateur
• DVD d’instructions
Les accessoires suivants sont en option et vendus séparément :
• Adaptateur c.a.
• Masque pour enfant
CONSERVEZ CES DIRECTIVES
Veuillez inscrire les renseignements demandés à des fins de référence
DATE D’ACHAT :
NUMÉRO DE SÉRIE :
Agrafez votre reçu d’achat ici.
Le MICROAir
®est un appareil médical de prescription.  Utilisez cet appareil uniquement
tel que prescrit par votre médecin ou votre professionnel de la santé autorisé.
F3
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page F3


Il est important de toujours respecter les mesures de sécurité de base ainsi que les
avertissements et les mises en garde de ce guide de l’utilisateur afin d’assurer une
utilisation appropriée du produit.
UTILISATION DE L’APPAREIL
Lisez tous les renseignements fournis dans le guide de l’utilisateur et dans tout document
inclus dans la boîte avant d’utiliser l’appareil.
Utilisez toujours le type, la dose et le régime posologique des médicaments prescrits par votre
médecin ou votre professionnel de la santé autorisé.
L’utilisation de la pentamidine avec cet appareil n’est pas approuvée.
N’utilisez pas l’eau du robinet ou de l’eau minérale dans le nébuliseur dans le but de la pulvériser.
Nettoyez et désinfectez le réservoir de médicament, le bouchon-filtre, le masque, l’embout buccal et
l’adaptateur pour masque et embout buccal avant la première utilisation de l’appareil après l’achat..
Si l’appareil n’a pas servi pendant une longue période, nettoyez et désinfectez le réservoir de
médicament, le bouchon-filtre, le masque, l’embout buccal et l’adaptateur pour masque et embout
buccal avant de les utiliser.
Jetez toujours tout reste de médicament qui se trouve dans le réservoir à médicament après
chaque utilisation. Utilisez un médicament frais à chaque utilisation de l’appareil.
Ne laissez pas l’appareil ni ses composants dans un endroit où ils pourraient être exposés à des
températures extrêmes ou à des changements d’humidité, par exemple en les laissant dans un
véhicule pendant les mois chauds, où ils seront exposés aux rayons directs du soleil.
F4
RENSEIGNEMENTS
 SUR
 LA
 SÉCURITÉ
SYMBOLES DE SÉCURITÉ UTILISÉS DANS CE GUIDE DE L
’UTILISATEUR
AVERTISSEMENT
Indique une situation potentiellement dangereuse qui, 
si elle n’est pas évitée, pourrait causer la mort ou une 
blessure grave.
MISE EN GARDE
Indique une situation potentiellement dangereuse qui, 
si elle n’est pas évitée, pourrait causer une blessure 
mineure ou modérée à l’utilisateur ou au patient ou 
bien endommager l’équipement ou d’autres objets.
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page F4


CONSIGNES DE
 SÉCURITÉ
 IMPORTANTES
UTILISATION DE L’APPAREIL (suite)
Assurez une supervision étroite quand cet appareil est utilisé par ou sur des bébés,
des enfants ou des personnes à risque ou en présence de ceux-ci.
Inspectez l’unité principale et les pièces du nébuliseur avant chaque utilisation de l’appareil.
Assurez-vous qu’aucune pièce n’est endommagée, que l’appareil est bien assemblé et que
l’appareil fonctionne normalement.
Ajoutez le médicament lentement pour éviter d’endommager l’appareil. Assurez-vous que le
médicament ne déborde pas de l’orifice d’admission du médicament.
Ne mettez pas plus de 7 ml de médicament dans le réservoir à médicament.
Pour éviter d’endommager l’appareil, assurez-vous que le bouchon-filtre est bien en place. 
Si le bouchon-filtre n’est pas bien fermé, le médicament se renversera.
N’utilisez pas l’appareil à des températures supérieures à +104 ºF (+40 ºC)
Ne soumettez pas l’appareil ni les autres composants à un grand choc, tel que le laisser tomber sur
le plancher.
Cet appareil est approuvé uniquement pour utilisation par des humains.
Ne démontez et ne tentez pas de réparer l’appareil ou ses composants.
Utilisez l’appareil uniquement pour la fonction pour laquelle il est destiné. Ne l’utilisez pas à d’autres
fins.
Jetez l’appareil, les composants et les accessoires en option conformément aux
règlements locaux applicables. La disposition illégale peut causer de la pollution environnementale.
Utilisez uniquement les pièces et les accessoires Omron autorisées. Les pièces et accessoires 
non approuvés pour l’utilisation avec l’appareil pourraient endommager l’appareil.
Tout changement ou altération non approuvés par Omron Healthcare entraînera l’annulation
de la garantie.  
RISQUE DE CHOC ÉLECTRIQUE LORS DE L’UTILISATION DE 
L’ADAPTATEUR C.A.
Ne branchez ou ne débranchez pas le cordon d’alimentation dans une prise de courant lorsque vous
avez les mains mouillées.
N’utilisez que l’adaptateur c.a. conçu par Omron pour cet appareil. L’utilisation de tout autre
adaptateur c.a. pourrait endommager l’appareil.
F5
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page F5


F6
CONSIGNES DE
 SÉCURITÉ
 IMPORTANTES
RISQUE DE CHOC ÉLECTRIQUE LORS DE L’UTILISATION DE 
L’ADAPTATEUR C.A. (suite)
Ne surchargez pas les prises de courant. Branchez l’appareil dans une prise à la tension appropriée.
N’utilisez pas de rallonges électriques. Branchez le cordon d’alimentation directement dans la 
prise de courant.
Débranchez le cordon d’alimentation de la prise de courant après avoir utilisé l’appareil.
Débranchez le cordon d’alimentation de la prise de courant avant de nettoyer l’appareil.
ENTRETIEN ET ENTREPOSAGE
Gardez l’appareil hors de la portée des bébés ou des enfants sans surveillance. L’appareil peut
contenir de petites pièces qui peuvent être avalées.
N’immergez pas l’unité principale dans l’eau ou un autre liquide.
N’utilisez ou n’entreposez pas l’appareil dans un endroit humide, comme la salle de bain. Utilisez
l’appareil dans les conditions de température et d’humidité recommandées.
Ne laissez pas de solution nettoyante dans les pièces du nébuliseur. Rincez les pièces du 
nébuliseur à l’eau chaude du robinet après les avoir désinfectées.
Rincez les pièces du nébuliseur après chaque usage.  Asséchez les pièces immédiatement 
après les avoir lavées.
Rangez l’appareil et ses composants dans un endroit sûr et sec.
Pour éviter d’endommager l’appareil, ne transportez et ne laissez pas le réservoir de médicament
rempli de médicament ou d’eau distillée.
N’essayez pas de sécher ou de mettre l’appareil ou l’une de ses pièces au four à micro-ondes.
Pour éviter d’endommager l’appareil, ne rincez pas l’unité principale ou ne l’immergez pas dans
aucun liquide, ne lavez ni ne rincez aucune pièce à grande eau et ne touchez pas au bouchon-filtre
avec la main ou un objet.
N’utilisez pas de javellisant ménager. Le filtre rouillera et le bouchon-filtre ne sera plus utilisable.
Pour éviter d’endommager l’appareil, ne nettoyez pas l’unité principale à l’aide de nettoyants
abrasifs ou de tout autre produit chimique et ne laissez pas l’humidité toucher les électrodes ou la
prise d’adaptateur c.a. de l’unité principale.
Ne placez pas l’adaptateur c.a. dans l’étui de rangement. L 
’étui de rangement n’est pas conçu pour
transporter l’adaptateur c.a..
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page F6


FAMILIARISEZ-VOUS AVEC L
’APPAREIL
F7
Touche ON/OFF
(MARCHE/ARRÊT)
Met l’unité principale en marche et
à l’arrêt
Languette de verrouillage du bouchon du réservoir
Ouvre le réservoir de médicament pour le nettoyage
Réservoir de médicament
Reçoit un quantité maximale de 7 ml pour le
traitement
Orifice d’admission du médicament
Permet d’ajouter le médicament au réservoir
Électrode
Conducteur d’alimentation de 
l’unité principale vers le vibrateur sur le
réservoir de médicament
Indicateur de piles faibles
Un voyant lumineux orange
clignote lorsque les piles
sont usées
Indicateur d’alimentation
Le voyant vert indique que l’appareil est en marche
Unité principale
Partie inférieure de l’unité principale
Couvercle des piles
Poussez la languette
pour enlever le
couvercle
Réservoir de médicament
Bouchon-filtre
Le filtre en alliage
métallique produit un
aérosol de grande
efficacité
Adaptateur pour masque et
embout buccal
Embout buccal
Couvercle de
l’unité principale
Protège l’unité
principale,
le réservoir de
médicament et
le bouchon-filtre
qui y sont fixés
lors de
l’entreposage
Maintient l’embout buccal ou le masque
bien en place sur le dispositif
Interface du patient
Électrode
Conducteur d’alimentation
de l’unité principale au support de
branchement de l’adaptateur c.a.
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page F7


FAMILIARISEZ-VOUS AVEC L
’APPAREIL
DVD d’instructions
F8
Étui de rangement
Fiche d’alimentation
Bande pour cordon
Support de branchement pour l’adaptateur c.a.
Contient l’unité principale, le
réservoir de médicament ainsi que
l’adaptateur pour masque et embout
buccal
Adaptateur c.a., modèle no U22-5
Accessoire en option
Accessoire en option
Pièces de rechange
No de modèle
COUVERCLE DES PILES
U22-8
COUVERCLE DE L’UNITÉ PRINCIPALE
U22-9
ADAPTATEUR POUR MASQUE ET
EMBOUT BUCCAL
U22-2
RÉSERVOIR DE MÉDICAMENT 
U22-3
BOUCHON-FILTRE
U22-4
EMBOUT BUCCAL
U22-1
ÉTUI DE RANGEMENT
U22-7
Masque pour enfant
modèle no C922
Interface du patient
à usage pédiatrique
Guide de l’utilisateur
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:50 PM  Page F8


PRÉPARATION DU NÉBULISEUR POUR L
’UTILISATION
Insérez
verticalement le
bouchon-filtre
N’ouvrez pas le 
bouchon du 
réservoir
Fermez-le bien
Vous avez terminé
l’installation.
AVERTISSEMENT
Lisez tous les renseignements fournis dans le guide de l’utilisateur et dans tout document
inclus dans la boîte avant d’utiliser l’appareil.
AVERTISSEMENT
Nettoyez et désinfectez le réservoir de médicament, le bouchon-filtre, le masque, l’embout
buccal et l’adaptateur pour masque et embout buccal avant la première utilisation de
l’appareil après l’achat.
AVERTISSEMENT
Si l’appareil n’a pas servi pendant une longue période, nettoyez et désinfectez le réservoir de
médicament, le bouchon-filtre, le masque, l’embout buccal et l’adaptateur pour masque et
embout buccal avant de les utiliser.
Pour des directives sur le nettoyage et la désinfection, consultez la section Entretien et nettoyage
aux pages 16 et 17. 
L’appareil doit être assemblé avant son utilisation.
Renseignements généraux
• Les composants peuvent s’ajuster bien serrés puisqu’ils sont prévus pour empêcher le
médicament de couler.
• Tenez bien l’appareil des deux mains.
• Fixez bien les pièces. Il se peut que vous entendiez un cliquement lorsque vous installez  certaines pièces.
1. Fixez le bouchon-filtre au réservoir de médicament.
Clic
F9
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page F9


F10
PRÉPARATION DU NÉBULISEUR POUR L
’UTILISATION
Vous avez terminé 
l’installation.
Vous avez terminé
l’assemblage.
Vous avez terminé
l’assemblage.
Alignez les 
électrodes l’une
vers l’autre.
Vous avez terminé
l’installation.
Clic
2.Fixez le réservoir de médicament à l’unité principale.
3. Fixez l’adaptateur pour masque et embout buccal à l’unité principale.
4.Fixez l’embout buccal ou le masque pour enfant à l’adaptateur pour masque et embout buccal.
• Comment fixer le masque pour enfant
• Comment fixer l’embout buccal
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page F10


Cet appareil fonctionne à l’aide de deux (2) piles alcalines  AA ou de deux (2) piles AA NiMH rechargeables.
N’utilisez pas une pile usée et une pile neuve ensemble.
N’utilisez pas différents types de piles. 
Retirez les piles lorsque vous prévoyez que l’appareil 
ne sera pas utilisé pendant au moins trois mois.   
1.  Ouvrez le couvercle des piles.
(A)   Faites tourner le couvercle des piles dans le sens
de la flèche comme le montre l’illustration.
(B) Ouvrez le couvercle des piles. Le couvercle des piles
peut sembler s’ajuster serré puisqu’il est prévu
pour éviter que les liquides pénètrent dans l’appareil.
2. Insérez les piles.
Alignez correctement les polarités (+ et -) avec les repères
des piles sur l’appareil.
3. Fermez le couvercle des piles.
À l’aide de vos pouces, poussez les deux extrémités du couvercle des piles
Appuyez fermement jusqu’à ce que vous entendiez les deux languettes cliquer 
en place.
Abcdefg H
i
jk Lmnop
INSTALLATION DES
 PILES
F11
Partie inférieure de
l’unité principale
Piles alcalines
• L’appareil peut être utilisé environ 8 jours à raison
de 30 minutes par jour.
• L’indicateur de piles faibles (voyant orange)
clignote pour signaler que les piles sont usées.
Remplacez les deux piles par des neuves.
• L’indicateur de piles faibles (voyant orange)
s’allume pour signaler que les piles sont à 
 plat.
L’appareil ne nébulisera pas. Remplacez
immédiatement les deux piles par des neuves.
Piles NiMH rechargeables
• L’appareil peut être utilisé environ 8 jours à
raison de 30 minutes par jour lorsque les piles
sont complètement chargées.   
• L’indicateur de piles faibles (voyant orange)
clignote pour signaler que les piles rechar geables
sont à plat ou presque à plat. Si l’appareil ne
nébulise pas immédiatement, rechargez les piles.
• Rechargez les piles au moyen d’un char geur 
de piles disponible sur le marché et adapté aux
piles utilisées dans cet appareil.
• L’adaptateur c.a. ne sert pas de char geur de piles.  
Durée et remplacement des piles
Clic
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page F11


UTILISATION DE
 L
’ADAPTATEUR c
.a
.
F12
L’appareil est conçu de façon à ne pas consommer la puissance des piles lorsque l’adaptateur c.a. est utilisé.
L’adaptateur c.a. n’est pas un char geur de piles.
AVERTISSEMENT
Utilisez uniquement l’adaptateur c.a. conçu par Omron pour cet appareil. 
L’utilisation d’un autre adaptateur c.a. pourrait endommager l’appareil.
Pour brancher l’adaptateur c.a. à l’unité principale
(1) Placez l’unité principale sur le support de branchement
de l’adaptateur c.a. tel qu’illustré ci-dessous.       
REMARQUE : Il émettra un clic et s’enclenchera au support.
(2)  Insérez la fiche d’alimentation de l’adaptateur c.a. 
dans une prise de courant de 120 V
.   
AVERTISSEMENT
Ne branchez ou ne débranchez pas le cordon d’alimentation dans une prise de 
courant lorsque vous avez les mains mouillées.
MISE EN GARDE
Ne surchargez pas les prises de courant. Branchez l’appareil dans une prise à la tension appropriée.
MISE EN GARDE
N’utilisez pas de rallonges électriques. Branchez le cordon d’alimentation directement dans 
la prise de courant.
MISE EN GARDE
Débranchez le cordon d’alimentation de la prise de courant avant de nettoyer l’appareil.
Pour retirer l’adaptateur c.a. de l’unité principale
(1) Débranchez la fiche de l’adaptateur c.a. dela prise de courant.
(2) Poussez les deux côtés du support de branchement
pour débloquer l’unité principale.
(3) Retirez l’unité principale.
MISE EN GARDE
Débranchez le cordon d’alimentation de la prise de courant après l’utilisation de l’appareil.
(1) Débranchez
(3) Retirez
(2) Poussez les deux extrémités
Le branchement est terminé.
(1)
(2)
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page F12


REMPLISSAGE DU RÉSERVOIR DE MÉDICAMENT
F13
Retirez l’embout buccal ou le masque ainsi que l’adaptateur pour masque et embout buccal de l’unité principale.
1. Ouvrez le bouchon-filtre.
Tenez le dispositif fermement
dans votre main.
2. Remplissez le réservoir de médicament.
L’utilisation de la pentamidine avec cet appareil 
n’est pas approuvée.
N’utilisez pas l’eau du robinet ou de l’eau minérale 
dans le nébuliseur dans le but de la pulvériser 
.
Prenez garde que le bouchon-filtre ne se ferme 
comme le montre l’illustration.
La capacité maximale du réservoir de médicament est de 7 ml.
Ne mettez pas plus de 7 ml de médicament dans le
réservoir à médicament. 
Ajoutez le médicament lentement pour éviter d’endommager le
dispositif. Assurez-vous que le médicament ne déborde pas de
l’orifice d’admission du médicament.
3.  Fermez le bouchon-filtre.
Pour éviter d’endommager l’appareil, assurez-vous que le bouchon-filtre est bien en
place. Si le bouchon-filtre n’est pas bien fermé, il y aura fuite de médicament.
4. Fixez l’adaptateur pour masque et embout buccal à l’unité principale
Fixez l’embout buccal ou le masque pour enfant à l’adaptateur pour masque et embout buccal.
REMARQUE Pour des directives sur la façon de fixer l’adaptateur pour masque et embout buccal,
retournez la section Assemblage de l’unité à page 10.
N’ouvrez pas le
réservoi
Soulevez le 
bouchon-filtre en
poussant le bord vers 
le haut avec le pouce.
Vérifiez si le
bouchon-filtre
est fermé.
Clic
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page F13


F14
SÉLECTION
 DU
 MODE
 DE
 NÉBULISATION
Ce dispositif fonctionne en mode de nébulisation continue ou en mode de nébulisation manuelle.
• Mode de nébulisation continue
Pour démarrer l’appareil en mode de nébulisation
continue, appuyez sur la touche ON/OFF (MARCHE/ARRÊT)
en la maintenant enfoncée pendant 1 seconde.
Appuyez à nouveau sur la touche ON/OFF (MARCHE/ARRÊT)
pour arrêter la nébulisation.
• Mode de nébulisation manuelle
En mode de nébulisation manuelle, l’appareil
nébulise seulement si vous appuyez sur
la touche ON/OFF (MARCHE/ARRÊT)
en la maintenant enfoncée.
Ce mode permet l’inhalation sur demande.
Pour démarrer l’appareil en mode de nébulisation
manuelle, appuyez sur la touche ON/OFF (MARCHE/ARRÊT)
et maintenez-la enfoncée pendant au moins 2 secondes.
Appuyez sur la touche ON/OFF (MARCHE/ARRÊT)
en la maintenant enfoncée pour commencer la nébulisation.
REMARQUE :Le voyant d’alimentation (voyant vert)
s’allume pendant la nébulisation.  
Appuyez sur la touche
ON/OFF (MARCHE/ARRÊT)
en la maintenant enfoncée
pendant 1 seconde
Appuyez sur la touche
ON/OFF (MARCHE/ARRÊT)
et maintenez-la enfoncée
pendant 2 secondes.
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page F14


UTILISATION
 DE
 L
’APPAREIL
Utilisez toujours le type, la dose et le régime posologique des médicaments prescrits par
votre fournisseur de soins de santé.
AVERTISSEMENT
Jetez toujours tout reste de médicament qui se trouve dans le réservoir à médicament après
chaque utilisation. Utilisez un médicament frais à chaque utilisation de l’appareil.
MISE
 EN
 GARDE
Assurez une supervision étroite quand cet appareil est utilisé par ou en présence des bébés,
des enfants ou des personnes à risque ou en présence de ceux-ci.
MISE
 EN
 GARDE
Inspectez l’unité principale et les pièces du nébuliseur avant chaque utilisation de l’appareil. 
Assurez-vous qu’aucune pièce n’est endommagée, que l’appareil est bien assemblé et que
l’appareil fonctionne normalement.
MISE
 EN
 GARDE
N’utilisez pas l’appareil à des températures plus élevées que +104 ºF (+40 ºC).
MISE
 EN
 GARDE
Cet appareil est approuvé uniquement pour utilisation par des humains.
1.Inclinez légèrement l’unité principale vers vous pour immer ger le bouchon-filtre vibrant
dans le médicament.
REMARQUE : Si le vibrateur n’est pas immer gé dans le médicament, l’appareil ne nébulisera pas.
2.Commencez l’inhalation dans une position détendue.
3.Placez vos lèvres autour de l’embout buccal sans serrer 
. Si le masque pour enfant est utilisé,
positionnez-le délicatement contre le visage.
4.Commencez le traitement comme votre fournisseur de soins de santé vous l’a indiqué.
5.Appuyez sur la touche ON/OFF (MARCHE/ARRÊT) pour éteindre l’appareil lorsque vous avez
terminé votre traitement.
REMARQUE :L’appareil est muni d’une minuterie intégrée qui met l’appareil hors tension
environ 30 minutes après la mise sous tension.
Lorsque vous utilisez l’adaptateur c.a., retirez la fiche d’alimentation de 
la prise de courant.
F15
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page F15


F16
NETTOYAGE
 APRÈS
 CHAQUE
 UTILISATION
Respecter les directives de nettoyage après chaque utilisation évitera que du médicament restant dans le flacon s’assèche
et adhère au bouchon-filtre, ce qui aurait pour résultat que l’appareil ne nébulise plus efficacement. 
Lavez le réservoir de médicament, le bouchon-filtre, le masque, l’embout
buccal et l’adaptateur pour masque et embout buccal après chaque utilisation.
AVERTISSEMENT
Rincez les pièces du nébuliseur après chaque usage.  Asséchez les pièces immédiatement 
après les avoir lavées.
MISE EN GARDE
Pour éviter d’endommager l’appareil :
•   Ne rincez ou n’immer gez pas l’unité principale dans aucun liquide.
•   Ne lavez ou ne rincez aucune pièce sous un jet d’eau puissant.
•   Ne touchez pas au filtre avec la main ou tout autre objet. 
1. Retirez l’embout ou le masque ainsi que l’adaptateur pour masque et embout buccal de
l’unité principale.
2. Retirez le réservoir de médicament de l’unité principale.
3. Ouvrez le réservoir de médicament et jetez tout reste de médicament.
4. Fixez le réservoir de médicament à l’unité principale. Ouvrez le bouchon-filtre.
5. Versez une petite quantité d’eau distillée dans le réservoir de médicament et fermez le
bouchon-filtre.
6. Mettez l’appareil en marche pour nébuliser l’eau distillée pendant 1 à 2 minutes et
enlevez les restes de médicament du filtre.
7. Éteignez l’appareil et retirez le réservoir de médicament de l’unité principale.
8. Retirez le bouchon-filtre du réservoir de médicament et jetez toute l’eau distillée qui reste
dans le réservoir de médicament.
9. Rincez le réservoir de médicament, le bouchon-filtre, le masque, l’embout buccal et
l’adaptateur pour masque et embout buccal à l’eau distillée.  
10.Essuyez délicatement l’excès d’eau à l’aide d’un chif fon doux et propre ou laissez les 
pièces sécher à l’air libre dans un endroit propre.
11.Assemblez l’appareil. Rangez l’appareil dans l’étui de rangement ou dans un endroit
propre.
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page F16


DÉSINFECTION
 QUOTIDIENNE
Désinfectez le réservoir de médicament, le bouchon-filtre, le masque,
l’embout buccal et l’adaptateur pour masque et embout buccal chaque
jour après le dernier traitement. 
MISE EN GARDE
Pour éviter d’endommager l’appareil :
• Ne rincez ou n’immergez pas l’unité principale dans aucun liquide.
• Ne lavez ou ne rincez aucune pièce sous un jet d’eau puissant.
• Ne touchez pas au filtre avec la main ou tout autre objet.
1.Préparez l’une des deux solutions suivantes :  Vinaigre (1 partie de vinaigre blanc 
pour 3 parties d’eau distillée) OU savon déter gent doux (savon à vaisselle dans de 
l’eau distillée).
MISE EN GARDE
N’utilisez pas de javellisant ménager. Le filtre rouillera et le bouchon-filtre ne sera plus utilisable.
2. Ouvrez le bouchon-filtre en le soulevant et versez une petite quantité de solution désinfectante dans
le réservoir de médicament.
3. Mettez l’appareil en marche pour nébuliser la solution désinfectante pendant 1 à 2 minutes.
4. Éteignez l’appareil et retirez le réservoir de médicament de l’unité principale.
5. Retirez le bouchon-filtre du réservoir de médicament et jetez le reste de la solution
désinfectante du réservoir de médicament.
6. Faites tremper le réservoir de médicament, le bouchon-filtre, le masque, l’embout buccal et
l’adaptateur pour masque et embout buccal dans la solution désinfectante pendant 10 à 15 minutes.
7. Rincez le réservoir de médicament, le bouchon-filtre, le masque, l’embout buccal et l’adaptateur
pour masque et embout buccal à l’eau distillée.
AVERTISSEMENT
Ne laissez pas de solution nettoyante dans les pièces du nébuliseur. Rincez les
pièces dunébuliseur à l’eau distillée après les avoir désinfectées.
8. Essuyez délicatement l’excès d’eau à l’aide d’un chif fon doux et propre ou laissez les pièces sécher
dans un endroit propre.
9. Assemblez l’appareil. Rangez l’appareil dans l’étui de rangement ou dans un endroit propre.
F17
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F18
ENTRETIEN DE L
’APPAREIL
Afin de garder votre appareil dans le meilleur état possible et de bien le
protéger
, suivez les directives ci-dessous :
Gardez l’appareil hors de la portée des bébés ou des enfants sans surveillance. L’appareil peut
contenir de petites pièces qui peuvent être avalées.
Rangez l’appareil et ses composants dans un endroit sûr et sec.
N’utilisez ou n’entreposez pas l’appareil dans un endroit humide, comme la salle de bain. Utilisez
l’appareil dans les conditions de température et d’humidité recommandées.
Ne laissez pas l’appareil ni ses composants dans un endroit où ils pourraient être exposés à des
températures extrêmes ou à des changements d’humidité, par exemple en les laissant dans un véhicule
pendant les mois chauds, où ils seront exposés aux rayons directs du soleil.
Ne soumettez l’appareil ni les autres composants à un grand choc, tel que le laisser tomber
sur le plancher.
Ne démontez et ne tentez pas de réparer l’appareil ou ses composants.
Utilisez uniquement les pièces et les accessoires Omron autorisées. Les pièces et accessoires non
approuvés pour l’utilisation avec l’appareil pourraient endommager l’appareil.
Utilisez l’appareil uniquement pour la fonction pour laquelle il est destiné. Ne l’utilisez pas à
d’autres fins.
Tout changement ou altération non approuvés par Omron Healthcare entraînera l’annulation 
de la garantie.             
Jetez l’appareil, les composants et les  accessoires en option conformément aux règlements
locaux applicables. La disposition illégale peut causer de la pollution environnementale.
Retirez les piles lorsque vous prévoyez que l’appareil ne sera pas utilisé pendant au moins trois
mois. Remplacez toujours toutes les piles en même temps par des piles neuves. N’utilisez pas
différents types de piles.
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page F18


Nettoyage de l’unité principale
Nettoyez le boîtier de l’unité principale à l’aide d’un chif fon doux humidifié avec de l’eau ou un déter gent
doux. Essuyez le boîtier et séchez-le immédiatement à l’aide d’un chiffon doux et propre. 
MISE EN GARDE
N’essayez pas de sécher ou de mettre l’appareil ou l’une de ses pièces au four à micro-ondes.
MISE EN GARDE
Pour éviter d’endommager l’appareil :
• Ne rincez ou n’immergez pas l’unité principale dans un liquide.
• Ne nettoyez pas l’unité principale à l’aide de nettoyants abrasifs ou de tout autre produit chimique. 
• Ne laissez pas l’humidité entrer en contact avec les électrodes ou la prise de l’adaptateur c.a.
sur l’unité principale ou le support de branchement de l’adaptateur c.a. 
Transport de l’appareil dans l’étui de rangement
Assemblez l’appareil en fixant le bouchon-filtre et le réservoir de médicament à l’unité principale. 
Placez le couvercle de l’unité principale sur l’appareil.
Placez l’appareil dans l’étui de rangement tel qu’illustré.  
L’embout buccal et l’adaptateur pour masque se placent facilement dans l’étui de rangement avec
l’unité principale.
MISE EN GARDE
Pour éviter d’endommager l’appareil
• Ne transportez pas et ne laissez pas le nébuliseur lorsqu’il reste du 
médicament ou de l’eau distillée dans le réservoir de médicament.
• Ne placez pas l’adaptateur c.a. dans l’étui de rangement.
L’étui de rangement n’est pas conçu pour le transport de
l’adaptateur c.a. en option. 
Pour transporter l’adaptateur c.a., enroulez le cordon d’alimentation de
l’adaptateur c.a. et fixez-le à l’unité principale de l’adaptateur c.a.
à l’aide de la bande pour cordon, tel qu’illustré.
ENTRETIEN DE L
’APPAREIL
Bande de cordon
F19
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F20
GUIDE
 DE
 DÉPANNAGE
PROBLÈME
CAUSE
SOLUTIONS
Le voyant d’alimentation
ne s’éclaire pas. 
L’adaptateur c.a. n’est pas branché
dans une prise de courant. 
Le support de branchement n’est
pas fixé à l’unité principale. 
Les piles n’ont pas été insérées
correctement. Les piles sont presque
déchargées.
Éteignez en appuyant sur la touche ON/OFF
(MARCHE/ARRÊT). Branchez le cordon
d’alimentation dans une prise de courant. Mettez
l’appareil sous tension.
Assurez-vous que l’unité principale est bien fixée
au support de branchement.
Réinsérez les piles. 
Remplacez immédiatement les deux piles usagées.
Rechargez les piles NiMH à l’aide d’un char geur
disponible sur le marché.
Des résidus de médicament ont
séché sur les composants et les
accessoires.
Nettoyez et désinfectez les composants
et les accessoires.
Le bouchon-filtre doit être doit être
remplacé. 
Remplacez le bouchon-filtre.
Le voyant d’alimentation
s’éclaire, mais l’appareil
ne nébulise pas.
Les piles sont presque déchargées.
Remplacez les quatre piles du même type par des
piles neuves alcalines ou NiMH char gées.
Le réservoir de médicament
contient trop de médicament.
Remplissez le réservoir de médicament avec la
quantité prescrite de médicament.  La quantité
maximale est de 7 ml.
Il se peut que du liquide se soit
accumulé autour des électrodes de
l’unité principale.
Absorbez le liquide à l’aide d’un chif 
fon doux.
Il y a du liquide sur le bouchon-
filtre.
Enlevez le liquide délicatement à l’aide d’un
chiffon doux de manière à ne pas endommager
le filtre. 
Le médicament n’est pas entré en
contact avec les pièces du
nébuliseur
.
Inclinez légèrement l’unité principale vers vous
alors que la touche ON/OFF
(MARCHE/ARRÊT) pointe vers le bas.
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page F20


GUIDE
 DE
 DÉPANNAGE
PROBLÈME
CAUSE
SOLUTIONS
L’appareil est en marche;
toutefois, il nébulise
faiblement ou met trop de
temps pour le traitement.
Le réservoir de médicament n’est
pas bien installé.
Assurez-vous que le réservoir de médicament
est bien installé.  
L’unité doit être nettoyée.
Suivez les directives de nettoyage après
chaque utilisation.
L’unité doit être désinfectée.
Suivez les directives de désinfection.
Les piles sont presque déchargées.
Remplacez les piles en suivant les
directives d’installation.
La vitesse de nébulisation peut varier
selon le médicament utilisé.
La durée du traitement peut varier selon
les médicaments et les patients.
F21
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page F21


F22
RENSEIGNEMENTS SUR LA GARANTIE
GARANTIES RESTREINTES
Vo
 
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s
 
,
  
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t
de matériaux et de fabrication apparaissant dans les 2 années suivant la date d’achat, lorsqu’il est utilisé selon
les directives fournies avec l’appareil. La garantie ci-dessus n’est offerte qu’à l’acheteur au détail original.
À notre discrétion, nous réparerons ou remplacerons sans frais votre nébuliseur Omron. La réparation ou le
remplacement est notre seule responsabilité et votre seul recours en vertu des garanties ci-dessus.
Pour obtenir du service en vertu de cette garantie, communiquez avec le Service à la clientèle d’Omron
Healthcare en composant le 1 800 634-4350 pour obtenir l’adresse de l’emplacement pour la réparation
ainsi que les frais d’expédition de retour et de manutention. Les renseignements relatifs au service en
vertu de la garantie sont disponibles sur notre site  Web à l’adresse www.omronhealthcare.com.
Veuillez joindre une preuve d’achat.  Veuillez également joindre une lettre dans laquelle vous indiquez
vos nom, adresse, numéro de téléphone, et une description du problème spécifique. Emballez le produit
avec soin afin d’éviter tout risque de dommages  supplémentaires durant le transport. En raison des
risques de perte lors du transport, nous vous recommandons d’assurer le produit et de demander un avis de
réception.
TOUTES GARANTIES IMPLICITES INCLUANT, SANS S’Y LIMITER, LES GARANTIES
LIMITÉES DE QUALITÉ MARCHANDE ET D’ADAPTABILITÉ À DES FINS
PARTICULIÈRES, SONT LIMITÉES À LA DURÉE DE LA GARANTIE ÉCRITE 
APPLICABLE CI-DESSUS. Certaines provinces/états ne permettent pas de limites quant à la durée de
la garantie implicite; il se peut donc que les limites ci-dessus ne s’appliquent pas à vous.
OMRON NE SERA PAS TENUE RESPONSABLE DES PERTES DÉCOULANT DE 
L’UTILISATION OU D’ AUTRES  DOMMAGES I NDIRECTSOU ACCESSOIRES OU DE COÛTS
INDIRECTS, DÉPENSES OU DOMMAGES. Certaines provinces ne permettent pas d’exclusions ou de
limites de dommages indirects; il se peut donc que les exclusions ci-dessus ne s’appliquent pas à vous.
CCette garantie vous donne des droits précis reconnus par la loi, et vous pouvez également avoir d’autres
droits qui varient d’une province à l’autre.
POUR LE SERVICE À LA CLIENTÈLE (É.-U. et CANADA)
Visitez notre site Web au :                        www .omronhealthcare.com
Téléphonez sans frais au :                                         1 800 634-4350
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page F22


CONFORMITÉ
 FCC
Remarque :
INTERFÉRENCES POTENTIELLES POUR LA RADIO/TÉLÉVISION 
(pour les É.-U. seulement)
Ce produit a été testé et déclaré conforme aux limites de la section 15 du règlement
FCC, applicables aux appareils numériques de classe B.
Ces limites sont conçues pour fournir une protection satisfaisante contre les
interférences dans les installations résidentielles. Ce produit génère, utilise et émet des ondes de
fréquence radio et, s’il n’est pas installé conformément aux directives, les ondes risquent de
provoquer des interférences avec les communications radio. Il est cependant impossible de
garantir que des interférences ne surviendront pas dans une installation particulière. Si ce
produit est la cause d’interférences gênant la réception de programmes radio ou télévisés, ce qui
peut être déterminé en mettant l’appareil hors tension et de nouveau sous tension, l’utilisateur
doit tenter de remédier au 
problème en prenant une ou plusieurs des mesures suivantes:
• Réorienter ou relocaliser l’antenne de réception.
• Augmenter la distance séparant l’équipement et le récepteur 
.
• Brancher l’équipement à une prise de courant ou à un circuit différent de celui
auquel le récepteur est branché.
• Contacter votre revendeur ou un technicien radio/TV qualifié.
INTERFÉRENCES POTENTIELLES POUR LA RADIO/TÉLÉVISION 
(pour le Canada seulement)
Cet appareil numérique respecte les limites de bruits radioéléctriques applicables aux appareils
numériques de Classe B prescrites dans la norme sur le matériel brouilleur : « Appareils
numériques », ICES-003 édictée par le ministère des Communications.
Les changements ou modifications non approuvés expressément par l’autorité 
responsable de la conformité peuvent annuler l’autorisation accordée à l’utilisateur de faire
fonctionner cet équipement.
F23
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F24
SPÉCIFICATIONS
Modèle :
Nébuliseur Omron NE-U22V avec V
.M.T
.®
Source d’alimentation :
CC : 3 V
, c.a. : 120 V
, 60 Hz (avec adaptateur c.a.)
Consommation d’énergie :
1,5 W
Débit de nébulisation :
0,25 ml/min. minimum
Plage de taille des particules :
DMM environ 5µm 
Capacité du réservoir de
médicament :
7 ml maximum
Température/humidité 
d’utilisation :
+50 ºF à +104 ºF (+10 ºC à +40 ºC) /
30 % à 85 % HR
Température/humidité 
d’entreposage/pression d’air :
-4 ºF à +140 ºF (-20 ºC à +60 ºC) /
10 % à 95 % RH / 700 hPa à 1 060 hPa
Fréquence des vibrations :
180 kHz
Dimensions :
1,5 po (L.) x 2,1 po (l.) x 4,1 po (H.)
(38 mm x 51 mm x 104 mm)
Poids :
3.4 oz (97 g)
Pile :
2 piles « AA » ou NiMH rechargeables (non comprises)
Contenu :
Unité principale, réservoir de médicament, étui de transport, embout buccal, 
bouchon-filtre, adaptateur pour masque et embout buccal, vidéo et guide de l’utilisateur
Code CUP :
0 73796 45122 6
Pulmicort®
Intal
®
Salubutamol
®
DMM (microns)
6,76 µ
6,43 µ
5,79 µ
ETG 
(écart type géométrique)
2,08
2,56
2,75
Fraction inhalable
(% masse : 0,52 à 6 µ)
65,0 %
66,0 %
73,4 %
• Sujet à des modifications techniques sans préavis
Essai de l’impacteur en cascade à 13 lpm:
Durée du traitement: 5 minutes pour 2 ml
• Veuillez noter que les spécifications peuvent varier selon le type de médicament utilisé.
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/19/09  1:45 PM  Page F24


REMARQUES
F25
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page F25


Fabriqué au Japon
Distribué par :
OMRON HEALTHCARE, INC.
1200, Lakeside Drive
Bannockburn, Illinois 60015
www.omronhealthcare.com
Copyright © 2007 Omron Healthcare
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page F26


NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page e1


E2
ÍNDICE
Antes de usar el dispositivo
Introducción..................................................................................E3
Información de seguridad................................................................E4
Conozca su unidad ........................................................................E7
Accesorios y repuestos....................................................................E8
Armado de la unidad........................................................................E9
Instrucciones de funcionamiento
Instalación de las pilas ....................................................................E11
Uso del transformador de CA 
............................................................ E12
Llenado del depósito para el medicamento .......................................... E13
Selección del modo de nebulización .................................................. E14
Uso del dispositivo ........................................................................E15
Cuidado y mantenimiento
Limpieza después de cada uso ...................................................................... E16
Desinfección diaria ........................................................................E17
Cuidado del dispositivo....................................................................E18
Solución de problemas
Guía para la solución de problemas .................................................... E20
Información sobre la garantía ............................................................E22
Declaración de la FCC ....................................................................E23
Especificaciones............................................................................E24
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page E2


INTRODUCCIÓN
Gracias por adquirir el nebulizador vibrador con malla Omron®NE-U22V MICROAir®.
Omron Healthcare ha progresado en el desarrollo de la tecnología de nebulizadores 
electrónicos con la introducción del nebulizador vibrador con malla NE-U22VMICROAir®. Con el objetivo
de brindar comodidad al paciente y cumplir con la normativa vigente, este dispositivo ofrece la máxima
portabilidad dondequiera que vaya y una revolucionaria tecnología de malla vibradora que proporciona
un tratamiento preciso, poderoso y 
efectivo cada vez que lo utiliza. 
El MICROAir® es un sistema nebulizador vibrador con malla diseñado para convertir medicamentos
líquidos en aerosol para que los pacientes puedan inhalarlo. El dispositivo se puede usar con pacientes
pediátricos y adultos, en el hogar, en nosocomios y en 
entornos de cuidados subagudos.     
Su nebulizador NE-U22V MICROAir
® cuenta con los siguientes componentes:
• Unidad principal
• Cubierta de la unidad
• Depósito para el medicamento
• Tapa de la malla
• Adaptador para la mascarilla y la boquilla
• Boquilla
• Estuche
• Manual de instrucciones
• DVD instructivo
Los siguientes accesorios son opcionales y se venden por separado:
• Transformador de CA
• Mascarilla para niños
Complete
 los
 siguientes
 datos
 para
 futuras
 consultas
FECHA DE COMPRA:
NÚMERO DE SERIE:
El MICROAir®es un dispositivo médico. Utilícelo únicamente según las indicaciones
del médico o del profesional autorizado.
GUARDE ESTAS
 INSTRUCCIONES
E3
Abroche aquí su recibo de compra.
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:13 PM  Page E3


E4
INFORMACIÓN
 DE
 SEGURIDAD
Para asegurar el uso correcto del producto, siempre se deben tomar medidas de 
seguridad básicas, entre ellas las advertencias y precauciones que se describen en este
manual de instrucciones.
FUNCIONAMIENTO DEL DISPOSITIVO
Antes de utilizar la unidad, lea toda la información del manual de instrucciones y 
cualquier otro material impreso que se incluya en la caja.
Para el tipo, la dosis y el régimen de medicamento, siga las instrucciones del
médico y/o del profesional médico autorizado.
La pentamidina no es un medicamento aprobado para usar con este dispositivo.
No use agua mineral o agua corriente en el nebulizador para fines de nebulización.
Limpie y desinfecte el depósito para el medicamento, la tapa de la malla, la mascarilla, 
la boquilla y el adaptador para la mascarilla y la boquilla antes de utilizar el dispositivo 
por primera vez después de la compra.
Si el dispositivo no se ha utilizado durante un tiempo prolongado, limpie y desinfecte
el depósito para el medicamento, la tapa de la malla, la mascarilla, la boquilla 
y el adaptador para la mascarilla y la boquilla antes de utilizarlos.
Siempre deseche el medicamento que queda en el recipiente después de cada uso. 
Utilice medicamento nuevo cada vez que use el dispositivo.
No deje el dispositivo ni sus piezas en un lugar donde esté expuesto a extremas o 
a cambios en la humedad, por ejemplo, no deje el dispositivo en un vehículo durante 
los meses de temperatura cálida o alta o donde quede expuesto a la luz directa del sol.
ADVERTENCIA
Indica una situación potencialmente peligrosa que, si
no se evita, puede provocar la muerte o lesiones graves.
PRECAUCIÓN
Indica una situación potencialmente peligrosa que, si
no se evita, puede provocar lesiones leves o moderadas
al usuario o al paciente o puede provocar daños al equipo
o a otros bienes.
ÍCONOS DE SEGURIDAD USADOS EN ESTE MANUAL DE INSTRUCCIONES
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:50 PM  Page E4


E5
FUNCIONAMIENTO DEL DISPOSITIVO (continuación)
Supervise atentamente el uso del dispositivo cuando sea utilizado por, en o cerca de bebés,
niños o personas enfermas.
Inspeccione la unidad principal y las piezas del nebulizador antes de usar el dispositivo.
Asegúrese de que las piezas no estén dañadas, de que el dispositivo esté armado correctamente 
y de que el dispositivo funcione normalmente.
Para evitar que el dispositivo se dañe, agregue el medicamento lentamente. No permita que el
medicamento se derrame por el orificio del depósito para el medicamento.
No agregue más de 7 ml de medicamento en el recipiente del medicamento.
Para evitar que el dispositivo se dañe, asegúrese de que la tapa de la malla esté ubicada
correctamente. Si la tapa de la malla no está bien cerrada, el medicamento se derramará.
No haga funcionar el dispositivo a temperaturas superiores a los +104 ºF (+40 ºC).
No someta al dispositivo ni a ninguno de los componentes a golpes fuertes como, por ejemplo,
dejarlo caer al suelo.
Este dispositivo está aprobado para uso en seres humanos solamente.
No desarme ni trate de reparar el dispositivo ni los componentes.
Sólo haga funcionar el dispositivo para el fin para el que está diseñado. No use el dispositivo para 
ningún otro fin.
Al desechar el dispositivo, los componentes y los accesorios opcionales, siga las normas locales 
vigentes. Violar las normas establecidas para su eliminación puede provocar contaminación
ambiental.
Use sólo las piezas y los accesorios autorizados por Omron. Las piezas y los accesorios que 
no hayan sido aprobados para ser usados con el dispositivo pueden causar daños en la unidad.
Los cambios o las modificaciones que no hayan sido aprobados por Omron Healthcare 
anularán la garantía del usuario.  
RIESGO DE CHOQUES ELÉCTRICOS MIENTRAS SE USA
EL TRANSFORMADOR DE CA
Noenchufe ni desenchufe el cable de alimentación en el tomacorrientes con las manos  
mojadas.
Use sólo el transformador de CA diseñado por Omron para este dispositivo. El uso de 
cualquier otro transformador de CA puede dañar el dispositivo.
INFORMACIÓN
 DE
 SEGURIDAD
 IMPORTANTE
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:14 PM  Page E5


E6
RIESGO DE CHOQUES ELÉCTRICOS MIENTRAS SE USA EL
TRANSFORMADOR DE CA (Continuación)
No sobrecargue los tomacorrientes. Enchufe el dispositivo en un tomacorriente con el voltaje adecuado.
No use cables prolongadores. Enchufe el cable de alimentación directamente en el tomacorriente.
Desenchufe el cable de alimentación del tomacorriente después de usar el dispositivo.
Desenchufe el cable de alimentación del tomacorriente antes de limpiar el dispositivo.
MANTENIMIENTO Y ALMACENAMIENTO
Mantenga el dispositivo fuera del alcance de los bebés y niños si no están bajo estricta 
su pervisión. El dispositivo puede contener piezas pequeñas que se pueden tragar.
No sumerja la unidad principal en agua u otro líquido.
No use ni guarde el dispositivo en lugares húmedos como, por ejemplo, el baño. Use el
dispositivo teniendo en cuenta los límites de temperatura y humedad de funcionamiento.
No deje solución de limpieza en las piezas del nebulizador 
. Enjuague las piezas del
nebulizador con agua destilada después de desinfectar.
Enjuague las piezas del nebulizador después de cada uso. Seque las piezas inmediatamente 
después de lavarlas.
Guarde el dispositivo y los componentes en un lugar limpio y seguro.
Para evitar que el dispositivo se dañe, no transporte ni deje el depósito para el medicamento con
medicamento o agua destilada.
No coloque ni trate de secar el dispositivo o alguna de sus piezas en un horno de microondas.
Para evitar que el dispositivo se dañe, no enjuague ni sumerja la unidad principal en ningún
líquido, no lave ni enjuague ninguna de las piezas con un chorro de agua de alta presión y no toque la
malla con la mano ni con cualquier otro objeto.
No utilice un blanqueador de uso doméstico. La malla se oxidará y la tapa de la malla no se podrá usar.
Para evitar que el dispositivo se dañe, no limpie la unidad principal con limpiadores abrasivos 
ni con ningún tipo de químicos, y no permita que la humedad entre en contacto con los 
electrodos o el enchufe del transformador de CA en la unidad principal.
No coloque el transformador de CA en el estuche.  El estuche no está diseñado para 
transportar el transformador de CA.
INFORMACIÓN
 DE
 SEGURIDAD
 IMPORTANTE
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:14 PM  Page E6


E7
CONOZCA SU UNIDAD
Botón ENCENDIDO/APAGADO
Enciende y apaga la unidad principal
Palanca de bloqueo de la tapa del depósito
Abre el depósito para el medicamento para limpiarlo  
Depósito para el medicamento
Tiene una capacidad máxima de 7 ml 
por tratamiento
Orificio para el medicamento
Agregue aquí el medicamento para el depósito
Electrodo
Conductor eléctrico desde la unidad
principal hasta el vibrador del
depósito para el medicamento
Indicador de pilas 
descargadas
Una luz anaranjada titila cuando
las pilas están gastadas
Indicador de encendido
La luz verde indica que el dispositivo 
está en funcionamiento
Unidad principal
Parte inferior de la unidad principal
Tapa del compartimiento 
de las pilas
Presione la palanca para quitar
la tap
Depósito para el medicamento
Tapa de la malla
La malla de aleación
metálica produce 
un aerosol de gran 
eficacia
Adaptador para la mascarilla y
boquilla
Boquilla
Cubierta de la
unidad principal
Protege la unidad
principal, el depósito
para el medicamento
y la tapa de la
mallamientras está
almacenado
Mantiene la boquilla o la mascarilla
conectada firmemente al dispositivo
Pieza de contacto con el
paciente
Electrodo
Conductor eléctrico que transporta corriente 
desde la unidad principal hasta la base de conexión
del transformador de CA
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:14 PM  Page E7


E8
CONOZCA SU UNIDAD
DVD instructivo
Estuche
Enchufe de alimentación
Banda para el cable
Base de conexión del transformador de CA
El estuche está diseñado para
almacenar la unidad principal, 
el depósito para el medicamento y el
adaptador para la mascarilla y
boquilla
Transformador de CA, modelo N.º U22-5
Accesorio opcional
Accesorio opcional
Piezas de repuesto
Modelo N.º
TAPADEL COMPARTIMIENTO
 PARAPILAS 
U22-8
TAPA DE LA UNIDAD PRINCIPAL
U22-9
ADAPATADOR PARA LA
MASCARILLA Y BOQUILLA
U22-2
DEPÓSITO PARA EL MEDICAMENTO 
U22-3
TAPA DE LA MALLA
U22-4
BOQUILLA
U22-1
ESTUCHE U22-7
Mascarilla para niños
Modelo N.º C922
Pieza de contacto 
con el paciente
para uso pediátrico
Manual de instrucciones
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:14 PM  Page E8


E9
PREPARACIÓN
 DEL
 NEBULIZADOR
 PARA
 SU
 USO
No abra la tapa
del depósito. 
Ciérrela
bien.
Click
ADVERTENCIA
Antes de utilizar la unidad, lea toda la información del manual de instrucciones 
y toda otra información que se incluya en la caja.
ADVERTENCIA
Antes de utilizar el dispositivo por primera vez después de su compra, limpie y desinfecte
el depósito para el medicamento, la tapa de la malla, la mascarilla y el adaptador para la
mascarilla y la boquilla.
ADVERTENCIA
Si el dispositivo no se ha utilizado durante un tiempo prolongado, limpie y desinfecte el
depósito para el medicamento, la tapa de la malla, la mascarilla, la boquilla y el adaptador
para la mascarilla y boquilla antes de utilizarlos.
Para obtener instrucciones acerca de la limpieza y desinfección, consulte las páginas 16 y 17 de la
sección Cuidado y mantenimiento. 
El dispositivo debe armarse antes de su uso.
Información general
• Los componentes encajan herméticamente ya que están diseñados para evitar que el medicamento 
se derrame.
• Sostenga firmemente el dispositivo con las dos manos.
• Coloque
 las
 piezas
 correctamente
.
 
 Es
 probable que escuche un clic cuando instala alguna de las piezas.
1. Coloque la tapa de la malla en el depósito para el medicamento.
La instalación ha
finalizado.
Coloque 
la tapa 
de la malla 
de arriba 
hacia abajo.
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:14 PM  Page E9


PREPARACIÓN
 DEL
 NEBULIZADOR
 PARA
 SU
 USO
E10
La instalación
ha finalizado.
El armado
ha finalizado.
El armado
ha finalizado.
Alinee los dos 
electrodos 
ente sí.
La instalación
ha finalizado.
Click
2. Conecte el depósito para el medicamento a la unidad principal.
3. Conecte el adaptador para la mascarilla y boquilla a la unidad principal.
4.Conecte la boquilla o la mascarilla para niños al adaptador para la mascarilla y boquilla.
• Cómo conectar la mascarilla para niños
• Cómo conectar la boquilla
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:14 PM  Page E10


Este dispositivo funciona con dos (2) pilas alcalinas  AA o dos (2) pilas recargables NiMH AA.
No instale pilas gastadas junto con pilas nuevas.
No combine diferentes tipos de pilas. 
Quite las pilas si no se va a utilizar el dispositivo
durante tres meses o más.   
1.  Retire la tapa del compartimiento de las pilas.
(A)  Gire la palanca de la tapa del compartimiento de las pilas en la dirección
de la flecha, como se indica en el dibujo.
(B)  Retire la tapa del compartimiento de las pilas. Esta tapa
pude parecer que está demasiado ajustada, ya que fue diseñada
para impedir que ingresen líquidos dentro del dispositivo.  
2. Coloque las pilas.
Alinee de forma correcta las polaridades (+ y -) con las marcas de indicación
de las pilas que están en el dispositivo.
3. Vuelva a colocar la tapa.
Presione ambos extremos de la tapa del compartimiento de las pilas con los pulgares.
Presione firmemente hasta que escuche que ambas pestañas hagan clic y queden 
correctamente trabadas.
INSTALACIÓN DE
 LAS
 PILAS
Parte inferior de 
la unidad principal
Pilas alcalinas
• El dispositivo se puede utilizar durante
aproximadamente 8 días si se lo hace funcionar durante
30 minutos por día.
• El indicador de pilas descargadas (luz anaranjada)
titila para indicar que las pilas tienen poca car ga.
Cambie las dos pilas por pilas nuevas.
• El indicador de pilas descargadas (luz anaranjada) se
enciende para indicar que las pilas están  agotadas. El
dispositivo no funcionará. Reemplace
inmediatamente las dos pilas por otras nuevas.
Pilas NiMH recargables
• El dispositivo se puede utilizar durante
aproximadamente 8 días si se lo hace  funcionar
durante 30 minutos por día cuando las pilas están
totalmente cargadas.   
• El indicador de pilas descar gadas (luz anaranjada) titila
para indicar que las pilas recar gables tienen poca o casi
nada de carga. Si el dispositivo no nebuliza, recar gue
inmediatamente las pilas.
• Recargue las pilas con un car gador que esté  disponible
en el mercado y que sea adecuado para las pilas que se
utilizan en el dispositivo.
• El transformador de CA no funciona como un cargador
de batería.  
Vida útil y recambio de las pilas
Click
E11
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:14 PM  Page E11


El dispositivo está diseñado para no tomar ener gía de las pilas mientras se usa el transformador de CA. El
transformador de CA no es un cargador de pilas.
ADVERTENCIA
Use sólo el transformador de CA diseñado por Omron para este dispositivo. 
El uso de cualquier otro transformador de CA puede dañar el dispositivo.
Para conectar el transformador de CA
a la unidad principal
(1)  Coloque la unidad principal en la base de conexión
del transformador de CA, tal como se indica en la
siguiente figura.
NOTA: Se escuchará un clic y quedará sujeta a la base.
(2)  Conecte el enchufe del transformador de CA a
un tomacorriente de 120V
.   
ADVERTENCIA
No enchufe ni desenchufe el cable de alimentación del tomacorriente con las manos mojadas.
PRECAUCIÓN
No sobrecargue los tomacorrientes. Enchufe el dispositivo en un tomacorrientes con 
el voltaje adecuado.
PRECAUCIÓN
No use cables prolongadores.  Enchufe el cable de alimentación directamente en
el tomacorriente.
PRECAUCIÓN
Desenchufe el cable de alimentación del tomacorriente antes de limpiar el dispositivo.
Para quitar el transformador de CA de la unidad principal
(1) Desconecte el enchufe del transformador de CA del tomacorriente.
(2) Presione ambos lados de la base de conexión
para desbloquear la unidad principal.
(3) Retire la unidad principal.
PRECAUCIÓN
Desenchufe el cable de alimentación del tomacorriente
después de usar el dispositivo.
E12
USO DEL
 TRANSFORMADOR DE
 CA
La conexión se completó.
(1)
(2)
(1) Desenchufe
(3) Retire
(2) Presione ambos extremos
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:50 PM  Page E12


E13
1. Abra la tapa de la malla.
Sostenga el dispositivo firmemente 
con las manos.
2. Llene el depósito para el medicamento.
ADVERTENCIA
La pentamidina no es un medicamento aprobado 
para usar con este dispositivo.
ADVERTENCIA
No use agua mineral o agua corriente en el nebulizador 
para fines de nebulización.
Tenga cuidado y evite que la tapa de la malla se cierre
como se indica en el dibujo.
La capacidad máxima del depósito para el medicamento es de 7 ml.
PRECAUCIÓN
No agregue más de 7 ml de medicamento en el
recipiente de medicamento. 
PRECAUCIÓN
Para evitar que el dispositivo se dañe, agregue el medicamento
lentamente. No permita que el medicamento se derrame por el
orificio del depósito para el medicamento.
3.  Cierre la tapa de la malla.
PRECAUCIÓN
Para evitar que el dispositivo se dañe, asegúrese de que la tapa de la 
malla esté colocada correctamente.  De lo contrario, el medicamento 
se derramará.
4. Conecte el adaptador para la mascarilla y boquilla a la unidad principal.
Conecte la boquilla o la mascarilla para niños al adaptador para la mascarilla y boquilla.
NOTA:Para obtener instrucciones acerca de cómo conectar el adaptador para la mascarilla 
y boquilla, consulte la página 10 de la sección  Armado de la unidad.
LLENADO DEL DEPÓSITO PARA
 EL
 MEDICAMENTO
Quite la boquilla o la mascarilla y el adaptador para la mascarilla y boquilla de la unidad principal.
No abra la tapa
del depósito. 
Ve
 
r
 
i
 
f
 
i 
q 
u 
e
  
q 
u 
e
 
la tapa de la malla
esté cerrada.
Levante la tapa 
de la malla mientras
presiona el borde 
hacia arriba con 
el pulgar.
Click
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:50 PM  Page E13


E14
SELECCIÓN
 DEL
 MODO
 DE
 NEBULIZACIÓN
Este dispositivo funciona en modo de nebulización continua o en modo de nebulización manual.
• Modo de nebulización continua
Para utilizar el dispositivo en modo de nebulización 
continua, mantenga presionado el botón de 
APAGADO/ENCENDIDO durante 1 segundo.
Pulse el botón de ENCENDIDO/APAGADO 
nuevamente para detener la nebulización.
• Modo de nebulización manual
En el modo de nebulización manual, el dispositivo 
sólo funcionará cuando presione y mantenga presionado 
el botón de ENCENDIDO/APAGADO.
En este modo, pude inhalar el tiempo que necesite.
Para utilizar el dispositivo en modo de nebulización 
manual, mantenga presionado el botón de 
ENCENDIDO/APAGADO durante por lo menos 2 segundos.
Presione y mantenga presionado el botón de 
ENCENDIDO/APAGADO para iniciar la nebulización.
NOTA:El indicador de encendido (luz verde) estará encendido 
durante la nebulización.   
Presione y mantenga 
presionado el botón de 
ENCENDIDO/APAGADO 
con el dedo durante 1 segundo.
Presione y mantenga 
presionado el botón de 
ENCENDIDO/APAGADO 
con el dedo durante 2 segundos.
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:14 PM  Page E14


E15
USO
 DEL
 DISPOSITIVO
ADVERTENCIA
Para el tipo, la dosis y el régimen de medicamento, siga las instrucciones del médico.
ADVERTENCIA
Siempre deseche el medicamento que queda en el recipiente después de cada
uso. Utilice medicamento nuevo cada vez que use el dispositivo.
PRECAUCIÓN
Se requiere una supervisión estricta cuando este dispositivo es usado por, o cerca de 
bebés, niños o personas enfermas.
PRECAUCIÓN
Inspeccione la unidad principal y las piezas del nebulizador antes de usar el dispositivo. 
Asegúrese de que las piezas no estén dañadas, de que el dispositivo esté armado 
correctamente y de que el dispositivo funcione normalmente.
PRECAUCIÓN
No haga funcionar el dispositivo a temperaturas superiores a los +104 ºF (+40 ºC).
PRECAUCIÓN
Este dispositivo está aprobado para uso en seres humanos solamente.
1.Incline levemente la unidad principal hacia usted para sumer gir la tapa de la malla vibradora en el
medicamento.
NOTA: Si el vibrador no está sumergido en el medicamento, el dispositivo no nebulizará.
2.Comience a inhalar en una posición relajada.
3.Coloque los labios ligeramente alrededor de la boquilla.  Si utiliza la mascarilla para niños, 
colóquela ligeramente contra la cara. 
4.Comience el tratamiento según las indicaciones del médico.
5.Pulse el botón de ENCENDIDO/APAGADO para apagar el dispositivo cuando termine el
tratamiento.
NOTA:El dispositivo cuenta con un temporizador incorporado que lo apaga 
aproximadamente 30 minutos después de que ha sido encendido.
Cuando utilice el transformador de CA, quite el enchufe del tomacorriente.
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E16
LIMPIEZA
 DESPUÉS
 DE
 CADA
 USO
Si sigue las instrucciones de limpieza después de cada uso, evitará que cualquier medicamento que haya quedado en el
depósito se seque y se adhiera a la tapa de la malla, lo que afectaría la efectividad de la nebulización.  
Lave el depósito para el medicamento, la tapa de la malla, la mascarilla, la
boquilla y el adaptador para la mascarilla y boquilla después de cada uso.
ADVERTENCIA
Enjuague las piezas del nebulizador después de cada uso. Seque las piezas inmediatamente
después de lavarlas.
PRECAUCIÓN
Para evitar que el dispositivo se dañe:
•   No enjuague ni sumerja la unidad principal en ningún líquido.
•   No lave ni enjuague ninguna de las piezas con un chorro de agua de alta presión.
•   No toque la malla con la mano ni con ningún otro objeto.  
1. Quite la boquilla o la mascarilla y el adaptador para la mascarilla y boquilla de la unidad
principal.
2. Retire el depósito para el medicamento de la unidad principal.
3. Abra el depósito para el medicamento y elimine cualquier resto que pudiera quedar.
4. Conecte el depósito para el medicamento a la unidad principal.  Abra la tapa de la malla.
5. Vierta una pequeña cantidad de agua destilada en el depósito para el medicamento y
cierre la tapa de la malla.
6. Encienda el dispositivo para nebulizar el agua destilada durante 1 ó 2 minutos para
eliminar los restos de medicamento que pudieran quedar en los orificios de la malla.
7. Apague el dispositivo y quite el depósito para el medicamento de la unidad principal.
8. Quite la tapa de la malla del depósito para el medicamento y elimine cualquier resto
de agua destilada que pudiera quedar en el depósito. 
9. Enjuague con agua destilada el depósito para el medicamento, la tapa de la malla, la 
mascarilla, la boquilla y el adaptador para la mascarilla y boquilla.  
10.Seque cuidadosamente el exceso de agua con un paño suave y limpio o deje que 
las piezas se sequen solas en un ambiente limpio.
11.Arme el dispositivo.  Guarde el dispositivo en el estuche o en un lugar limpio.     
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:14 PM  Page E16


E17
DESINFECCIÓN
 DIARIA
Desinfecte el depósito para el medicamento, la tapa de la malla, la mascarila, la
boquilla y el adaptador para la mascarilla y boquilla después del último
tratamiento de cada día. 
PRECAUCIÓN
Para evitar que el dispositivo se dañe:
• No enjuague ni sumerja la unidad principal en ningún líquido.
• No lave ni enjuague ninguna de las piezas con un chorro de agua de alta presión.
• No toque la malla con la mano ni con ningún otro objeto.  
1. Prepare una solución con alguna de las siguientes soluciones:   Vinagre (1 parte de vinagre
blanco y 3 partes de agua destilada) O deter gente o jabón suave (jabón para lavavajillas en
agua destilada).
PRECAUCIÓN
No utilice un blanqueador de uso doméstico. La malla se oxidará y la tapa de la malla no 
se podrá usar.
2. Levante la tapa de la malla y vierta una pequeña cantidad de solución desinfectante 
dentro del depósito para el medicamento.
3. Encienda el dispositivo para nebulizar la solución desinfectante durante 1 ó 2 minutos.
4. Apague el dispositivo y quite el depósito para el medicamento de la unidad principal.
5. Quite la tapa de la malla del depósito para el medicamento y elimine cualquier resto
de solución desinfectante que pudiera quedar en el depósito.
6. Enjuague el depósito para el medicamento, la tapa de la malla, la mascarilla, la boquilla y el
adaptador para la mascarilla y boquilla en la solución desinfectante durante 10 ó 15 minutos.
7. Enjuague con agua destilada el depósito para el medicamento, la tapa de la malla, 
la mascarilla, la boquilla y el adaptador para la mascarilla y boquilla.
ADVERTENCIA
No deje solución de limpieza en las piezas del nebulizador 
. Enjuague las piezas del
nebulizador con agua destilada después de desinfectar.
8. Seque cuidadosamente el exceso de agua con un paño suave y limpio o deje que las piezas 
se
sequen solas en un ambiente limpio.
9. Arme el dispositivo. Guarde el dispositivo en el estuche o en un lugar limpio.
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:14 PM  Page E17


E18
CUIDADO DEL DISPOSITIVO
Para mantener el dispositivo en buen estado y pr oteger la unidad para que no se
dañe, siga estas instrucciones:
Mantenga el dispositivo fuera del alcance de los bebés y niños si no están bajo estricta 
supervisión. El dispositivo puede contener piezas pequeñas que se pueden tragar.
Guarde el dispositivo y los componentes en un lugar limpio y seguro.
No use ni guarde el dispositivo en lugares húmedos como, por ejemplo, el baño. Use el 
dispositivo dentro de los límites de temperatura y humedad de funcionamiento.
No deje el dispositivo ni sus piezas en lugares que estén expuestos a temperaturas extremas o  
cambios en la humedad, como por ejemplo en un vehículo durante los meses de calor o 
donde quede expuesto a la luz directa del sol.
No someta al dispositivo ni a ninguno de los componentes a golpes fuertes como, por 
ejemplo, dejarlo caer al suelo.
No desarme ni trate de reparar el dispositivo ni los componentes.
Use sólo las piezas y los accesorios autorizados por Omron. Las piezas y los accesorios  
que no están aprobados para ser usados con el dispositivo pueden causar daños en la unidad.
Sólo haga funcionar el dispositivo para el fin para el que está diseñado. No use el dispositivo 
para ningún otro fin.
Los cambios o las modificaciones que no hayan sido aprobados por Omron Healthcare 
dejarán sin efecto la garantía del usuario.
Respete las normas locales vigentes al desechar  el dispositivo, los componentes y los 
accesorios opcionales. Violar las normas establecidas para su eliminación puede provocar 
contaminación ambiental.
Retire las pilas si no va a utilizar la unidad durante tres meses o un período más 
prolongado. Siempre reemplace todas las pilas por pilas nuevas al mismo tiempo. No 
utilice diferentes tipos de pilas al mismo tiempo.
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:14 PM  Page E18


E19
CUIDADO DEL DISPOSITIVO
Limpieza de la unidad principal 
Limpie la carcasa de la unidad principal con un paño suave humedecido con agua o detergente suave. Limpie
la carcasa y séquela inmediatamente con un paño suave y limpio. 
PRECAUCIÓN
No coloque ni trate de secar el dispositivo o alguna de sus piezas en un horno de microondas.
PRECAUCIÓN
Para evitar que el dispositivo se dañe:
• No enjuague ni sumerja la unidad principal en ningún líquido.
• No limpie la unidad principal con limpiadores abrasivos ni con ningún tipo de producto químico. 
• No permita que la humedad entre en contacto con los electrodos o con la entrada del
transformador de CA en la unidad principal o en la base de conexión del transformador de CA. 
Transporte del dispositivo en el estuche 
Arme el dispositivo, colocando la tapa de la malla y el depósito para el medicamento en la unidad principal.
Coloque la cubierta de la unidad principal en el dispositivo.
Coloque el dispositivo en el estuche, como se indica en el dibujo.  
El adaptador para la boquilla y la mascarilla se puede colocar fácilmente en el estuche para transportarlo junto
con la unidad principal.
PRECAUCIÓN
Para evitar que el dispositivo se dañe
• No transporte ni deje el nebulizador con medicamento 
o agua destilada en el depósito para el medicamento.
• No coloque el transformador de CA en el estuche.
El estuche no está diseñado para transportar el transformador 
de CA opcional.  
Para transportar el transformador de CA, enrolle el cable de alimentación 
del transformador de CA y sujételo a la unidad principal del adaptador 
de CA con la banda para el cable, como se indica en el dibujo.
Banda para el cable
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E20
GUÍA
 PARA
 LA
 SOLUCIÓN
 DE
 PROBLEMAS
PROBLEMA
CAUSA
SOLUCIONES
El indicador de encendido 
no se enciende. 
El transformador de CA no está
conectado a un tomacorriente. 
La base de conexión no está
conectada a la unidad principal. 
Las pilas no se instalaron
correctamente. Las pilas tienen poca
carga.
Apague la unidad con el interruptor. Conecte 
el enchufede alimentación a un tomacorriente.
Encienda el dispositivo.
Asegúrese de que la unidad haya encajado 
en la base de conexión.
Vuelva a colocar las pilas.
Reemplace ambas pilas gastadas de forma 
inmediata. Recargue las pilas NiMH con 
un argador que esté disponible en el mercado.
Hay restos de medicamento seco
en los componentes y accesorios.
Limpie y desinfecte los componentes
y accesorios.
Se debe reemplazar la tapa de la 
malla. 
Reemplace la tapa de la malla.
El indicador de encendido
está prendido, pero la
unidad no nebuliza.
Las pilas tienen poca carga.
Reemplace el mismo tipo de pilas con pilas
alcalinas nuevas o cargue las pilas NiMH.
El depósito para el medicamento 
tienemucha cantidad de 
medicamento.
Llene el depósito para el medicamento con la
cantidad correcta de medicamento recetado.  
La cantidad máxima es 7 ml. 
Se puede haber acumulado líquido 
alrededorde los electrodos de la 
unidad principal.
Absorba toda la humedad con un paño suave.
Hay líquido en la parte superior de la
tapa de la malla.
Quite el líquido visible con un paño suave,
con cuidado, para no dañar la malla. 
El medicamento no ha tenido
contacto con las piezas de
nebulización.
Incline ligeramente la unidad principal hacia usted
con el botón de ENCENDIDO/APAGADO 
apuntando hacia abajo.
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:14 PM  Page E20


E21
GUÍA
 PARA
 LA
 SOLUCIÓN
 DE
 PROBLEMAS
PROBLEMA
CAUSA
SOLUCIONES
La unidad está 
encendida; sin embargo, 
nebuliza de forma suave
o demora mucho tiempo
por cada tratamiento.
El depósito para el medicamento 
no está colocado correctamente.
Asegúrese de que el depósito para 
el medicamento esté colocado correctamente.  
Se debe limpiar la unidad.
Siga las instrucciones de limpieza después de
cada uso.
Se debe desinfectar la unidad.
Siga las instrucciones para la desinfección.
Las pilas tienen poca carga.
Reemplace las pilas según las instrucciones
de instalación.
Las velocidades de nebulización 
varían en base almedicamento que
se utiliza.
Los tiempos de duración de un tratamiento 
pueden variar según los medicamentos y los
pacientes.
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E22
INFORMACIÓN SOBRE
 LA
 GARANTÍA
GARANTÍAS LIMITADAS
Su Nebulizador NE-U22V
, salvo la tapa de la malla y los accesorios, estará garantizado contra defectos de
materiales y mano de obra que surjan dentro de los 2 años a partir de la fecha de compra, si se usa de acuerdo
con las instrucciones suministradas con el dispositivo. La garantía a la que se hace referencia
anteriormente se extiende sólo al comprador minorista original.
Nos comprometemos a reparar o reemplazar sin car go y según nuestro criterio su nebulizador Omron. La
reparación o el reemplazoson nuestra única responsabilidad y su único recurso conforme a las garantías
anteriormente mencionadas.
Para recibir el servicio de garantía, póngase en contacto con el servicio de atención al cliente de Omron
Healthcare llamando al 1-800-634-4350 para obtener la dirección donde se realizan las reparaciones y las
tarifas de envío y manipulación.  Para obtener información relativa al servicio de garantía, visite nuestro
sitio Web en: www.omronhealthcare.com.  
Adjunte el comprobante de compra.  Incluya una carta con su nombre, dirección, número de teléfono y la
descripción del problema específico.  Empaque el producto cuidadosamente para evitar que se dañe
durante el traslado. Dado que existe la posibilidad de pérdida durante el traslado, le recomendamos que
asegure el producto con solicitud de acuse de recibo.
TODAS LAS GARANTÍAS IMPLÍCITAS, INCLUIDAS, ENTRE OTRAS, LAS GARANTÍAS
IMPLÍCITAS DE COMERCIALIZACIÓN Y APTITUD PARA UN PROPÓSITO EN
PARTICULAR, SE LIMITAN A LA DURACIÓN DE LA GARANTÍA ESCRITA PERTINENTE
QUE APARECE ANTERIORMENTE.Algunos estados no aceptan limitaciones en cuanto a la
duración de una garantía implícita, de modo que es posible que la limitación anteriormente mencionada
no se aplique en su caso.
OMRON NO SERÁ RESPONSABLE DE LA PÉRDIDA DE USO O CUALQUIER OTRO COST O,
GASTO O DAÑO INCIDENTAL, INDIRECTO O RESULTANTE.  Algunos estados no aceptan la
exclusión o limitación de los daños incidentales o resultantes, de modo que es posible que las exclusiones
anteriores no se aplique en su caso.
Esta garantía le otorga derechos legales específicos, y es posible que también le correspondan otros 
derechos que pueden variar de un estado a otro.
SERVICIO DE ATENCIÓN AL CLIENTE (EE.UU. y CANADÁ)
Visite nuestro sitio Web en:                  
www
.omronhealthcare.com
Llame sin cargo al:                                                   
1-800-634-4350
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:14 PM  Page E22


DECLARACIÓN
 DE
 LA
 FCC
Nota:
POTENCIAL DE INTERFERENCIA DE RADIO/TELEVISIÓN (para EE.UU. solamente)
Este producto ha sido probado y cumple con los límites de un dispositivo digital de Clase B, de
acuerdo con la parte 15 de las normas de la FCC.
Estos límites fueron diseñados para proporcionar una protección razonable contra interferencias
perjudiciales cuando se utilice el equipo en una instalación residencial.  El producto genera,
utiliza y puede irradiar energía de radiofrecuencia y, si no se 
instala y utiliza de acuerdo con las instrucciones, puede provocar interferencias 
perjudiciales en las comunicaciones por radio. Sin embar go, no se puede garantizar que no e
producirán interferencias en una instalación en particular. Si el producto 
provoca interferencias perjudiciales en la recepción de radio o televisión, lo que se puede
determinar encendiendo y apagando el equipo, se sugiere que el usuario intente corregir la
interferencia a través de una o más de las siguientes medidas:
• Reoriente o reubique la antena receptora
• Aumente la distancia entre el equipo y el receptor 
.
• Conecte el equipo a un tomacorrientes que esté en un circuito distinto de aquél 
al que se encuentra conectado el receptor.
• Consulte al distribuidor o a un técnico experimentado en radio/TV para obtener  más
información.
POTENCIAL DE INTERFERENCIA DE RADIO/TELEVISIÓN (para Canadá solamente)
Este aparato digital no excede los límites de Clase B para las emisiones de ruido de radio 
de los dispositivos digitales tal como se establece en la norma con respecto a equipos que causan
interferencia denominada “Dispositivos digitales”, ICES-003 del Departamento Canadiense de
Comunicaciones.
Cet appareil numérique respecte les limites de bruits radioeléctriques applicables aux 
appareils numériques de Clase B prescrites dans la norme sur le materiel brouilleur: “Appareils
Numériques”, ICES-003 édictée par le minister des communications.
Todo cambio o modificación que no esté expresamente aprobado por la parte responsable encar gada
del cumplimiento podrá anular la autoridad del usuario para operar el equipo.
E23
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:14 PM  Page E23


E24
ESPECIFICACIONES
Modelo:
Nebulizador Omron NE-U22V con V
.M.T
.®
Fuente de alimentación:
CC 3V CA 120V 60 Hz (con adaptador de CA)
Consumo eléctrico:
1.5 W
Velocidad de nebulización:
0.25 ml/min. mínimo
Tamaño de las partículas:
MMD aproximadamente 5µm
Capacidad de medicamento:
7 ml máximo
Temperatura/Humedad de
funcionamiento:
+50 ºF a +104 ºF (+10 ºC a +40 ºC) / 
30% a 85% HR
Temperatura/Humedad/
Presión de aire de 
almacenamiento:
-4 ºF a +140 ºF (-20 ºC a +60 ºC) /
10% a 95% HR / 700hPa a 1060 hPa
Frecuencia de vibración:
180 kHz
Dimensiones:
1.5” (largo) x 2.1” (ancho) x 4.1” (alto)
(38 mm x 51 mm x 104 mm)
Peso:
3.4 onzas (97 gramos)
Pilas:
2 pilas alcalinas “AA” o pilas recar gables NiMH (no incluidas)
Contenido:
Unidad principal, depósito para el medicamento, estuche para transportar 
el dispositivo, tapa de la malla, adaptador para mascarilla y boquilla, 
video y manual de instrucciones.
Código UPC:
0 73796 45122 6
Pulmicort®
Intal
®
Salubutamol
®
MMD (micrón)
6.76µ
6.43µ
5.79µ
Desv
iac
ión
 Es
tándar
Geomé
tr
ica
 (GSD
,
 
por
 sus
 s
ig
las
 en
 
ing
lés)
2.08
2.56
2.75
Fracc
ión
 resp
irab
le
(%
 de
 masa
 0
.52
 a
 6
 µ)
65.0%
66.0%
73.4%
• Sujeto a modificaciones técnicas sin previo aviso.
Impactador de cascada probado a 13 Ipm (pulgadas por minutos):
Tiempo que dura el tratamiento: 5 minutos para 2 ml.
• Tenga en cuenta que las especificaciones pueden variar según el tipo de medicamento utilizado.
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/19/09  1:45 PM  Page E24


NOTAS
E25
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:14 PM  Page E25


Hecho en Japón
Distribuido por:
OMRON HEALTHCARE, INC.
1200 Lakeside Drive
Bannockburn, Illinois 60015
www.omronhealthcare.com
Copyright © 2007 Omron Healthcare
1628676-6C
NE-U22V_EN_FR_SP_Q6_6.3L.qxd  2/18/09  3:14 PM  Page E26


Protocol Number: GSP304-201 
 
Version 3.0 
 
Date: 11-Apr-2017 
 
Confidential 
156 
Glenmark Specialty, SA 
APPENDIX 4. INSTRUCTIONS FOR THE USE OF SPIRIVA® 
RESPIMAT® 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
Instructions for Use 
SPIRIVA® RESPIMAT
® (speh REE vah - RES peh mat)  
(tiotropium bromide)  
inhalation spray  
For Oral Inhalation Only  
Do not spray SPIRIVA RESPIMAT into your eyes.  
Read these Instructions for Use before you start using SPIRIVA RESPIMAT and each time you get 
a refill. There may be new information. This leaflet does not take the place of talking to your 
doctor about your medical condition or your treatment. 
You will need to use this inhaler ONCE A DAY, at the same time each day. Each time you use it 
take TWO PUFFS. 
Use SPIRIVA RESPIMAT exactly as prescribed by your doctor. Do not change your dose or 
how often you use SPIRIVA RESPIMAT without talking with your doctor. 
Tell your doctor about all of the medicines you take. SPIRIVA RESPIMAT may affect the 
way some medicines work and some other medicines may affect the way SPIRIVA RESPIMAT 
works. Do not use other inhaled medicines with SPIRIVA RESPIMAT without talking to your 
doctor. 
The SPIRIVA RESPIMAT inhaler has a slow moving mist that helps you inhale the medicine. 
Do not turn the clear base before inserting the cartridge.  
Your SPIRIVA RESPIMAT may have either an aqua or a blue cap, depending on the strength 
prescribed by your doctor.  The steps shown below should be followed. 
How to store your SPIRIVA RESPIMAT inhaler 
• Store SPIRIVA RESPIMAT at room temperature 68°F to 77°F (20°C to 25°C). 
• Do not freeze your SPIRIVA RESPIMAT cartridge and inhaler. 
Reference ID: 3943617 


 
 
 
 
 
 
 
 
 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
• If SPIRIVA RESPIMAT has not been used for more than 3 days, release 1 puff towards the 
ground. 
• If SPIRIVA RESPIMAT has not been used for more than 21 days, repeat steps 4 to 6 under the 
“Prepare for first use” until a mist is visible. Then repeat steps 4 to 6 three more times. 
• Keep your SPIRIVA RESPIMAT cartridge and inhaler out of the reach of children. 
How to care for your SPIRIVA RESPIMAT inhaler 
Clean the mouthpiece, including the metal part inside the mouthpiece, with a damp cloth or 
tissue only, at least once a week. Any minor discoloration in the mouthpiece does not affect your 
SPIRIVA RESPIMAT inhaler. 
When to get a new SPIRIVA RESPIMAT inhaler 
 Your inhaler contains 60 puffs (30 doses) if used as indicated (2 puffs once daily). If you have 
a sample, your inhaler contains 28 puffs (14 doses) if used as indicated (2 puffs once daily). 
 The dose indicator shows approximately how much medicine is left. 
• When the dose indicator enters the red area of the scale you need to get a refill; there is 
approximately medicine for 7 days left (if you have a sample, there is approximately medicine 
for 3 days left). 
• When the dose indicator reaches the end of the red scale, your SPIRIVA RESPIMAT is empty 
and automatically locks. At this point, the clear base cannot be turned any further. 
• Three months after insertion of cartridge, throw away the SPIRIVA RESPIMAT even if it has 
not been used, or when the inhaler is locked, or when it expires, whichever comes first. 
Prepare for first use 
1.  Remove clear base 
 Keep the cap closed. 
 Press the safety catch while firmly pulling off the 
clear base with your other hand. Be careful not to 
touch the piercing element. 
 Write the  discard by date on the label (3 months 
from the date the cartridge is inserted). 
Reference ID: 3943617 


 
2.  Insert cartridge 
 Insert the narrow end of the cartridge into the  
inhaler. 
 Place the inhaler on a firm surface and push down  
firmly until it clicks into place. 
3.  Replace clear base 
 Put the clear base back into  place until it clicks.  
 Do not remove the  clear base or the cartridge 
 
after it has been put together.  
4.  Turn 
 Keep the cap closed. 
 Turn the clear base in the direction of the arrows 
on the label until it clicks (half a turn).  
5.  Open 
 Open the cap until it snaps fully open.  
6.  Press 
 
 
 
 
 
 
 Point the inhaler toward the ground. 
 Press the dose-release button.  
 Close the cap.  
 If you do not see a mist, repeat steps 4 to 6 until 
a mist is seen. 
 After a mist is seen, repeat steps 4 to 6 
three more times. 
 After complete preparation of your inhaler, it will 
be ready to deliver the number of puffs on the 
label. 
 
 
 
 
Daily use (T O P) 
Turn 
 Keep the cap closed. 
 Turn the clear base in the direction 
of the arrows on the label until it 
clicks (half a turn). 
 
Reference ID: 3943617 


 
Open 
 Open the cap until it snaps fully 
open. 
 
Press 
 Breathe out slowly and fully.  
 Close your lips around the  
mouthpiece without covering the air 
vents.  
 Point the inhaler to the back of your 
throat. 
 While taking 
 
a slow, deep breath 
through your mouth, Press the 
dose-release button  and continue to  
breathe in.  
 Hold your breath for 10  seconds or 
 
for as long as comfortable. 
 Repeat Turn, Open, Press (TOP)  
for a total of 2 puffs. 
 Close the cap until you use your  
inhaler again. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Answers to Common Questions  
It is difficult to insert the cartridge deep enough:  
Did you accidentally turn the clear base before inserting the cartridge? Open the cap, 
press the dose-release button, then insert the cartridge. 
Did you insert the cartridge with the wide end first? Insert the cartridge with the narrow 
end first. 
I cannot press the dose-release button:  
Did you turn the clear base? If not, turn the clear base in a continuous movement until it  
clicks (half a turn).  
Is the dose indicator on the SPIRIVA RESPIMAT pointing to zero? The SPIRIVA RESPIMAT  
inhaler is locked after 60 puffs (30 doses). If you have a sample, the SPIRIVA RESPIMAT inhaler  
is locked after 28 puffs (14 doses). Prepare and use your new SPIRIVA RESPIMAT inhaler.   
I cannot turn the clear base:  
Did you turn the clear base already? If the clear base has already been turned, follow steps  
“Open” and “Press” under “Daily use” to get your medicine.  
Reference ID: 3943617 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
Is the dose indicator on the SPIRIVA RESPIMAT is pointing to zero? The SPIRIVA  
RESPIMAT inhaler is locked after 60 puffs (30 doses). If you have a sample, the SPIRIVA  
RESPIMAT inhaler is locked after 28 puffs (14 doses). Prepare and use your new SPIRIVA  
RESPIMAT inhaler.  
The dose indicator on the SPIRIVA RESPIMAT reaches zero too soon:  
Did you use SPIRIVA RESPIMAT as indicated (2 puffs once daily)? SPIRIVA RESPIMAT  
will deliver 60 puffs and last 30 days if used at 2 puffs once daily. If you have a sample, SPIRIVA  
RESPIMAT will deliver 28 puffs and last 14 days if used at 2 puffs once daily.  
Did you turn the clear base before you inserted the cartridge? The dose indicator counts 
each turn of the clear base regardless whether a cartridge has been inserted or not. 
Did you spray in the air often to check whether the SPIRIVA RESPIMAT is working? 
Once you have prepared SPIRIVA RESPIMAT, no test-spraying is required if used daily. 
Did you insert the cartridge into a used SPIRIVA RESPIMAT? Always insert a new  
cartridge into a NEW SPIRIVA RESPIMAT.  
What should I do if my SPIRIVA RESPIMAT sprays automatically:  
Was the cap open when you turned the clear base? Close the cap, then turn the clear base.  
Did you press the dose-release button when turning the clear base? Close the cap, so 
the dose-release button is covered, then turn the clear base. 
Did you stop when turning the clear base before it clicked? Turn the clear base in a 
continuous movement until it clicks (half a turn). 
My SPIRIVA RESPIMAT doesn’t spray:  
Did you insert a cartridge? If not, insert a cartridge.  
Did you repeat Turn, Open, Press (TOP) less than three times after inserting the 
cartridge? Repeat Turn, Open, Press (TOP) three times after inserting the cartridge as shown in 
steps 4 to 6 under “Prepare for first use”. 
Is the dose indicator on the SPIRIVA RESPIMAT pointing to 0? You have used up all your 
medicine and the inhaler is locked. 
For more information about SPIRIVA RESPIMAT or a video demonstration on how to use SPIRIVA 
RESPIMAT, go to www.spiriva.com, or scan the code below. You may also call 1-800-542-6257 
or (TTY) 1-800-459-9906 for further information about SPIRIVA RESPIMAT. 
This Instructions for Use has been approved by the U.S. Food and Drug Administration.  
Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877 USA  
Reference ID: 3943617 


 
 
 
 
 
 
 
 
 
 
 
 
 
SPIRIVA® and RESPIMAT
® are registered trademarks and are used under license from 
Boehringer Ingelheim International GmbH 
Copyright © 2016 Boehringer Ingelheim International GmbH 
ALL RIGHTS RESERVED 
Revised: 6 2016 
IT5904EE102016 
304478-04 
Reference ID: 3943617 


Protocol Number: GSP304-201 
 
Version 3.0 
 
Date: 11-Apr-2017 
 
Confidential 
79 
Glenmark Specialty, SA 
APPENDIX 5. GUIDANCE FOR SPIROMETRY  
Spirometers must meet the specifications and performance criteria recommended in the 
American Thoracic Society / European Respiratory Society Standardization of Spirometry. All 
spirometers must be calibrated.  
Preparing the test subject 
On study days when spirometry will be performed, subjects will refrain from the following: 
• Coffee, tea, chocolate, cola, other caffeine-containing beverages, foods, ice-cold 
beverages and heavy meals within 2 hours prior to spirometry.  Decaffeinated beverages 
are acceptable. 
• Smoking will not be permitted in 30-minute period prior to spirometry testing.  As such 
smoking will be discouraged for 12 hours prior to spirometry.  
• Strenuous activity for 12 hours prior to spirometry testing.  Exposure to cold 
temperatures, environmental smoke, dust or areas with strong odors (eg, perfumes). 
• Use of rescue medication within 6 hours prior to spirometry testing.  
Prior to Screening spirometry for subject’s eligibility, subjects taking prohibited medications 
should undergo washout for appropriate period as per Appendix 1. 
At Visit 3 through Visit 5, dosing of the study drug has to be withheld until baseline or trough 
spirometry, as applicable, has been conducted. 
Performing Spirometry 
The subject’s age, height and gender will be entered into the spirometer.  It is important that the 
height is measured accurately at the study site.  Spirometry will be conducted with the subject in 
a seated position and it is preferable that the same trained individual performs the tests for a 
given subject by using the same spirometer.  Spirometry assessments will be initiated between 
6:00 AM and 10:00 AM.  The start time of the first spirometry effort will be used for all 
spirometry time points recorded.  Spirometry, an effort-dependent test, requires careful 
instruction to and cooperation of the subject.  The technician should ensure a good seal around 
the mouthpiece, and confirm that the subject’s posture is correct.  The subject should be 
instructed to perform a maximal inspiration, followed by maximum forced expiration until no 
more air can be exhaled or for at least 6 seconds.  Expiration must be rapid with exertion of 
maximal effort.  The results of spirometry should meet the ATS/ERS criteria for acceptability 
and repeatability.  Acceptability criteria should be applied before repeatability is determined.   
For FEV1 and FVC, at least 3 (and no more than 8) acceptable maneuvers will be obtained; the 
largest FEV1and FVC from the 3 acceptable maneuvers will be recorded, regardless of whether 
they are from the same maneuver.  
Acceptability Criteria of a Maneuver 
An acceptable maneuver has the following characteristics: 
• Without unsatisfactory start of expiration, characterized by excessive hesitation or 
false start extrapolated volume or EV >5% of FVC or 0.150 L, whichever is greater; 


Protocol Number: GSP304-201 
 
Version 3.0 
 
Date: 11-Apr-2017 
 
Confidential 
80 
Glenmark Specialty, SA 
• Without cough, especially during the first second of the maneuver, or any other cough 
that, in the technician’s judgment, interferes with the measurement of accurate 
results; 
• No early termination of exhalation (minimum exhalation time of 6 seconds is 
recommended, or no volume change for at least 1 second) or the subject cannot 
continue to exhale further). 
• Without Valsalva maneuver (no glottis closure) or obstruction by tongue or dentures 
or hesitation during the maneuver that causes a cessation of airflow; 
• Without a leak;  
• Without evidence of an extra breath being taken during the maneuver. 
Repeatability Criteria 
The 2 largest values of FVC must be within 0.150 L of each other. 
The 2 largest values of FEV
1 must be within 0.150 L of each other. 
If both of these criteria are met, the test session may be concluded.  
If both of these criteria are not met: 
• Continue testing until both of the criteria are met with analysis of additional 
acceptable spirograms 
Or  
• A total of 8 tests have been performed 
Or  
• The subject cannot or should not continue.  
Save, as a minimum, the 3 satisfactory maneuvers. 
Testing for Screening Spirometry  
Screening spirometry will be performed during the screening period prior to Visit 2 after a 
washout period if applicable (Refer to Appendix 1).  Both pre- and post-bronchodilator 
spirometry will be performed for subject eligibility.  Spirometry will be conducted before and 
approximately 30 minutes following inhalation of albuterol/salbutamol (400 μg ie, 4 inhalations, 
approximately 30 seconds apart) from an MDI (100 μg per inhalation).  


Protocol Number: GSP304-201 
 
Version 3.0 
 
Date: 11-Apr-2017 
 
Confidential 
81 
Glenmark Specialty, SA 
APPENDIX 6. SUMMARY OF CHANGES IN CURRENT PROTOCOL 
AMENDMENT 
 
PROTOCOL GSP304-201 
 
PROTOCOL AMENDMENT 2.0 
SUMMARY OF CHANGES 
 
A DOSE RANGING, PARALLEL GROUP, ACTIVE (SPIRIVA® RESPIMAT®) AND 
PLACEBO-CONTROLLED STUDY TO ASSESS RELATIVE BIOAVAILABILITY, 
PHARMACODYNAMICS AND SAFETY OF THREE DOSES OF TIOTROPIUM 
BROMIDE INHALATION SOLUTION IN SUBJECTS WITH MILD TO MODERATE 
CHRONIC OBSTRUCTIVE PULMONARY DISEASE 
 
 
PROTOCOL HISTORY 
PROTOCOL VERSION 1.0, 11-Oct-2016 
PROTOCOL VERSION 2.0 (Amendment 1.0), 05-Jan-2017 
PROTOCOL VERSION 3.0 (Amendment 2.0), 11-Apr-2017 


GSP304-201 
 
 
Glenmark Pharmaceuticals SA  
 
Protocol Amendment 2.0 
11 Apr 2017 
Page 82 of 87 
AD-CS-02.02 14-Mar-2014  
Description of Changes in Protocol Version 3.0 dated 11-Apr-2017 
Minor editorial changes for accuracy, clarity, and consistency have been made throughout the document and are not included in the 
description(s) below. 
A. Details of Substantial Changes to the Protocol  
From 
Original Protocol Version 2.0, 05-Jan-2017 
To  
Protocol Version 3.0 (Amendment 2.0), 
11-Apr-2017 
Rationale for Amendment 
1. 8.2, Subject Exclusion Criteria, added new exclusion criterion 9  
Used to read: 
(Not Applicable) 
Added: 
9. Subjects with a screening serum creatinine 
value >1.5 mg/dL 
Subsequent exclusion criteria have been 
renumbered 10 through 30. 
 
PK considerations regarding tiotropium excretion 
by the renal pathway.  
2. 8.2, Subject Exclusion Criteria, former exclusion criterion 22 (now exclusion criterion 23) 
Used to read:  
22. Subject has a history or suspected history of 
abuse of a barbiturate, amphetamine, or narcotic 
and/or has a positive screening result for any of 
these substances at study start 
Now reads:  
23. Subject has a positive serum alcohol test 
during screening.  Subjects with a known history 
of alcohol use may be enrolled in the study if the 
alcohol use is not indicative of abuse, as 
considered by the Investigator.  Note: Positive 
drug screening results are not exclusionary for 
prescription narcotics, amphetamines, or 
barbiturates, if taken only as prescribed under 
the supervision of a physician for a well-
documented medical indication, without any 
evidence or suspicion of abuse.  However, 
methadone and cannabinoids are exclusionary 
for this study even when taken by prescription. 
Expanded criterion to include subjects using 
prescription therapies (that do not affect tiotropium 
PK) if used for well-documented medical 
indication.  Renumbered due to addition of 
Exclusion Criterion #9.  
3. 8.2, Subject Exclusion Criteria, former exclusion criterion 25 (now exclusion criterion 26) 
Used to read:  
25. Subject has received oral anticoagulant 
therapy within 90 days before screening except use 
of low dose aspirin (up to 325 mg daily) to prevent 
heart attack or a stroke. 
Now reads:  
26. Subject has received oral anticoagulant therapy 
within 90 days before screening except use of low 
dose aspirin (up to 325 mg daily) to prevent heart 
attack or a stroke.  Certain types of 
Elaboration of Exclusion Criterion #26 to allow 
Medical Monitor discretion to distinguish 
antiplatelet drugs on a case by case basis.   
Renumbered due to addition of Exclusion 
Criterion #9. 


GSP304-201 
 
 
Glenmark Pharmaceuticals SA  
 
Protocol Amendment 2.0 
11 Apr 2017 
Page 83 of 87 
AD-CS-02.02 14-Mar-2014  
anticoagulant therapy (ie, clopidogrel, 
prasugrel) may be permitted, but all must be 
reviewed on a case-by-case basis with the 
Medical Monitor. 
 
B. Details of Non-substantial Changes to the Protocol 
From 
Original Protocol Version 2.0, 05-Jan-2017 
To  
Protocol Version 3.0 (Amendment 2.0), 
11-Apr-2017 
Rationale for Amendment 
1. Sponsor’s Signature 
Used to read: 
Cynthia F. Caracta, MD FCCP 
Vice President, Clinical Sciences, Respiratory 
Glenmark Pharmaceuticals   
750 Corporate Drive, Mahwah, NJ 07430, USA 
E-mail: cynthia.caracta@glenmarkpharma.com 
Now reads:  
Elizabeta Zovko, MD  
Executive Director, Clinical Sciences, Respiratory 
Glenmark Pharmaceuticals   
750 Corporate Drive, Mahwah, NJ 07430, USA 
E-mail: Elizabeta.Zovko@glenmarkpharma.com 
Change of Clinical Lead 
2. Synopsis, Pharmacokinetic Assessments 
Used to read:  
In addition, urine will be collected into pre-
weighed containers at pre-dose (within 1 hour 
prior to dosing), and at the following intervals 
post-dose from 0-6, 6-12, and 12-24 hours on Day 
1 and Day 21.  Collection times and the accurate 
volume of urine will be noted.   
Now reads:  
In addition, urine will be collected into pre-
weighed containers at pre-dose (within 1 hour 
prior to dosing), and at the following intervals 
post-dose from 0-6, 6-12, and 12-24 hours on Day 
1 and Day 21.  Collection times time intervals and 
the accurate volume of urine weights of 
containers before and after urine collection at 
each interval will be noted.   
Clarification of procedure.  
3. Synopsis, Pharmacodynamic, Biomarker, and Pharmacogenomic Assessments; Table 2, Schedule of Assessments Footnote 10; Section 11.2.2.2, 
Pharmacodynamic Assessments 
Used to read: 
… On Day 1 and Day 21, FEV1 will be recorded, 
at the following time points after the morning 
dose: immediately post-dose at 5 minutes (±1 
minute),… 
Now reads: 
… On Day 1 and Day 21, FEV1 will be recorded, 
at the following time points after the morning 
dose: immediately post-dose at 5 minutes (±13 
minutes),… 
 
Increase of the allowable time window at the 
5 minute post-dose time point due to multiple 
clinical assessments occurring at this time point 
4. Synopsis, Statistical Methods; Section 13.2, Analysis Sets 


GSP304-201 
 
 
Glenmark Pharmaceuticals SA  
 
Protocol Amendment 2.0 
11 Apr 2017 
Page 84 of 87 
AD-CS-02.02 14-Mar-2014  
Used to read: 
Per Protocol Analysis Set (PP) 
This will include all subjects who are randomized, 
received at least 1 dose of study medication, 
completed the study and do not have any major 
protocol deviations.  Major protocol deviations 
will be defined in the SAP. 
 
PK Analysis Set (PKAS) 
This will include all subjects who are randomized, 
received at least 1 dose of study treatment and 
have at least 1 quantifiable PK sample and do not 
have any major protocol deviations.  The PKAS 
will be used to analyze the PK endpoints unless 
otherwise specified in the SAP. 
Now reads: 
This will include all subjects who are randomized, 
received at least 1 dose of study medication, 
completed the study and do not have any 
exclusionary major protocol deviations.  
Major protocol and exclusionary protocol 
deviations and PP exclusions will be defined in 
the SAP and by clinical review prior to 
unblinding. 
 
PK Analysis Set (PKAS) 
This will include all subjects who are randomized, 
received at least 1 dose of study treatment and 
have at least 1 quantifiable PK sample and do not 
have any major exclusionary major protocol 
deviations.  The PKAS will be used to analyze the 
PK endpoints unless otherwise specified in the 
SAP.  Major and exclusionary protocol 
deviations will be defined in the SAP and by 
clinical review prior to unblinding. 
To define exclusionary protocol deviations that 
would exclude subjects from analysis, and to 
clarify how major and exclusionary protocol 
deviations will be determined. 
5. Table 2, Schedule of Assessments, Footnote 4 added 
Used to read: 
(Not applicable) 
Added: 
New footnote 4 to 12-lead ECG on Screening Visit 
within the table.     
4. Triplicate ECG will be performed at the 
screening visit. 
All subsequent footnotes have been renumbered. 
Clarification of ECG procedure at Screening visit 
to align with exclusion criterion number 7.  
6. Table 2, Schedule of Assessments, Footnote 8 
Used to read: 
8. On days on which subject visits are scheduled, 
subjects will take the study drug at the Investigator 
site (ie, after any required pre-dose blood samples 
and pre-dose PD measures have been collected).  
On all other days, subjects will be requested to 
take the study medication at home as instructed by 
the study staff. 
Now reads: 
8. On days on which subject visits are scheduled, 
subjects will take the study drug at the Investigator 
site (ie, after any required pre-dose blood samples 
and pre-dose PD measures have been collected), 
EXCEPT on Day 20 when subjects will be 
requested to take the study medication at home 
as instructed by the study staff.  
On all other 
days, subjects will be requested to take the study 
medication at home as instructed by the study 
staff. 
Clarification of subject dosing procedure for 
Day 20.  


GSP304-201 
 
 
Glenmark Pharmaceuticals SA  
 
Protocol Amendment 2.0 
11 Apr 2017 
Page 85 of 87 
AD-CS-02.02 14-Mar-2014  
7. Section 10.5, Administration 
Used to read:  
On days where subject visits are scheduled, 
subjects will bring all used and unused study drug 
(GSP304/GSP304 placebo or Spiriva® 
Respimat®) and rescue medication containers to 
each study visit, along with the nebulizer, if 
required for treatment administration, per 
randomization group.   
On all other days, subjects will be requested to 
take the study medication at home as instructed by 
the study staff.   
 
Now reads: 
On days where subject visits are scheduled, 
subjects will bring all used and unused study drug 
(GSP304/GSP304 placebo or Spiriva® 
Respimat®) and rescue medication containers to 
each study visit, along with the nebulizer, if 
required for treatment administration, per 
randomization group EXCEPT on Day 20 when 
subjects will be requested to take the study 
medication at home as instructed by the study 
staff.   
On all other days, subjects will be requested to 
take the study medication at home as instructed by 
the study staff.   
 
Clarification of subject dosing procedure for 
Day 20. 
8. Section 11.2.2.1.1, Blood Sample Collection; Table 2, Footnote 9 
Used to read:  
Blood samples (approximately 6 mL) will be 
collected in dipotassium 
ethylenediaminetetraacetic acid (EDTA) coated 
vacutainers on Day 1 and Day 21 according to the 
below schedule: Pre-dose (0 hour), and at 2, 4, 6, 
10, 15, 30, and 45, 60, 75, and 90 minutes post-
dose, as well as 2, 4, 6, 8, 12, 16, 20 and 24 hours 
post-dose.  … 
Now reads:  
Blood samples (approximately 6 mL) will be 
collected in dipotassium 
ethylenediaminetetraacetic acid (EDTA) coated 
vacutainers on Day 1 and Day 21 according to the 
below schedule: Pre-dose (0 hour), and at 2, 4, 6, 
10, 15, 30, and 45, 60, 75, and 90 minutes post-
dose, as well as 2, 4, 6, 8, 12, 16, 20 and 24 hours 
post-dose.  Blood samples for PK should not be 
drawn or processed in the same room that the 
subject was dosed with study medication.  … 
Precautionary measure to prevent contamination of 
the PK plasma. 
9. Section 11.2.2.1.2, Urine Sample Collection  
Used to read:  
…  During each collection period, the containers 
will be stored in refrigerators at 2°C to 8°C.  
Collection times and the accurate volume of urine 
collected for each interval will be noted.  Two 
representative aliquots of equal volume 
(approximately 20 mL each, estimated using a 
Now reads:  
…  During each collection period, the containers 
will be stored in refrigerators at 2°C to 8°C.  
Collection time intervals accurate volume of urine 
collected for each interval will be noted.  Two 
representative aliquots of equal volume 
(approximately 20 mL each, estimated using a 
nominal specific gravity of 1.018) and the 
Clarification of procedure. 


GSP304-201 
 
 
Glenmark Pharmaceuticals SA  
 
Protocol Amendment 2.0 
11 Apr 2017 
Page 86 of 87 
AD-CS-02.02 14-Mar-2014  
nominal specific gravity of 1.018) will be taken 
from each collection interval… 
accurate weights of containers before and 
after 
collection of urine for each interval will be 
noted.  Weight of urine (weight of container 
with urine – weight of empty container) 
will be 
converted to volume using a nominal specific 
gravity of 1.018.  Two representative aliquots of 
equal volume (approximately 20 mL each, 
estimated) will be taken from each collection 
interval…  
10. Section 11.2.2.2, Pharmacodynamic Assessments 
Used to read: 
…Spirometry testing is to be performed according 
to the procedure detailed in Appendix 5.  For 
FEV1 and FVC… 
Now reads:  
…Spirometry testing is to be performed according 
to the procedure detailed in Appendix 5.   The 
start time of the first spirometry effort will be 
used for all spirometry time points recorded.  
For FEV1 and FVC… 
Clarification of spirometry start time. 
11. Section 12.1.2, Vital Signs; Table 2, Schedule of Assessments, Footnote 1 
Used to read:  
Vital sign measurements (ie, systolic and diastolic 
blood pressure [BP] [mmHg], pulse rate [beats per 
minute], respiratory rate [per minute] and oral 
temperature [degrees in Centigrade])… 
Now reads:  
Vital sign measurements (ie, systolic and diastolic 
blood pressure [BP] [mmHg], pulse rate [beats per 
minute], respiratory rate [per minute] and oral 
temperature [degrees in Centigrade])… 
Allow flexibility in measurement of subject 
temperature.   
12. Section 12.1.2, Vital Signs 
Used to read:  
Blood pressure and pulse will be measured after 
the subject has been sitting for 5 minutes.  
 
Now reads: 
Blood pressure and pulse will be measured after 
the subject has been sitting or lying down for 5 
minutes.  
 
Allow flexibility in measurement of subject vital 
signs.   
13. Appendix 2, List of Clinical Laboratory Tests 
Used to read: 
(Not applicable) 
Added: 
Glomerular filtration rate (GFR); GFR will be 
estimated by the Cockcroft-Gault formula utilizing 
serum creatinine values, age, weight, and gender, 
from the screening visit. 
Added GFR calculation to screening clinical 
laboratory tests.  
14. Appendix 5, Guidance for Spirometry  
Used to read: 
…Spirometry assessments will be initiated 
between 6:00 AM and 10:00 AM.  Spirometry, an 
effort-dependent test, requires careful instruction 
to and cooperation of the subject.  … 
Now reads:  
…Spirometry assessments will be initiated 
between 6:00 AM and 10:00 AM.  The start time 
of the first spirometry effort will be used for all 
spirometry time points recorded.  Spirometry, an 
Clarification of spirometry start time.  


GSP304-201 
 
 
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Protocol Amendment 2.0 
11 Apr 2017 
Page 87 of 87 
AD-CS-02.02 14-Mar-2014  
effort-dependent test, requires careful instruction 
to and cooperation of the subject.  … 
15. Appendix 6, title of appendix and content 
Used to read:  
Appendix 6, Protocol Amendment 1.0 Summary of 
Changes 
 
Now reads: 
Appendix 6, Summary of Changes in Current 
Protocol Amendment 
  
Updated Appendix 6 to show summary of changes 
in current amendment. 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_000.pdf: 
 
   
 
Confidential 
 
 
                      Page 1 of 1 
 
 
 
Tiotropium Bromide Inhalation Solution GSP304-201 A Dose Ranging, Parallel Group, Active 
(Spiriva® Respimat®) And Placebo Controlled Study To Assess Relative Bioavailability, 
Pharmacodynamics And Safety Of Three Doses Of Tiotropium Bromide Inhalation Solution In 
Subjects With Mild To Moderate Chronic Obstructive Pulmonary Disease. 
 
Identifiers 
                 NCT03118765    
 
Date of Document            12 September 2017 


Glenmark Specialty SA 
Statistical Analysis Plan – Protocol #GSP304-201 
SEPT 12, 2017 
 
 
1 
 
 
  
 
 
STATISTICAL ANALYSIS PLAN 
PHASE 2 
 
VERSION: 2.0 
DATE OF PLAN: 
 
12-SEPT-2017 
 
 
BASED ON: 
GSP304-201 Protocol V3.0 11-APR-2017    
 
STUDY DRUG: 
GSP304 (tiotropium bromide) Inhalation Solution 
PROTOCOL NUMBER: 
GSP304-201 
STUDY TITLE: 
A DOSE RANGING, PARALLEL GROUP, ACTIVE 
(SPIRIVA® RESPIMAT®) AND PLACEBO-CONTROLLED 
STUDY TO ASSESS RELATIVE 
BIOAVAILABILITY, PHARMACODYNAMICS AND 
SAFETY OF THREE DOSES OF TIOTROPIUM BROMIDE 
INHALATION SOLUTION IN SUBJECTS WITH MILD 
TO MODERATE CHRONIC OBSTRUCTIVE PULMONARY DISEASE 
 
 
SPONSOR: 
Glenmark Specialty SA 
Avenue Léopold-Robert 37 
2300 La Chaux-de-Fonds 
Switzerland 
 
This study is being conducted in compliance with good clinical practice, including the archiving 
of essential documents. 




Glenmark Specialty SA 
Statistical Analysis Plan – Protocol #GSP304-201 
SEPT 12, 2017 
 
 
3 
 
 
  
 
TECHNICAL SUMMARY REPORT (TSR) 
 
Name of Sponsor/Company 
Glenmark Specialty SA 
Name of Investigational  Product: 
GSP304 (tiotropium bromide) Inhalation Solution 
Name of Active Ingredient: 
Tiotropium Bromide 
Title Of Study: 
A Dose Ranging, Parallel Group, Active (Spiriva® Respimat®) and Placebo-controlled Study to Assess 
Relative Bioavailability, Pharmacodynamics and Safety of Three Doses of Tiotropium Bromide 
Inhalation Solution in Subjects With Mild to Moderate Chronic Obstructive Pulmonary Disease 
Phase of development:  Phase 2 
Objectives: 
Primary:  
To assess the relative bioavailability of GSP304 (tiotropium bromide) Inhalation Solution at dose levels of 10 μg, 
20 μg, and 40 μg once daily (QD) compared with Spiriva® Respimat® inhalation spray (5 μg QD) in subjects with 
COPD. 
To characterize the dose response of GSP304 at dose levels of 10 μg, 20 μg, and 40 μg with respect to 
pharmacodynamics (PD). 
Secondary:  
To assess the safety and tolerability of GSP304 at dose levels of 10 μg, 20 μg, and 40 μg QD.   
Methodology: 
This is a phase 2, randomized, parallel group, active- and placebo-controlled, 5-arm study to compare the PK profile 
of 3 blinded doses of GSP304 with open label Spiriva® Respimat®. The study will also evaluate the dose response 
PD profile of 3 blinded doses of GSP304 compared with blinded GSP304 placebo, using spirometry in subjects with 
mild to moderate COPD. A total of 155 male and female subjects will be randomized in a 1:1:1:1:1 ratio to 1 of 5 
treatment arms. A subject will receive 1 of the 3 double-blind doses of GSP304, or double-blind GSP304 placebo, or 
open-label Spiriva® Respimat®. The study will include a screening period of up to 2 weeks, followed by a 2 week 
run-in period, 3 weeks of treatment, and a 2 week post treatment follow up period. The total duration of study 
participation will be approximately 9 weeks. In this study, PK of tiotropium in plasma and urine will be assessed on 
Day 1 and Day 21 (at steady state).   
Number of Subjects (planned):  
A total of 155 subjects will be randomized in this study.   
Study Endpoints: 
Primary Endpoint 
 
The PK endpoints for tiotropium in plasma to assess the relative bioavailability are: 
 
Peak concentrations during the dosing interval at steady-state (CmaxSS) 
 
Area under the plasma concentration-time curve over the dosing interval at steady state (AUC0-tauSS) 
 
Change from baseline (Day 1) at Day 21 (Week 3) in trough FEV1 response at approximately 24 hours after 
the last dose (average of 23 hours 15 minutes and 23 hours 45 minutes post-dose measurements), in 
comparison with GSP304 placebo 
Secondary Endpoints 
 
Amount (Aetau) and fraction of dose (Fe) of tiotropium excreted in urine over the dosing interval on Day 1 
and Day 21 
 
Peak concentrations during the dosing interval (Cmax) on Day 1 
 
Area under the plasma concentration-time curve over the dosing interval (AUC0-tau) on Day 1 
 
Time of peak drug concentration over the dosing interval (tmax) on Day 1 and Day 21 
 
Average concentration during a dosing interval at steady state (CavSS) on Day 21 
 
Accumulation ratio (Rac) 


Glenmark Specialty SA 
Statistical Analysis Plan – Protocol #GSP304-201 
SEPT 12, 2017 
 
 
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 
Change from baseline in peak FEV1 within 12 hours post-dose on Day 1 and Day 21 
 
Change from baseline (Day 1) at Day 21 (Week 3) in trough FVC response at approximately 24 hours after 
the last dose (average of 23 hours 15 minutes and 23 hours 45 minutes post-dose measurements), in 
comparison with GSP304 placebo 
 
Change from baseline in time-normalized area under the curve for FEV1 measured over 12 hours on Day 1 
and Day 21 
 
Time to onset of response, defined as at least 12% and 200 mL increase in FEV1 within 12 hours of dosing 
on Day 1  
 
Time to achieving steady state as measured by FEV1 trough assessments 
 
Time to achieving steady state as measured by FVC trough assessments 
Safety Endpoints 
 
Vital signs, laboratory parameters, 12-lead electrocardiogram (ECG) 
 
Incidence of all adverse events (AEs) 
Diagnosis and main criteria for inclusion: 
Males and females of non-childbearing potential ≥40 and ≤85 years of age with a primary clinical diagnosis of mild 
to moderate COPD, a FEV1/FVC ratio of <70% and a baseline FEV1 of ≥50% of predicted normal value as per the 
NHANES III predicted normal values at screening 
Investigational product, dose and mode of administration: 
Name of Investigational Products: 
GSP304 (tiotropium bromide) Inhalation Solution, 10 μg 
GSP304 (tiotropium bromide) Inhalation Solution, 20 μg 
GSP304 (tiotropium bromide) Inhalation Solution, 40 μg 
Dosage Form: Inhalation Solution 
Dosage: Oral inhalation   
Dosage Frequency: Once daily (QD)   
Mode of Administration: By oral inhalation using a nebulizer 
Comparator, dosage and mode of administration: 
Placebo to match GSP304 
Dosage Form: Inhalation Solution 
Dosage Frequency: QD 
Mode of Administration: By oral inhalation using a nebulizer 
Reference therapy, dose and mode of administration: 
Name of Comparator: Spiriva® Respimat® inhalation spray 2.5 μg per actuation 
Dosage Form: Inhalation Spray 
Dosage: 5 μg (2 actuations of 2.5 μg each)    
Dosage Frequency: Once Daily (QD) 
Mode of Administration: By oral inhalation using Respimat® Soft Mist Inhaler 
Duration of treatment:   
3 weeks (21 days) 
Criteria for evaluation :  
Efficacy:  
Spirometry 
FEV1 and FVC 
Refer to ‘Pharmacodynamics Assessments’ sub-section below. 
Pharmacokinetic, Pharmacodynamics, Biomarker, and Pharmacogenomics Assessments: 
Pharmacokinetic Assessments 
Blood samples (approximately 6 mL) will be collected in dipotassium ethylenediaminetetraacetic acid (EDTA) 


Glenmark Specialty SA 
Statistical Analysis Plan – Protocol #GSP304-201 
SEPT 12, 2017 
 
 
5 
 
 
  
 
coated vacutainers on Day 1 and Day 21 according to the below schedule: Pre-dose (0 hour), and 2, 4, 6, 10, 15, 30, 
45, 60, 75, and 90 minutes post-dose, as well as 2, 4, 6, 8, 12, 16, 20 and 24 hours post-dose. The pre-dose sample 
on Day 1 should be collected within 30 minutes prior to dosing while on Days 7, 14, and 21 the pre-dose sample 
should be collected within 10 minutes prior to the morning dose. On Day 1 and Day 21, samples will be collected 
within the following collection windows: 
For the 2 minute sample, within a window of ±30 seconds 
For the 4, 6, 10, 15, and 30 minute samples, within a window of ± 1 minute 
For the 45, 60, 75, 90 minute, and 2.0 hour samples, within a window of ± 2 minutes 
For the 4, 6, 8, 12, 16, 20 and 24 hour samples, within a window of ± 5 minutes. 
 
In addition, urine will be collected into pre-weighed containers at pre-dose (within 1 hour prior to dosing), and at the 
following intervals post-dose from 0-6, 6-12, and 12-24 hours on Day 1 and Day 21. 
Collection times and the accurate volume of urine will be noted. In each urine container, approximately 5 mL of 1M 
citric acid must be added prior to start of collection. Plasma and urine concentrations of tiotropium will be quantified 
by a validated liquid chromatography-mass spectrometry (LC/MS/MS) method.   
Pharmacokinetic Parameters 
Plasma: 
• 
AUC0-tauSS     
• 
CmaxSS 
• 
CminSS 
• 
CavSS 
• 
Cmax on Day 1 
• 
tmax on Day 1 and Day 21     
• 
AUC0-tau on Day 1 
• 
Rac        
Urine: 
• 
Aetau 
• 
Fe% 
 
Additional Pharmacokinetics 
Additional parameters may be evaluated depending on the data obtained during the study. 
 
tlast on Day 1 and Day 21 
Pharmacodynamics, Biomarker, and Pharmacogenomics Assessments 
In addition to screening, pre-dose FEV1 and FVC will be assessed at -45 minutes and -15 minutes prior to dosing on 
Day 1, Day 7, Day 14, and Day 21. Trough FEV1 will be assessed on Day 22 (ie, 24 hours after the Day 21 dose). 
On Day 1 and Day 21, FEV1 will be recorded, at the following time points after the morning dose: immediately 
post-dose at 5 minutes (±3 minutes), 15 minutes (±2 minutes), 30 minutes (±5 minutes), 60 minutes, 90 minutes, and 
2 hours (120 minutes); and post-dose at 4, 6, 8, 10, 12, 23 hours15 minutes and 23 hours 45 minutes post dose. The 
window for 1-hour spirometry and thereafter is ±5 minutes. 
 
Spirometry Effort Start Time is defined as the time of the end of the first effort (Test 1) regardless of whether this is 
an acceptable effort  instead of  “start time of first spirometry effort ” as described in the protocol. 
 
FEV1: FEV1 is the volume of air forcibly exhaled in one second as measured by a spirometer. 
Peak FEV1: It is defined as the maximum FEV1 over the period of 12 hours post-morning dose. 
Trough FEV1: It is defined as the mean FEV1 obtained 23 hours 15 minutes and 23 hours 45 minutes post-morning 
dose of the previous day. 
Baseline FEV1: It is defined as the average of the pre-dose FEV1 measured at -45 minutes and -15 minutes at Day 1 
FVC: FVC is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath 
possible. 
Baseline FVC: It is defined as the average of the pre-dose FVC measured at -45 minutes and -15 minutes at Day 1. 
Safety: 
Safety assessments will consist of monitoring and recording all Adverse Events (AEs) and serious adverse events 
(SAEs) including treatment related AEs and SAEs as well as AEs leading to discontinuation, clinical laboratory 
measurements, vital signs, 12-lead ECG, and physical examinations. 


Glenmark Specialty SA 
Statistical Analysis Plan – Protocol #GSP304-201 
SEPT 12, 2017 
 
 
6 
 
 
  
 
Analysis Sets 
Full Analysis Set (FAS) 
This will include all subjects who are randomized, have received at least 1 dose of study medication and have at 
least 1 post-baseline PD assessment. This analysis set will be the primary analysis set for the PD endpoints. 
Safety Analysis Set (SAF) 
This will include all subjects who are randomized and received at least 1 dose of study medication. All safety 
endpoints will use the SAF unless otherwise specified. 
Per Protocol Analysis Set (PP) 
This will include all subjects who are randomized, received at least 1 dose of study medication, completed the study 
and do not have exclusionary major protocol deviations.  Major and exclusionary protocol deviations will be defined 
in this SAP and by clinical review prior to unblinding. 
PK Analysis Set (PKAS) 
This will include all subjects who are randomized, received at least 1 dose of study treatment and have at least 1 
quantifiable PK sample and do not have exclusionary major protocol deviations.  The PKAS will be used to analyze 
the PK endpoints unless otherwise specified in the SAP.  Major and exclusionary protocol deviations will be defined 
in this SAP and by clinical review prior to unblinding. 
Determination of Sample Size 
A sample size of 28 subjects per treatment arm will have 90% power to detect a difference in mean change from 
baseline in trough FEV1 of 150 mL between GSP304 and GSP304 placebo assuming a 2-sided alpha of 5% and a 
standard deviation (SD) of 170 mL. These assumptions are based on available literature from similar studies 
conducted for Spiriva® Respimat®. 
Given the overall 1:1:1:1:1 study treatment allocation ratio, 140 subjects are required for the analysis of the primary 
endpoint. Assuming a dropout rate of 10%, a total of 155 subjects (31 subjects per treatment arm) will be 
randomized. 
This sample size is also considered to be sufficient for the relative bioavailability endpoint. 
Pharmacodynamics Analyses 
The PD comparisons will be made between each dose of GSP304 and GSP304 placebo as well as Spiriva and 
Placebo. 
Analysis of Primary Pharmacodynamics Endpoint. 
Change from baseline in trough FEV1 at 24-hours after the last dose of treatment on Day 21 in comparison to 
GSP304 placebo.The primary endpoint measures the change from baseline (Day 1) at Day 21 (Week 3) in trough 
FEV1 response at approximately 24 hours after the last dose (average of 23 hours 15 minutes and 23 hours 45 
minutes post-dose measurements). This will be analyzed using a Mixed-effect Model Repeated Measure (MMRM) 
model to produce treatment differences for each dose of GSP304 vs GSP304 placebo. The MMRM model will 
include the trough FEV1 assessment on day 1 and pre-dose data from all visits (Days 7, 14, and 21, which are the 
trough FEV1 assessments on days 6, 13 and 20) and fixed terms for treatment, visit, baseline, center, treatment by 
visit and baseline by visit interactions. The adjusted means for each treatment and the estimated treatment 
differences for the treatment comparisons will be presented together with 95% confidence intervals (CIs). Multiple 
imputation-based methods will be considered as a sensitivity analysis for missing data, with further detail provided. 
The primary endpoint will be analyzed using the FAS and primary inference will be based on Day 21 trough values. 
A sensitivity analysis will be based on the Full Analysis Set. 
Analysis of Secondary Pharmacodynamics Endpoints 
Analysis of secondary PD endpoints will be performed on the FAS. 
Change from baseline in peak FEV1 within 12 hours post dose on Day 1 and Day 21: This endpoint measures the 
peak FEV1 from the serial readings taken through 12 hours post-dose and then calculates the change from baseline. 
The change from baseline will be analyzed using MMRM in a similar way to that of the primary endpoint to 
produce treatment differences for each dose of GSP304 versus GSP304 placebo. 
Change from baseline (Day 1) at Day 21 (Week 3) in trough FVC response at approximately 24 hours after the last 
dose (average of 23 hours 15 minutes and 23 hours 45 minutes post-dose measurements) will be analyzed using 
MMRM in a similar way to that of the primary endpoint to produce treatment differences for each dose of GSP304 
versus GSP304 placebo. 
Change from baseline in time-normalized area under the curve for FEV1 measured over 12 hours on Day 1 and Day 
21: The endpoint measures a series of FEV1 readings taken within 12 hours of dosing. 
The trapezoidal rule will be used to calculate AUC0-12h and then normalized to the length of time. The change from 


Glenmark Specialty SA 
Statistical Analysis Plan – Protocol #GSP304-201 
SEPT 12, 2017 
 
 
7 
 
 
  
 
baseline will be analyzed using MMRM in a similar way to that of the primary endpoint to produce treatment 
differences for each dose of GSP304 versus GSP304 placebo. 
All PD data will also be displayed in summaries and listings. 
Time to steady-state: This is the time period from the first dose to two consecutive similar trough FEV1 or FVC 
measurements. The trough values will be tabulated and plotted by time for each active dose and placebo. 
Time to onset of action (of both a 12% increase and 200 mL increase in FEV1 within 12 hours of dosing): This is the 
time period from the first dose to first onset of at least 12 percent and 200 mL improvement in FEV1 over the 
baseline value. The trough values will be tabulated and plotted by time for each active dose and placebo.  
Pharmacokinetic, Pharmacogenomics, and Other Biomarker Analyses 
Pharmacokinetic Analyses 
Pharmacokinetic analysis will be performed using the PKAS. 
Plasma: Individual subject plasma PK parameters will be determined from plasma concentrations using non-
compartmental methods for each subject. Actual collection times will be used for the analyses. 
Urine: Amount and fraction of dose of tiotropium excreted in urine during the collected time interval in individual 
subjects will be estimated. Nominal collection times and urine volumes will be used for the estimation. 
Additional parameters may be evaluated depending on the data obtained during the study. The derived PK 
parameters will be listed by treatment, subject and day and summarized by treatment and day. Wherever appropriate, 
data will be visualized by means of graphical representations. For the summaries, descriptive statistics for all 
relevant PK parameters will include: n, arithmetic mean, SD, coefficient of variation (%CV), geometric mean, 
geometric mean %CV, median, minimum and maximum. The plasma concentrations and amount in urine of 
tiotropium will also be listed by subject, summarized by treatment, and presented graphically as mean plots, and 
spaghetti plots.   
Statistical Analysis of Pharmacokinetic Parameters 
An analysis of variance (ANOVA) will be performed on the ln-transformed PK parameters AUC0-tauSS, and CmaxSS. 
The ANOVA model will include treatment as fixed effect. The results from the model will be back-transformed and 
the adjusted geometrics means for each treatment and the estimated treatment ratios for the treatment comparisons 
will be presented together with 90% CIs. 
The ratios and corresponding 90% CIs will be expressed as a percentage. 
The following comparisons will be made: 
GSP304 (tiotropium bromide) Inhalation Solution, 10 μg 
GSP304 (tiotropium bromide) Inhalation Solution, 20 μg 
GSP304 (tiotropium bromide) Inhalation Solution, 40 μg 
For GSP304, dose-proportionality of tiotropium CmaxSS and AUC0-tauSS parameters will be assessed using a power 
model (linear regression relating log-transformed CmaxSS and AUC0-tauSS to the log- transformed dose). Estimates of 
the mean slopes of log-transformed dose will be reported along with corresponding 90% CIs. Dose proportionality 
will also be assessed based on amount of tiotropium excreted in urine.  
Pharmacogenomics, and Other Biomarker Analyses 
Not applicable. 
Safety Analyses 
All safety analyses will be performed on the SAF and will be presented by the study treatment. Safety data will be 
summarized descriptively. Data describing quantitative measures will be summarized as mean, SD, median and 
range (minimum and maximum). Qualitative variables will be presented as counts and percentages. 
All safety data will also be displayed in listings. 
Other Analyses   
Not applicable.  
 
 
 
 
 
 


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Statistical Analysis Plan – Protocol #GSP304-201 
SEPT 12, 2017 
 
 
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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS.....................................................................................12 
2. 
INTRODUCTION ......................................................................................................14 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................15 
3.1. 
Study Objectives .........................................................................................................15 
3.1.1. 
Primary Objective .......................................................................................................15 
3.1.2. 
Secondary Objective ...................................................................................................15 
3.2. 
Study Endpoints ..........................................................................................................15 
3.2.1. 
Primary Endpoints ......................................................................................................15 
3.2.2. 
Secondary Endpoints ..................................................................................................15 
3.2.3. 
Safety Endpoints .........................................................................................................16 
4. 
STUDY DESIGN .......................................................................................................17 
4.1. 
Summary of Study Design ..........................................................................................17 
4.2. 
Definition of Study Drugs ..........................................................................................17 
4.3. 
Sample Size Considerations .......................................................................................18 
4.3.1. 
Sample Size Justifications ..........................................................................................18 
4.3.2. 
Sample Size Re-estimation .........................................................................................18 
4.4. 
Randomization ............................................................................................................18 
4.5. 
Clinical Assessments ..................................................................................................19 
5. 
PLANNED ANALYSES ............................................................................................21 
5.1. 
Interim Analyses .........................................................................................................21 
5.2. 
Final Analyses ............................................................................................................21 
6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING ...............................................................................................................22 
6.1. 
General Summary Table and Individual Subject Data Listing Consideration ...........22 
6.2. 
General Post Text Summary Table and Individual Subject Data Listing 
Format Considerations ................................................................................................22 
6.3. 
Data Management .......................................................................................................22 
6.4. 
Data Presentation Conventions ...................................................................................23 
6.5. 
Analysis Sets ...............................................................................................................24 
6.5.1. 
Full Analysis Set (FAS) ..............................................................................................24 
6.5.2. 
Safety Set (SAF) .........................................................................................................24 
6.5.3. 
Per-Protocol Set (PP) ..................................................................................................24 


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6.5.4. 
Pharmacokinetic Set (PKAS) .....................................................................................25 
6.6. 
Baseline Definition .....................................................................................................25 
6.7. 
Derived and Transformed Data ..................................................................................26 
6.7.1. 
Age ..............................................................................................................................26 
6.7.2. 
Study Day ...................................................................................................................26 
6.7.3. 
Change from Baseline .................................................................................................26 
6.7.4. 
Visits ...........................................................................................................................26 
6.7.5. 
Unscheduled Assessments ..........................................................................................27 
6.7.6. 
Pharmacokinetic Parameters .......................................................................................27 
6.7.7. 
Pharmacodynamics Parameter Calculation: Time-normalized Area under the 
Curve (AUC) for FEV1 measured over 12 hours ........................................................31 
6.8. 
Handling of Missing Data ...........................................................................................32 
6.8.1. 
Missing Pharmacodynamics Endpoints ......................................................................32 
6.8.2. 
Missing Start and Stop Dates for Prior and Concomitant Medication .......................32 
6.8.3. 
Missing Start and Stop Dates for Adverse Events ......................................................32 
7. 
STUDY POPULATION .............................................................................................35 
7.1. 
Overview of Planned Analyses ...................................................................................35 
7.2. 
Subjects Disposition ...................................................................................................35 
7.3. 
Screen Failures ............................................................................................................36 
7.4. 
Protocol Deviations ....................................................................................................36 
7.5. 
Demographic Characteristics ......................................................................................36 
7.6. 
Listing of Subject Inclusion and Exclusion Criteria ...................................................37 
7.7. 
Medical History and Medical Conditions Present at Entry ........................................37 
7.8. 
Prior and Concomitant Medication .............................................................................37 
7.9. 
Total Duration of Therapy, Average Daily Dose, Maximum Daily Dose, 
Final Daily Dose of Study Medication, and Compliance ...........................................39 
8. 
PHARMACOKINETICS ...........................................................................................40 
8.1. 
Overview of Pharmacokinetic Analyses .....................................................................40 
8.2. 
Presentation of PK Data, Descriptive Statistics and PK Assessment .........................40 
8.3. 
Statement of the Null and Alternative Hypotheses .....................................................42 
8.4. 
Analysis of the Primary Pharmacokinetic Endpoints .................................................42 
8.5. 
Exploratory Analysis ..................................................................................................42 
9. 
PHARMACODYNAMICS ........................................................................................44 


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9.1. 
Overview of Pharmacodynamics Analyses ................................................................44 
9.2. 
General Considerations ...............................................................................................46 
9.3. 
Testing Statistical Assumptions Including Comparability at Baseline .......................46 
9.4. 
Statement of the Null and Alternate Hypotheses ........................................................46 
9.5. 
Multiple Comparisons and Multiplicity......................................................................46 
9.6. 
Analysis of the Primary Pharmacodynamics Endpoint ..............................................47 
9.6.1. 
Primary Pharmacodynamics Analysis ........................................................................47 
9.6.2. 
Sensitivity Analyses of the Primary Pharmacodynamics Results ..............................47 
9.6.3. 
Exploratory Analysis ..................................................................................................50 
9.7. 
Analysis of the Secondary Pharmacodynamics Endpoints .........................................51 
9.8. 
Subgroup Analyses .....................................................................................................52 
9.9. 
Summary of Reasons for Efficacy Non-Evaluability /Exclusion from 
Efficacy Analyses .......................................................................................................52 
10. 
SAFETY AND TOLERABILITY ..............................................................................53 
10.1. 
Overall Summary of Tolerability ................................................................................53 
10.2. 
Adverse Event Preferred Term and Body/Organ System Summary Tables ...............54 
10.2.1. 
Summaries of Adverse Event for All Subjects ...........................................................54 
10.2.2. 
Missing and Partial AE Onset Dates ..........................................................................55 
10.2.3. 
Summaries of Serious Adverse Events (SAE), Adverse Event Dropouts, and 
Death ...........................................................................................................................55 
10.3. 
Concomitant and Other Medications ..........................................................................55 
10.4. 
Laboratory Data ..........................................................................................................56 
10.5. 
Vital Signs ..................................................................................................................56 
10.6. 
Electrocardiogram (ECG) ...........................................................................................56 
10.7. 
Physical Examination .................................................................................................57 
10.8. 
Study Termination Status ...........................................................................................57 
10.9. 
Changes from Protocol ...............................................................................................57 
11. 
REFERENCES ...........................................................................................................59 
12. 
APPENDIX.................................................................................................................60 
12.1. 
Table of Contents for Data Display Specifications ....................................................60 
12.2. 
Data Display Specification .........................................................................................65 


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LIST OF TABLES 
Table 1:  List of Abbreviations ......................................................................................................12 
Table 2:  GSP304 ...........................................................................................................................17 
Table 3:  Other Study Drugs ..........................................................................................................18 
Table 4:  Baseline...........................................................................................................................25 
Table 5:  Visits (Days) ...................................................................................................................26 
Table 6:  Plasma Pharmacokinetic Parameters (Day 1) .................................................................27 
Table 7:  Plasma Pharmacokinetic Parameters (Day 21) ...............................................................27 
Table 8:  Urine Pharmacokinetic Parameters (Day 1 and Day 21) ................................................28 
Table 9: Overview of Planned Study Population Analyses ...........................................................35 
Table 10: Overview of Pharmacokinetic Analyses ........................................................................40 
Table 11: Overview of Pharmacodynamics Analyses ...................................................................44 
Table 12: Overview of Planned Safety Analyses ..........................................................................53 
 
  


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1. 
LIST OF ABBREVIATIONS 
Table 1:  List of Abbreviations 
Abbreviation 
Term 
AE 
Adverse Event 
AIC 
Akaike Information Criteria 
ANOVA 
Analysis of Variance 
AUC 
Area Under the Plasma Concentration-time Curve 
AR 
Auto Regressive   
BLQ 
Below the Limit Quantification  
BMI 
Body Mass Index 
CI 
Confidence Interval 
CV 
Coefficient Variation  
COPD 
Chronic Obstructive Pulmonary Disease 
CRF 
Case Report Form 
CS 
Compound Symmetry 
CSR 
Clinical Statistical Report 
CTCAE 
Common Terminology Criteria for Adverse Events  
ECG 
Electrocardiogram   
EDC 
Electronic Data Collection 
eCRF 
Electronic Case Report Form 
EDTA 
Ethylenediaminetetraacetic Acid 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practices 
GFR 
Glomerular filtration rate 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
IRB 
Institutional Review Board 
J2R 
Jump to Reference  
LLOQ 
Lower Limit of Quantitative  
MMRM 
Mixed-effect Model Repeated Measure 
MedDRA 
Medical Dictionary for Regulatory Activities Terminology 
PD 
Pharmacodynamics 
%CV 
Coefficient of Variation 


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PK 
Pharmacokinetics 
PKAS 
Pharmacokinetics Analysis Set 
PP 
Per-Protocol Population 
PT 
Preferred Term 
QCD 
Quantitative Clinical Development  
QD 
Once Daily 
SD 
Standard Deviation 
SAE 
Serious Adverse Event 
SAF  
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TOEP 
Toeplitz 
VC 
Variance Components 
 


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2. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide details of the planned statistical 
methodology for the analysis of the study data. The SAP also outlines the statistical 
programming specifications for the tables, listings and figures. 
This SAP describes the study endpoints, derived variables, anticipated data transformations and 
manipulations, and other details of the analyses not provided in the study protocol. This SAP 
therefore outlines in detail all other aspects pertaining to the planned analyses and presentations 
for this study. 
The following documents were reviewed in preparation of this SAP: 
Protocol Revision Chronology: 
Protocol 1.0 
11-Oct-2016 
Original 
Protocol 2.0 
05-Jan-2017 
Amendment 1 
Protocol 3.0 
11-Apr-2017 
Amendment 2 
This SAP was developed in accordance with ICH E9 guideline. All decisions regarding final 
analysis, as defined in this SAP document, will be made prior to Database Lock (unblinding) of 
the study data. Further information can be found in the protocol. 
 
 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
 
3.1. 
Study Objectives 
3.1.1. 
Primary Objective 
The primary objectives are: 
 To assess the relative bioavailability of GSP304 (tiotropium bromide) Inhalation Solution at 
dose levels of 10 μg, 20 μg, and 40 μg QD compared with Spiriva® Respimat® inhalation 
spray (5 μg QD) in subjects with COPD. 
 To characterize the dose response of GPS304 at dose levels of 10 μg, 20 μg, and 40 μg QD 
with respective PD.  
3.1.2. 
Secondary Objective 
The secondary objective is to assess the safety and tolerability of GSP304 at dose levels of 
10 μg, 20 μg, and 40 μg QD.  
3.2. 
Study Endpoints 
3.2.1. 
Primary Endpoints 
The primary endpoints are:  
 The PK endpoints for tiotropium in plasma to assess the relative bioavailability are: 
− Peak concentrations during the dosing interval at steady-state (CmaxSS) 
− Area under the plasma concentration-time curve over the dosing interval at steady state  
     (AUC0-tauSS) 
 Change from baseline (Day 1) at Day 21 (Week 3) in trough FEV1 response at approximately 
24 hours after the last dose (average of 23 hours 15 minutes and 23 hours 45 minutes 
post-dose measurements), in comparison with GSP304 placebo 
3.2.2. 
Secondary Endpoints 
The secondary endpoints are:  
 Amount (Aetau) and fraction of dose of tiotropium (Fe) excreted in urine over the dosing 
interval on Day 1 and Day 21 
 Peak concentrations during the dosing interval (Cmax) on Day 1 
 Area under the plasma concentration-time curve over the dosing interval (AUC0-tau) on Day 1 


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 Time of peak drug concentration over the dosing interval (tmax) on Day 1 and Day 21  
 Average concentration during a dosing interval at steady state (CavSS) on Day 21 
 Accumulation ratio (Rac)    
 Change from baseline in peak FEV1 within 12 hours post-dose on Day 1 and Day 21 
 Change from baseline (Day 1) at Day 21 (Week 3) in trough FEV1 response at approximately 
24 hours after the last dose (average of 23 hours 15 minutes and 23 hours 45 minutes 
post-dose measurements), in comparison with GSP304 placebo 
 Change from baseline in time-normalized area under the curve for FEV1 measured over 12 
hours on Day 1 and Day 21  
 Time to onset of response, defined as at least 12% and 200 mL increase in FEV1 within 12 
hours of dosing on Day 1 
 Time to achieving steady state as measured by FEV1 trough assessments 
 Time to achieving steady state as measured by FVC trough assessments 
 
3.2.3. 
Safety Endpoints 
 
The safety endpoints are: 
 
 Vital signs, laboratory parameters, 12-lead ECG 
 Incidence of all AEs 


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4. 
STUDY DESIGN 
4.1. 
Summary of Study Design 
 
This is a phase 2, randomized, parallel group, active-and placebo-controlled, 5-arm study to 
compare the PK profile of 3 blinded doses of GSP304 with open label Spiriva® Respimat®. The 
study will also evaluate the dose response PD profile of 3 blinded doses of GSP304 compared 
with blinded GSP304 placebo, using spirometry in subjects with mild to moderate COPD. 
The study will consist of a screening period of up to 2 weeks, followed by a 2-week run-in 
period, a 3-week treatment period, and a 2-week post treatment follow-up period.  The total 
duration of study participation will be approximately 9 weeks. 
A total of 155 male and female subjects will be randomized in a 1:1:1:1:1 ratio to 1 of 5 
treatment arms. A subject will receive 1 of the 3 double-blind doses of GSP304, or double-blind 
GSP304 placebo, or open-label Spiriva® Respimat®. 
4.2. 
Definition of Study Drugs 
Table 2 and Table 3 provide a description of the double-blind GSP304, double-blind GSP304 
placebo, and the open label Spiriva® Respimat® comparator to be used in the study.  
Table 2:  GSP304 
Product name: 
GSP304 
GSP304 
GSP304 
Dosage Form: 
Inhalation solution  
Inhalation solution  
Inhalation solution  
Unit Dose 
10 μg 
20 μg 
40 μg 
Route of Administration 
Oral inhalation  
Oral inhalation 
Oral inhalation 
Method of Administration 
Nebulization 
Nebulization 
Nebulization 
Physical Description  
A clear solution in a 
semitransparent, soft 
plastic ampule 
A clear solution in a 
semitransparent, soft 
plastic ampule 
A clear solution in a 
semitransparent, soft 
plastic ampule 
 
 
 
 
 


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Table 3:  Other Study Drugs 
 
Comparator Product 
GSP304 Placebo 
Product Name 
Spiriva® Respimat® 
Matching placebo for GSP304 
Dosage Form 
Inhalation spray for oral inhalation 
Inhalation solution 
Unit Dose 
2.5 μg 
0 μg 
Route of Administration 
Oral inhalation 
Oral inhalation 
Method of Administration 
Metered spray for inhalation 
Nebulization 
Physical Description 
A clear solution in a green/grey 
plastic Respimat® inhaler 
A clear solution in a semi-
transparent, soft plastic ampule 
Manufacturer 
Boehringer Ingelheim Pharma 
GmbH & Co 
Glenmark or designee 
 
4.3. 
Sample Size Considerations 
4.3.1. 
Sample Size Justifications 
 
A sample size of 28 subjects per treatment arm will have 90% power to detect a difference in 
mean change from baseline in trough FEV1 of 150 mL between GSP304 and GSP304 placebo 
assuming a 2-sided alpha of 5% and a standard deviation (SD) of 170 mL. These assumptions are 
based on available literature from similar studies conducted for Spiriva® Respimat® (Caillaud et 
al., 2007).  Given the overall 1:1:1:1:1 study treatment allocation ratio, 140 subjects are required 
for the analysis of the primary endpoint. Assuming a dropout rate of 10%, a total of 155 subjects 
(31 subjects per treatment arm) will be randomized.  
This sample size is also considered to be sufficient for the relative bioavailability endpoint. 
 
4.3.2. 
Sample Size Re-estimation 
No sample size re-estimation is planned for this study. 
4.4. 
Randomization 
Randomization and investigational product (IP) assignment will occur in the morning of Day 1 
after all screening procedures have been performed, run-in has been completed and eligibility of 
the subject for the study confirmed. Randomization numbers will be issued centrally using 
interactive voice response system (IVRS)/interactive web response system (IWRS). Randomized 


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subjects who terminate their study participation for any reason, regardless of whether study drug 
has been taken or not, will retain their randomization number. 
Subjects will be assigned in the ratio of 1:1:1:1:1 to receive treatments with either of double-
blind GSP304 at 1 of 3 dose levels, open-label Spiriva® Respimat®, or double-blind GSP304 
placebo based on a computer-generated randomization scheme that will be reviewed and 
approved by a statistician. The randomization scheme will be stored within the IVRS/IWRS 
database until unblinding of this study is requested. The randomization scheme and identification 
for each subject will be included in the final clinical study report for this study. 
4.5. 
Clinical Assessments 
 
The following clinical assessments will be performed during the study. 
1. Vital signs: vital signs will be taken at screening (Day -28 to -15), Day -1, Day 1 (1 hour 
pre-dose and 1 hour post-dose), Day 2, Day 7, Day 14 (1 hour pre-dose and 1 hour post-
dose), Day 20, Day 21 (post-dose), Day 22 (ie 24 hours after Day 21 dose), and Day 35 
(±2; ie 2 weeks follow-up after last dose date).  
2. Physical Examination: physical examination will be performed at screening (Day -28 to 
Day -15 (comprehensive physical examination)), Day -1 (ie, 24 hours before Day 1 dose), 
Day 7 (pre-dose), Day 14 (pre-dose), and Day 20 (pre-dose). 
3. 12 Lead Electrocardiogram (ECG): 12 lead ECG will be performed at screening (Day -28 
to Day -15), Day 1 (pre-dose) and Day 21 (pre-dose). 
4. Laboratory Tests: hematology, biochemistry, and urine analysis tests will be performed at 
screening (Day -28 to Day -15), Day 7 (pre-dose), Day 14 (pre-dose), Day 21 (pre-dose), 
and Day 35 (±2; ie 2 weeks follow-up after last dose date). Urine analysis for drugs of 
abuse and cotinine and blood alcohol tests will be performed on screening (Day -28 to 
Day -15), Day -1, and Day 20 (pre-dose).  Serum pregnancy testing will be performed in 
all female subjects on screening (Day -28 to Day -15), and urine pregnancy testing will 
be performed in female subjects on Day -1 and Day 35 (±2).  
5. Other safety assessments consisting of monitoring and recording all Adverse Events, 
serious adverse events (SAEs) and Concomitant Medications will be collected throughout 
the study. 
6. Pharmacodynamics: The spirometry test will be performed at screening (Day -28 to Day -
15), Day 1 (pre-dose -45 mins and -15 mins),   Day 7 (pre-dose -45 mins and -15 mins), 
Day 14 (pre-dose -45 mins and -15 mins), Day 21 (pre-dose -45 mins and -15 mins), and 
Day 22 (ie 24 hours after Day 21 dose). Pre-dose FEV1 and FVC will be assessed   at -45 
minutes and -15 minutes prior to dosing on Day 1, Day 7, Day 14, and Day 21. Trough 
FEV1 will be assessed on Day 22 (ie 24 hours after Day 21 dose). On Day 1 and Day 21, 


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FEV1 will be recorded, at the following time points after the morning dose: immediately 
post-dose at 5 minutes (±3 minutes), 15 minutes (±2 minutes), 30 minutes (±5 minutes), 
60 minutes, 90 minutes, and 2 hours (120 minutes); and post-dose at 4, 6, 8, 10, 12, 23 
hours 15 minutes and 23 hours 45 minutes post-dose. All post-dose timings are relative to 
the end of dosing (ie, end of nebulization of GSP304/GSP304 placebo or after the second 
actuation of Spiriva®Respimat®). The window for 1-hour spirometry and thereafter is ±5 
minutes.   
7. Pharmacokinetic Plasma and Urine Concentrations: Blood samples (approximately 6 mL) 
will be collected in dipotassium ethylenediaminetetraacetic acid (EDTA) coated 
vacutainers on Day 1 and Day 21 according to the below schedule: Pre-dose (0 hour), and 
2, 4, 6, 10, 15, 30, 45, 60, 75, and 90 minutes post-dose, as well as 2, 4, 6, 8, 12, 16, 20 
and 24 hours post-dose. All post-dose timings are relative to the end of dosing (ie, end of 
nebulization of GSP304/GSP304 placebo or after the second actuation of 
Spiriva®Respimat®).  The pre-dose sample on Day 1 should be collected within 30 
minutes prior to dosing while on Days 7, 14, and 21 the pre-dose sample should be 
collected within 10 minutes prior to the morning dose.  
On Day 1 and Day 21, samples will be collected within the following collection 
windows: 
 For the 2 minute sample, within a window of ±30 seconds 
 For the 4, 6, 10, 15, and 30 minute samples, within a window of ± 1 minute 
 For the 45, 60, 75, 90 minute, and 2.0 hour samples, within a window of ± 2 minutes 
 For the 4, 6, 8, 12, 16, 20 and 24 hour samples, within a window of ± 5 minutes. 
In addition, urine will be collected into pre-weighed containers at pre-dose (within 1 hour 
prior to dosing), and at the following intervals post-dose from 0-6, 6-12, and 12-24 hours 
on Day 1 and Day 21. 
Collection times and the accurate volume of urine will be noted. In each urine container, 
approximately 5 mL of 1M citric acid must be added prior to start of collection. Plasma 
and urine concentrations of tiotropium will be quantified by a validated liquid 
chromatography-mass spectrometry method.  
Plasma: Plasma PK parameters will be determined from plasma concentrations using 
non-compartmental methods for each subject. Actual collection times will be used for the 
analyses. 
Urine: Amount and fraction of dose of tiotropium excreted in urine during the collected 
time interval in individual subjects will be estimated. Nominal collection times and urine 
volumes will be used for the estimation. 
 


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5. 
PLANNED ANALYSES 
5.1. 
Interim Analyses 
No interim analyses are planned for this study. 
5.2. 
Final Analyses 
All planned analyses will be carried out once the clinical database lock (DBL) has taken place. 
Once this has been achieved, unblinding will occur and the analyses will be performed. 


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6. 
GENERAL CONSIDERATIONS FOR DATA ANALYSES AND 
HANDLING 
6.1. 
General Summary Table and Individual Subject Data Listing 
Consideration  
In general, listings will be sorted and presented by treatment and subject number.  Subject 
number when broken down consists of the site number and 4 digits sequential number. Study 
visits will be labeled as Screening, Baseline (Day 1), Day 2, Day 7, Day 14, Day 20 and Day 21 
as well as End of Study (Follow Up) and Unscheduled. When required, the time of the scheduled 
assessment will be included.  
The following treatment levels will be used for all tables, figures, and listings in the order below. 
Spiriva R will be used for Spiriva® Respimat® in tables, figures and listings for simplicity.  
GSP304 10 μg 
GSP304 20 μg 
GSP304 40 μg 
GSP304 Total  (AE/SAE-related tables) 
GSP304 Placebo  
Spiriva R 5 μg 
 
6.2. 
General Post Text Summary Table and Individual Subject Data 
Listing Format Considerations 
Tables, figures and listings are numbered following the ICH structure. Table headers, variables 
names and footnotes will be modified as needed following data analyses. Additional tables, 
figures and listings will be generated, as needed, following the data analysis (post-hoc).  
6.3. 
Data Management 
 
Data from the study will be managed by the Sponsor’s Clinical Research Operations group or 
designee. The Investigator will allow representatives of the Sponsor, regulatory agencies, and 
their designees to inspect all study documents (including, but not limited to, consent forms, IP 
accountability forms, IRB/IEC approvals) and pertinent hospital or clinic records for 
confirmation of data throughout and after completion of the study. Monitoring visits will be 


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conducted as needed during the course of the study. A complete review of source documentation 
of key efficacy and safety data will be conducted at each monitoring visit for verification that all 
information recorded in the CRF/eCRF accurately reflects the data recorded in the subject's 
source documents. 
All data verification, using hospital or clinic records, will be performed respecting subject 
confidentiality and will be carried out in accordance with SOPs.  
All subject data generated during the study will be recorded and transcribed into a database. The 
final authorization of the CRF/eCRF data is the Investigator Signature Form. This form must be 
approved by the Principal Investigator to signify that he/she has reviewed the CRF/eCRF, 
including all laboratory and safety assessments, and that all of the data therein is complete and 
accurate.   
The data will be reviewed to ensure that the forms were completed properly. 
Datasets will be prepared using headings from Clinical Data Interchange Consortium (CDISC) 
Study Data Tabulation Model (SDTM) implementation for human clinical trials and ADaM 
(Analysis Dataset Model). 
All tables, figures and listings will be produced using SAS® statistical software Version 9.3 or a 
later version, unless otherwise noted in a secure and validated environment.  Each output will be 
provided in PDF format, with all tables and listings also being produced in RTF format.   
All analyses will be performed using SAS® Version 9.3 in a secure and validated environment. 
All tables, figures and data listings to be included in the report will be independently checked for 
consistency, integrity and in accordance with standard PAREXEL procedures. 
6.4. 
Data Presentation Conventions 
 
Continuous data will be summarized in terms of the mean, SD, median, minimum, maximum, 
and number of observations, unless otherwise stated. Continuous data that are expected to be 
skewed will be presented in terms of the maximum, upper quartile, median, lower quartile, 
minimum, and number of observations.  The minimum and maximum will be reported to the 
same number of decimal places as the raw data recorded in the database.  The mean, median, 
lower quartile and upper quartile will be reported to one more decimal place than the raw data 
recorded in the database.  The SD will be reported to two more decimal places than the raw data 
recorded in the database.  In general, the maximum number of decimal places reported shall be 
four for any summary statistic. 
Categorical data will be summarized in terms of the number of subjects providing data at the 
relevant time point (n), frequency counts, and percentages.  Any planned collapsing of categories 
will be detailed in the corresponding sections of this SAP and within the data displays.  


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Percentages will be presented to one decimal place.  Percentages will not be presented for zero 
counts.   
Percentages will be calculated using n as the denominator. 
Changes from baseline in categorical data will be summarized using shift tables where 
appropriate. 
P-values greater than or equal to 0.001, in general, will be presented to three decimal places.  P-
values less than 0.001 will be presented as “<0.001” and p-values greater than 0.999 will be 
presented as “>0.999”.  
Confidence intervals will be presented to one more decimal place than the raw data. 
A table, figure, listing is to be generated for any required item where no data is available or 
reported, with either a table or listing stating “No Data Available” or “No Data Reported”, or 
print a one line message indicating there was no report data available: “NO DATA 
AVAILABLE FOR THIS REPORT”. 
6.5. 
Analysis Sets  
6.5.1. 
Full Analysis Set (FAS) 
This will include all subjects who are randomized, have received at least 1 dose of study 
medication and have at least 1 post-baseline PD assessment.  This analysis set will be the 
primary analysis set for the PD endpoints. 
6.5.2. 
Safety Set (SAF) 
  
This will include all subjects who are randomized and received at least 1 dose of study 
medication. All safety endpoints will use the SAF.  
6.5.3. 
Per-Protocol Set (PP) 
  
This will include all subjects who are randomized, received at least 1 dose of study medication, 
completed the study and do not have exclusionary major protocol deviations.  Major and 
exclusionary protocol deviations will be defined in section 7.3 and by clinical review prior to 
unblinding. 


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6.5.4. 
Pharmacokinetic Set (PKAS) 
 
This will include all subjects who are randomized, received at least 1 dose of study treatment and 
have at least 1 quantifiable PK sample and do not have exclusionary major protocol deviations.  
The PKAS will be used to analyze the PK endpoints unless otherwise specified in this SAP.  
Major and exclusionary protocol deviations will be defined in section 7.3 and by clinical review 
prior to unblinding. 
Subjects or data may be excluded from the PKAS at the discretion of the PK Scientist upon 
consultation with the sponsor. Any data excluded will be discussed in the CSR. Any excluded 
subject will have his or her concentration and PK parameter data (if available) listed only. 
Subjects who receive placebo will not be part of the PKAS. The PKAS will be used for all tables 
and graphical summaries of the PK data 
6.6. 
 Baseline Definition  
The Baseline value will be defined as the Visit 3 (Day 1) measurement.  If this measurement is 
not available, the Visit 1 (D-28 to D-15) measurement will be used as the baseline value.  Table 
4 below contains a list of definitions of PD parameters and baseline of parameters covered in this 
SAP.  
Table 4:  Baseline 
Parameter 
Definition  
Baseline 
Peak FEV1 
Maximum FEV1 over the period of 12 
hours post-morning dose. 
Average of the pre-dose FEV1 
measured at -45 minutes and -15 
minutes at Day 1 
Trough FEV1  
Mean FEV1 obtained 23 hours 15 
minutes and 23 hours 45 minutes post-
morning dose of the previous day. 
Average of the pre-dose FEV1 
measured at -45 minutes and -15 
minutes at Day 1 
Time-normalized Area Under the 
Curve FEV1 
 
Average of the pre-dose FEV1 
measured at -45 minutes and -15 
minutes at Day 1 
FVC 
Amount of air which can be forcibly 
exhaled from the lungs after taking the 
deepest breath possible 
 
Mean FVC obtained 23 hours 15 
minutes and 23 hours 45 minutes post-
morning dose of the previous day. 
The baseline assessment is the 
average of the pre-dose FVC 
measured at -45 minutes and -15 
minutes at Day 1 
Laboratory Parameters 
(hematology, blood chemistry, 
liver function and urinalysis) 
 
Screening (Day -28 to Day -15). 
Vital Signs 
 
 
Day 1 (1hr pre-dose) 


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Parameter 
Definition  
Baseline 
ECG 
 
Day 1 (pre-dose) 
Physical Examinations  
 
Day -1 
 
6.7. 
Derived and Transformed Data 
6.7.1. 
Age  
Age is the subject’s age in complete years – calculated based on the informed consent date and 
subject’s date of birth.  
If the month and day of informed consent is on or after the month and day of birth:   
           Age = year of informed consent – year of birth 
If the month and day of informed consent is before the month and day of birth: 
            Age = year of informed consent – year of birth – 1 
6.7.2. 
Study Day 
If the date of interest occurs on or after the randomization date: 
Study day = date of interest – randomization date + 1 
If the date of interest occurs before the randomization date: 
 
Study day = date of interest – randomization date 
There is no study day 0. 
6.7.3. 
Change from Baseline 
 
Change from baseline will be calculated by subtracting the baseline measurement from the post 
baseline measurement.  
Change from baseline = post baseline measurement – baseline measurement. 
6.7.4. 
Visits 
Table 5 contains a list of visits in the study period. Data will be analyzed based on the nominal 
visit/time. 
Table 5:  Visits (Days) 
Visit 
Scheduled Day 
Days  
Visit 1 (Screening) 
-15 
-28 to -15 
Visit 2 (Run-in) 
-14 
-14 to -2 


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Visit 3 (Baseline) 
1 
-1 to 2* 
Visit 4 (Week 1) 
7 
  
Visit 5 (Week 2) 
14 
  
Visit 6 (Week 3) 
21 
20 to 22* 
Visit 7 (Follow-up) 
35 
33 to 37 
*: Subjects will stay in the clinic as in-patients for about 36 to 48 hours at Visit 3 and Visit 6. 
6.7.5. 
Unscheduled Assessments 
Unscheduled assessments (laboratory data, ECG or vital signs associated with non-protocol 
clinical visits or obtained in the course of investigating or managing adverse events) will be 
included in listings, but not in summaries. If more than one assessment is available for a given 
visit, the first or most valid observation will be used in summaries presented in listings and other 
assessments will be classed as unscheduled measurement. 
6.7.6. 
Pharmacokinetic Parameters    
Derivation of PK parameters will be the responsibility of Early Phase, Quantitative Clinical 
Development (QCD), PAREXEL International and will be conducted either with Phoenix 
WinNonlin® Professional v. 6.3 (or higher) or SAS® v.9.3 (or higher).  The PK parameters in 
Table 6 will be determined for Tiotropium in plasma after administration of the first dose: 
Table 6:  Plasma Pharmacokinetic Parameters (Day 1) 
Parameter  
 Definition 
AUC0-tau   
Area under the concentration-time profile over the dosing interval 
Cmax   
Peak concentrations during the dosing interval  
tlast 
Time of last quantifiable concentration 
tmax   
Time of peak drug concentration 
The PK parameters in Table 7 will be determined for Tiotropium in plasma following multiple 
dose administration (Day 21). The terminal elimination half-life will be reported only if data 
permit a reliable estimation. 
Table 7:  Plasma Pharmacokinetic Parameters (Day 21) 
Parameter  
 Definition 
AUC0-tauSS 
Area under the concentration-time profile over the dosing interval at steady state 
AUC0-tauSS/Dose 
Dose normalized area under the concentration-time profile over the dosing interval at steady 
state 
CavSS 
Average concentration during a dosing interval at steady state 
CmaxSS  
Peak concentrations during the dosing interval at steady-state 
CmaxSS/Dose 
Dose normalized peak concentration during the dosing interval at steady state 


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CminSS   
Minimum of trough concentrations during the dosing interval at steady-state 
Rac 
Accumulation ratio for Cmax and AUC 0-tau 
t1/2   
Terminal elimination half-life  
tlast 
Time of last quantifiable concentration 
tmax   
Time of peak drug concentration 
The PK parameters in Table 8 will be calculated for Tiotropium Bromide in urine following 
treatment administration (Day 1 and Day 21): 
Table 8:  Urine Pharmacokinetic Parameters (Day 1 and Day 21) 
Parameter  
 Definition 
Aetau   
Cumulative amount of unchanged drug excreted into the urine over the dosing interval 
Aetau/Dose 
Dose normalized cumulative amount of unchanged drug excreted into the urine over the dosing 
interval 
Fe% 
Fraction of dose (%) excreted into the urine over the dosing interval 
 
6.7.6.1. 
Handling of Values Below the Limit of Quantification 
All plasma/urine concentrations below the lower limit of quantification (LLOQ) or missing data 
will be labeled as below the limit of quantification (BLQ) or missing, respectively, in the 
concentration data listings. 
Considerations in the handling of BLQ data for the generation of plasma PK Parameters 
and for plotting of individual plasma PK concentration data 
BLQ values will be imputed in the PK concentration dataset used for the derivation of PK 
parameters. The following rules will be applied: 
 BLQs at the beginning of a subject profile (ie before the first incidence of a 
measurable concentration on the first day of dosing) will be assigned to zero; 
 BLQs at the end of a subject profile (ie after the last incidence of a measurable 
concentration on last day of dosing) will be set to missing; 
 Single or consecutive BLQs which fall between measurable concentrations will be set 
to missing. 
 Quantifiable concentrations falling between two BLQ values might be set to missing 
if considered anomalous by the PK Scientist after consultation with the sponsor.  
For linear plots, zero concentration value(s) will be included in the plot while missing values will 
be ignored. For log-linear plots, zero concentration value(s) will be assigned a ½ LLOQ value 
with the exception of the pre-dose sample collected on Day 1 while missing concentrations at the 
end of the profile will be ignored.   


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Considerations in the handling of BLQ data for summarizing plasma PK concentration 
data 
BLQ values will be imputed for mean concentration-time plots and tabular summaries according 
to the following rules: 
 All BLQ values will be set to zero, except when an individual BLQ falls between two 
measurable values or one or more BLQs fall at the end of a subject profile, in which 
case  they will be set to missing; 
 Mean values will be reported only if calculated on a minimum of 3 quantifiable 
concentrations. The number of subjects contributing to the calculation of the mean 
will be specified in a footnote to the mean plots (both in linear and semi-log scales) if 
lower than the total amount of samples available per time point; 
A high proportion of BLQ values may affect derivation of SD; if more than 30% of values at a 
time-point are imputed, then SD will not be displayed. 
Tabular summaries for concentration-time data will report N (number of subjects who received 
treatment), n (number of subjects with non-missing values) and, if applicable, number imputed 
(number of subjects with imputed values (ie, BLQ assigned zero concentration). 
Considerations in the handling of BLQ data for summarizing urine PK concentration data 
 For instances in which the subject did not void during the specified interval and ‘NS’ 
is present in the listing, the concentration value will be set to missing.   
Considerations in the handling of missing data for the generation of urine PK Parameters 
 For instances in which the subject did not void during the specified interval the 
concentration will be set to zero to allow calculation of urine PK parameters. 
6.7.6.2. 
Pharmacokinetic Parameters Calculation Methods 
PK parameters will be calculated by non-compartmental analysis methods from the 
concentration-time data following these guidelines: 
 Actual sampling times relative to dosing rather than nominal times will be used in the 
calculation of all derived PK parameters; 
 There will be no imputation of missing data;  
 Any subjects with missing concentration data will be included in the PK analysis set 
provided that at least CmaxSS and/or AUC0-tauSS can be reliably calculated. A decision 
will be taken on a case by case basis by the PK Scientist after consultation with the 
sponsor; 
 Cmax and CmaxSS will be obtained directly from the concentration-time data; 


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 tmax is the time at which Cmax or CmaxSS is observed; 
 λZ will be estimated at terminal phase by linear regression after log-transformation of 
the concentrations: 
o Only those data points that are judged to describe the terminal log-linear 
decline will be used in the regression  
o A minimum number of three data points in the terminal phase will be used in 
calculation λz with the line of regression starting at any post -Cmax data point 
(Cmax should not be part of the regression slope). The adjusted correlation 
coefficient (R2 adjusted) in general should be greater than 0.80.  
o The interval used to determine λz should be equal or greater than 1.5-fold the 
estimated half-life or otherwise flagged and used at the PK scientist’s best 
knowledge and judgment. The corresponding estimated t1/2 will need to be 
flagged or excluded from statistical analysis accordingly.  
 t1/2 will be calculated as ln2/λZ; 
 CavSS will be calculated as AUC0-tauSS/tau; 
 AUC0-tau and AUC0-tauSS will be calculated using the linear up/linear down method; 
 CminSS will be obtained directly from the concentration-time data. In the event of a 
minimum concentration during the dosing interval at steady state (CminSS) not 
coinciding with the pre-dose concentration at steady state (Ctrough on day 21), both 
parameters will be reported; 
 Rac(AUC) will be calculated as AUC0-tauSS/AUC0-tau;  
 Rac(Cmax) will be calculated as CmaxSS/Cmax; 
 Aetau is the cumulative amount excreted over the dosing interval and will be 
calculated as the sum of the products of concentration and urine volume over the 
appropriate collection intervals. For the calculation of urine PK parameters the 
protocol time intervals should be used. If a subject urinates into the toilet or a urine 
sample is lost any other way, or if no urine volume has been recorded for a sampling 
interval, the cumulative amount excreted starting with this interval cannot be 
calculated. If, however, a subject is unable to urinate, no amount excreted has been 
lost and the cumulative amount can continue to be calculated past that collection 
interval. For the affected time interval, the partial amount will be zero; 
 Fe% is the fraction of unchanged drug in urine expressed as a percentage and will be 
calculated as Fe%=(Aetau/Dose)*100.  
 
If tlast (last time point with measurable concentration) is before 24 hour post-dose in more than 


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50% of treated subjects s at any particular dose of GSP 304 or Spiriva® Respimat®, AUClast (area 
under the plasma concentration time curve from time zero to last time point with measurable 
concentration) may be estimated and compared between different doses of GSP 304 and Spiriva® 
Respimat® by ANOVA. 
 
Any inconsistency between plasma and urine PK would be will be further investigated and might 
be flagged and/or excluded from the analysis at the discretion of the PK Scientist after 
consultation with the sponsor. 
An exploratory PK/ glomerular filtration rate (GFR) analysis of GSP304 in urine and plasma 
may be performed if deemed appropriate following review of the summary PK and GFR data. 
The decision to perform this analysis will be made by the Sponsor upon review of the tables, 
figures and listings produced at the end of the study. If the decision is made not to proceed with 
the PK/ GFR analysis, this section of the SAP will not be applicable and the outputs described 
herein will not be presented. 
6.7.7. 
Pharmacodynamics Parameter Calculation: Time-normalized Area under the 
Curve (AUC) for FEV1 measured over 12 hours 
 
Time-normalized Area under the Curve (AUC) for FEV1 measured over 12 hours is defined as 
the area between baseline FEV1 and the FEV1 curve from 0 to 12 hours divided by 12 hours.   
12 hour serial spirometry will be performed at Day 1 and Day 21 of each treatment period: 
spirometry will be performed immediately at 5 minutes (±3 minutes), 15 minutes (±2 minutes), 
30 minutes (±5 minutes), 60 minutes, 90 minutes, and 2 hours (120 minutes); and post-dose at 4, 
6, 8, 10, 12, 23 hours 15 minutes and 23 hours 45 minutes. 
 
AUC is calculated from zero time to 12 hours (AUC0-12), using the trapezoidal method, divided 
by 12 hours to give the  AUC0-12/12h values in litres.  Non-missing FEV1 values at the following 
time points are required in order to calculate the normalised AUC0-12/12h: pre-dose; at least one 
value between 2 hours and 6 hours post-dose (inclusive); and at least one value after 6 hours 
post-dose. Otherwise the normalised AUC0-12/12h will be missing.   
 
AUC0-12/12h is calculated as follows: 
AUC0−12/12ℎ= 
1
𝑡11 −𝑡0
∑(𝑡𝑖−𝑡𝑖−1)(𝑑𝑖+ 𝑑𝑖−1)
2
11
𝑖=1
 
 
Where di is the spirometry value (FEV1) obtained at time ti; ti is the time (in hours) for which di 
is measured: t0 = 0, t1 = 0.08, t2 = 0.25, t3 = 0.5, t4 = 1, t5 = 1.5, t6 = 2, t7 = 4, t8 = 6, t9 = 8, t10 = 10   
and t11 = 12. d0 is the mean of the two pre-dose values at Day 1 or Day 21.  


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6.8. 
Handling of Missing Data 
6.8.1. 
Missing Pharmacodynamics Endpoints 
No explicit imputation for missing pharmacodynamics endpoints will be performed for this 
study. If either the baseline or the post-baseline result is missing, the change from baseline is set 
to missing. 
Section 9.6.2 describes the sensitivity analyses to be performed for the primary endpoint in 
handling missing data.  
6.8.2. 
Missing Start and Stop Dates for Prior and Concomitant Medication 
For the purpose of inclusion in prior and/or concomitant medication tables, incomplete 
medication start and stop dates will be imputed as follows: 
 If year and month are present and day is missing, then set day to first day of month 
for start date, and set day to last day of month for end date  
 If year and day are present and month is missing, then set month to January for start 
date, and set month to December for end date  
 If year is present and month and day are missing, then set month and day to January 1 
for start date, and set month and day to December 31 for end date  
 Completely missing date will not be imputed 
The partial dates will be provided as such in the subject data listings (with the imputed dates). 
When imputing a start date, ensure that the new imputed date is sensible ie is prior to the end 
date of prior and concomitant medications. 
 
6.8.3. 
Missing Start and Stop Dates for Adverse Events 
Due diligence will be done to obtain accurate AE information. If all planned methods to obtain 
accurate AE information have failed, missing and partial AE onset and end dates will be 
imputed. Imputed dates will be flagged in the individual supportive subject listings. Unless 
otherwise specified, the following conventions will be used: 
Missing and Partial AE onset dates 
 If onset date is completely missing, then onset date is set to date of first dose 
 If onset year is present and  
o month and day are missing: 
 If onset year = year of first dose, then set onset date to date of first dose 


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 If onset year < year of first dose, then set onset month and day to 
December 31st. 
 If onset year > year of first dose, then set onset month and day to January 
1st 
o month is missing: 
 If onset year = year of first dose, then set onset date to date of first dose 
 If onset year < year of first dose, then set onset month to December 
 If onset year > year of first dose, then set onset month to January 
 If onset month and year are present and day is missing: 
o If onset year = year of first dose and 
 onset month = month of first dose then set onset date to date of first dose 
 onset month < month of first dose then set onset date to last day of month 
 onset month > month of first dose then set onset date to 1st day of month 
o If onset year < year of first dose then set onset date to last day of month 
o If onset year > year of first dose then set onset date to 1st day of month 
 For all other cases, set onset date to date of first dose 
Missing and Partial AE end dates 
 If end date is completely missing, end date is not imputed and the AE is flagged as 
“ongoing” 
 If year is present and  
o month and day are missing 
 If year = year of last dose, then set end date to the date of last dose 
 If year < year of last dose, then set end month and day to December 31st 
 If year > year of last dose, then set end month and day to January 1st 
o month is missing 
 If year = year of last dose, then set end date to date of last dose 
 If year < year of last dose , then set end month to December 
 If year > year of last dose, then set end month to January 
 If month and year are present and day is missing: 
o If year = year of last dose and 


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 month = month of last dose then set day to day of last dose 
 month < month of last dose then set day to last day of month 
 month > month of last dose then set day to 1st day of month 
o If year < year of last dose, then set end date to last day of the month 
o If year > year of last dose, then set end date to 1st day of month 
 For all other cases, set end date to date of last dose 


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7. 
STUDY POPULATION 
7.1. 
Overview of Planned Analyses 
The analyses will be based on the SAF, unless otherwise specified. Table 9 provides an overview 
of the planned analyses and the associated study populations. 
Table 9: Overview of Planned Analyses and Study Populations Used 
Display Type 
Data Displays Generated 
Table 
Figure 
Listing 
Subject disposition 
Total   disposition  
Y[1] 
 
 
Protocol deviations   
Y[2] 
 
Y 
Summary of subjects in analysis population 
Y 
 
 
Subjects excluded from each analysis populations 
 
 
Y 
Demographic   Characteristics 
Y[3] 
 
Y 
Baseline Characteristics  
Y 
 
Y 
Medical History 
Y 
 
Y 
Summary of Chronic Obstructive Pulmonary Disease History  
Y 
 
Y 
Exposure 
Y[2] 
 
Y 
Treatment Compliance 
Y[2] 
 
Y 
Prior Medications 
Y 
 
Y 
Concomitant Medications 
Y 
 
Y 
Rescue Medications 
Y 
 
Y 
 
NOTES : 
 
Y = Yes display generated 
 
[1]: Data from clinic or database 
 
[2]: Display will be based on the SAF 
 
[3]: Display will be based on the SAF and repeated for the FAS, PP and PKAS 
 
7.2. 
Subjects Disposition 
A clear accounting of the disposition of all subjects who enter the study will be provided, from 
screening to end of study participation. Summaries of subject disposition presented by treatment 
arm and overall, will be provided as follows: 
 Number and percentage of subjects enrolled 
 Number and percentage of subjects randomized 
 Number and percentage of subjects in each of the SAF, FAS, PP, and PKAS 
 Number and percentage of subjects who withdrew early from the study (including 
reasons for early withdrawal) 


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By-subject listings of enrollment details, randomization details, visit dates, and withdrawal 
details (including reason for discontinuation and duration of treatment prior to discontinuation) 
will also be provided. 
7.3. 
Screen Failures 
Number and percentage of subjects who were screened for the study (enrolled subjects, ie, those 
who signed informed consent) and reasons for screen failure will be summarized.  
7.4. 
Protocol Deviations 
Deviations from the protocol including violations of inclusion/exclusion criteria will be assessed 
as ‘minor’ or ‘major’.  
Major deviations will lead to the exclusion of a subject from the PP population and the PKAS. 
Major deviations may lead to the exclusion of a subject from the PP population and the PKAS. 
Major protocol deviations and PP exclusions will be identified during the Blinded Data Review 
Meeting (BDRM) before database lock.  
 
Major protocol deviations may include: 
 Subjects who had their blinded randomization code broken. 
 Subjects with overall treatment compliance <80% or >120%. 
 Subjects who used prohibited medications (prior and/or concomitant) that may have 
significant influence on efficacy. 
 Subjects who did not satisfy the inclusion/exclusion that may have significant 
influence on efficacy. 
 Subjects not treated with the treatment assigned at randomization, but wrongly treated 
in another treatment group. 
A summary of protocol deviations, major protocol deviations and exclusionary major protocol 
deviations will be produced by treatment arm as well as by type of deviation will be provided. In 
addition, a by-subject listing of protocol deviations will be provided.   
7.5. 
Demographic Characteristics 
The following demographic characteristics will be summarized for subjects in the SAF, FAS, PP 
and PKAS populations by treatment arm: 
 Age (years, as a continuous variable) 
 Sex (Male, Female) 
 Race 


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 Ethnicity 
 Weight at screening (in kilograms) 
 Height at screening (in centimeters) 
 BMI at screening (in kg/m2) calculated at screening    
 Smoking Status at baseline 
 Chest X-Ray, CT Scan at baseline 
 Pregnancy Test  at baseline 
 COPD Exacerbation in the previous 3 months before screening at baseline 
Age will be calculated as the number of complete years between a subject’s birth date and the 
date of informed consent. 
Age will also be summarized in the following categories: 40 <=65 years and >65-85 years. All 
demographic data will be listed by treatment and subject. 
7.6. 
Listing of Subject Inclusion and Exclusion Criteria 
 
Subjects who failed any of the inclusion and exclusion criteria will be listed along with the 
reason. Any subject withdrawal during the study, along with the reason for withdrawal, will be 
documented in listings.   
Failed inclusion/exclusion criteria and withdrawal data will be listed by treatment and subject.  
7.7. 
Medical History and Medical Conditions Present at Entry 
Medical and surgical history, treatment history, current medical conditions and smoking status 
will be recorded at the Screening visit. Medical history will be coded by system organ class 
(SOC) and preferred term (PT) using the Medical Dictionary for Regulatory Activities 
(MedDRA™) Version 18.0 or later. Medical history data will be listed by treatment and subject. 
 
7.8. 
Prior and Concomitant and Rescue Medication  
Any medication (including over-the-counter medications) or therapy administered to the subject 
during the study (other than the study drug/treatment, starting at the date of informed consent)    
is considered a concomitant medication. All concomitant medications must be recorded in the 
EDC system. 
Rescue Medication(s) 


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Albuterol/salbutamol MDI will be permitted throughout the study as rescue medication and will 
be dispensed to the subjects at Visit 2 or at the start of washout (if the subject requires washout) 
and at subsequent scheduled visits as required, for self-administration as needed, at home. 
Subjects will be trained to abstain from using albuterol/salbutamol MDI, 6 hours prior to start 
ofeach visit. If this is not possible, the visit will need to be rescheduled. Any rescue 
medication(s) taken will be recorded in the subject diary and appropriate eCRFs. A summary 
showing the number of subjects who used rescue mediation at any time post randomization 
(based on the information reported in the subject diary) and a descriptive summary of the amount 
of rescue medication used (based on the information reported in the subject diary) will be 
provided by treatment arm, as change as from baseline in daily and weekly averages. A by-
subject listing of all rescue medication used, as reported on the patient diary, will also be 
provided. 
All concomitant medication will be coded using World Health Organization Drug Dictionary 
(WHO-DD) 1 June 2009.  
The following information must be recorded in the EDC system for each concomitant 
medication: preferred name or trade name, route of administration, start date, stop date, dose 
level, total daily dose, and indication. Any changes in the dosage or regimen of a concomitant 
medication must be recorded in the EDC system. 
Medications will be assigned to a time period (prior and/or concomitant) as follows: 
 If both the start and stop date exist and are before the first dose date of study drug, the 
medication will be counted as prior. 
 If the start date is on or after the first dose date of study drug, the medication will be 
counted as concomitant. 
 If the start date and stop date is on the first dose date of study drug, the medication 
will be counted as prior.  
 If the start date is before the first dose date of study drug and the stop date is after the 
first dose date of study drug or the medication is continuing, the medication will be 
counted as prior and concomitant.  
 If the start date is missing and the stop date is before the first dose of study drug, the 
medication will be counted as prior. 
 If the start date is missing and the stop date is after the first dose of study drug or the 
medication is continuing, the medication will be counted as concomitant. 
 If the start and stop dates are missing, the medication will be counted as concomitant. 
Summaries showing number of subjects and percentage taking each medication will be provided 
for each preferred medication term by treatment arm.  This will be done separately for prior and 


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for concomitant medications. A by-subject listing of all prior and concomitant medication data 
will also be provided. 
7.9. 
Total Duration of Therapy, Average Daily Dose, Maximum Daily 
Dose, Final Daily Dose of Study Medication, and Compliance 
 
The number of subjects exposed to each study treatment will be summarized.  
The number of days on treatment and the number of days on study (screening through to end of 
study/follow-up) will be summarized by study treatment.  
Treatment compliance will be calculated (the total number of doses actually taken / total number 
of doses expected*100). For subjects who have completed the study: 
 
Compliance Criteria 
Study Period 
Duration 
Scheduled Doses 
Not less than 
80% (doses) 
Not more than 120% (doses) 
Randomized Treatment 
21 Days 
21 
17  
25 
For subjects who are early terminated, treatment compliance will be determined from their 
duration in the study, up to the time they are considered early terminated. Subjects taking fewer 
than 80% or more than 120% of the required doses will be considered non-compliant with 
dosing.  
In addition, treatment compliance will be classified into four categories (<80%, ≥80% - ≤100%, 
>100% - <120%, ≥120%). Treatment compliance will be summarized by category and study 
treatment. 
 


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8. 
PHARMACOKINETICS  
 
8.1. 
Overview of Pharmacokinetic Analyses  
The pharmacokinetic analyses will be based on the PKAS, unless otherwise specified. Table 10 
provides an overview of the planned pharmacokinetic analyses. 
Table 10: Overview of Pharmacokinetic Analyses 
 
Stats Analysis 
Summary 
Individual 
T 
F 
T 
F 
L 
Plasma Concentrations on Day 1 and Day 21 
 
 
Y 
Y[1] 
Y 
Urine Concentrations on Day 1 and Day 21 
 
 
Y 
Y[1] 
Y 
Pharmacokinetic Parameters  on Day 1 and Day 21 
 
 
Y 
 
Y 
Primary Endpoints -PKAS 
Peak concentrations during the dosing interval at steady-state 
(CmaxSS) 
Y[ 2] 
Y  
Y 
 
  
Area under the plasma concentration-time curve over the 
dosing interval at steady state (AUC0-tauSS) 
Y[2] 
Y  
Y 
 
 
Exploratory Analysis   
Y[3]     
Y[4]   
 
 
 
 
NOTES : 
 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
 
Stats Analysis = Represents TF related to any formal statistical analyses (ie modeling) conducted. 
 
Summary = Represents TF related to summaries (ie descriptive statistics) of the baseline, post-treatment and change 
from baseline for the primary pharmacodynamics analyses method. 
 
Individual = Represents L related to any displays of individual subject observed raw data. 
 
[1] = mean graph and semi-log graph by treatment on Day 1 and Day 21; A spaghetti plot for plasma 
concentration 
 
[2] =ANOVA applied ; [3]= Power Model applied; [4] = Spaghetti plot and dose-proportionality plots for 
plasma and urine parameters  
 
8.2. 
 Presentation of PK Data, Descriptive Statistics and PK Assessment    
Pharmacokinetic plasma and urine concentration data will be listed by treatment, subject, day 
and actual sampling times relative to dosing for plasma data. Plasma and urine concentrations 
will be summarized by treatment, day and nominal time point. The following descriptive 
statistics will be presented for plasma and urine concentrations obtained at each nominal time 
point: n, arithmetic mean, SD, coefficient of variation (%CV), geometric mean, median, 
minimum and maximum values, where %CV = 100 × SD mean
⁄
. 
Plasma and urine pharmacokinetic parameters will be listed by treatment, subject and day and 
summarized by treatment and day. Descriptive statistics for calculated PK parameters will 
include: n, arithmetic mean, SD, %CV, geometric mean, geometric mean %CV, median, 
minimum and maximum values, where geometric mean %CV is the standard deviation of 


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logarithm of data expressed in anti-logarithmically as a percent (ie 100 × √exp( 𝑆𝐷2) −1).  For 
tmax and tlast , only median, minimum and maximum values will be presented. No descriptive 
statistics will be determined when fewer than three individual PK parameters are available. 
Combined individual plasma concentrations versus actual times will be plotted by treatment and 
day (spaghetti plots). 
For doses of GSP304, the arithmetic mean plasma concentration versus nominal times will be 
presented overlaid with the arithmetic mean profile of Spiriva®Respimat® by day both on linear 
and semi-logarithmic scales.  
The following rules will be followed with regards to the number of decimal places and 
presentation of data in the tables and listings of concentration data: 
 The individual concentrations will be reported to the same precision as the source 
data (for example, if the source data is presented to five significant digits, the 
individual values will be presented to five significant digits); 
 The mean, SD, geometric mean and median will be tabulated to one more significant 
digit compared to the source data, but with a maximum of four significant digits;  
 Minimum and maximum values will be tabulated to the same precision as the source 
data, but with a maximum of four significant digits; 
 Coefficient of variation (%CV) and geometric coefficient of variation will be 
presented to one decimal place. 
The following rules will be followed with regards to the number of decimal places and 
presentation of data in the tables and listings of PK parameters: 
 Individual PK parameters will be presented to four significant digits, with the 
exception of tmax, which will be presented to two decimal places.  In addition, 
parameters directly derived from source data (eg Cmax,) shall be reported with the 
same precision as the source data (if this is not four significant digits); 
 The mean, geometric mean, median and SD values will be reported to four significant 
digits, all other descriptive statistics will be reported to three significant digits except 
for %CV and the geometric %CV, which will be presented to one decimal place. For 
tmax the minimum and maximum will be presented to two decimals places and the 
rest of the descriptive statistics to three decimal places; 
 Estimates and confidence intervals in the form of percentages will be presented to 
two decimal places.  
Source data shall be used in all derived PK parameter calculations without prior rounding. 


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8.3. 
Statement of the Null and Alternative Hypotheses 
No formal hypothesis testing will be conducted for the primary pharmacokinetic endpoints.  
8.4. 
Analysis of the Primary Pharmacokinetic Endpoints 
The primary endpoint, AUC0-tauSS, and CmaxSS, will be analyzed using an analysis of variance 
(ANOVA) model. An ANOVA will be performed on the ln-transformed   AUC0-tauSS, and CmaxSS. 
The ANOVA model will include treatment as fixed effect. The results from the model will be 
back-transformed and the adjusted geometric means for each treatment and the estimated 
treatment ratios for the treatment comparisons will be presented together with 90% CIs. The 
ratios and corresponding 90% CIs will be expressed as a percentage. The following comparisons 
will be made: 
 GSP304 10 μg vs Spiriva® Respimat® 
 GSP304 20 μg vs Spiriva® Respimat® 
 GSP304 40 μg vs  Spiriva® Respimat® 
The statements of a SAS® PROC MIXED analysis would be: 
 PROC GLIMMIX   data=dataset; 
    CLASS subject dose;  
    MODEL log_normliased_pk_parameter= dose / ddfm=kr link=log;   
    RANDOM intercept /subject= subject; 
    ESTIMATE  'GSP1  vs  Spiriva' dose 1  0 0  -1 /cl alpha=0.1;  
    ESTIMATE  ‘GSP2  vs Spiriva'  dose 0  1 0 -1  /cl alpha=0.1; 
    ESTIMATE  ‘GSP3  vs Spiriva'  dose 0  0 1 -1  /cl alpha=0.1; 
    LSMEANS dose/diff cl ilink alpha=0.10  
RUN; 
The back-transformed and adjusted means for each treatment and the estimated treatment 
differences for the treatment comparisons will be presented together with 90% confidence 
intervals for the treatment comparisons. The adjusted means and estimated treatment differences 
for the treatment comparisons will also be plotted, with corresponding 90% confidence intervals. 
8.5. 
Exploratory Analysis   
 
Dose-proportionality  
Dose-proportionality of tiotropium CmaxSS and AUC0-tauSS parameters will be assessed using an 
ln-transformed power model: 
log𝑒 Yj =   α +  β log𝑒dosej + εj, 


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where Yj  = CmaxSS or AUC0-tauSS  at j th dose level. If β=0, then it implies that the response is 
independent from the dose and when β=1, dose-proportionality can be declared.  
 
A mixed effect model can be used to fit the Power Model. Estimates of the mean slopes of log-
transformed dose will be reported along with corresponding 90% CIs. If the 90% confidence 
interval for β is entirely contained within the a priori equivalence region, then dose 
proportionality is declared. If not, then dose non-proportionality is declared.  Dose 
proportionality will be declared if the estimate of slope lies between 0.5- 2. Dose proportionality 
will also be assessed based on amount of tiotropium excreted in urine.  Finally, dose normalized 
AUC0-tauSS and CmaxSS will also be evaluated across doses. Dose proportionality will be 
confirmed if the dose normalized parameters remain substantially constant in the range of 
explored doses. 
 
The statements of a SAS® PROC MIXED analysis would be: 
PROC MIXED data=dataset; 
CLASS subject; 
MODEL log_pk_parameter= log_dose/ ddfm=kr;  
RANDOM intercept log_dose /subject=subject type=UN gcorr s;   
ESTIMATE 'Logdose - 1 unit' log_dose 1/cl alpha=0.1;    
RUN; 
 
Duration of nebulization  
 
Upon review of the tables, figures and listings produced at the end of the study, an exploratory 
analysis may be performed to evaluate the effect of duration of nebulization on primary and/or 
secondary out comes if deemed appropriate following review of the summary data and 
nebulization times. The decision to perform this analysis will be made by the Sponsor. If the 
decision is made not to proceed, this section of the SAP will not be applicable and the outputs 
described herein will not be presented. 
  
 


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9. 
PHARMACODYNAMICS 
 
9.1. 
Overview of Pharmacodynamics Analyses  
The primary analysis of the primary pharmacodynamics endpoint will be performed on both the 
FAS (primary) and the PP (supportive) population. The secondary analysis of the primary 
pharmacodynamics endpoint will be performed on the FAS. The analysis of the secondary 
pharmacodynamics endpoint will be performed on the FAS. 
The primary endpoint is the change from baseline (Day 1) at Day 21 (Week 3) in trough FEV1 
response at approximately 24 hours after the last dose (average of 23 hours 15 minutes and 23 
hours 45 minutes post-dose measurements), in comparison with GSP304 placebo. 
  
Table 11 provides an overview of the planned primary pharmacodynamics analyses. 
Table 11: Overview of Pharmacodynamics Analyses 
 
Stats Analysis 
Summary 
Individual 
T 
F 
T 
F 
L 
Primary Endpoint - FAS     
Change from baseline (Day 1) at Day 21 (Week 3) in trough 
FEV1 response at approximately 24 hours after the last dose 
(average of 23 hours 15 minutes and 23 hours 45 minutes 
post-dose measurements) 
Y[1] 
Y 
Y 
 
Y- 
Perform on  PP 
Y[1] 
Y 
Y 
 
  
Sensitivity Analysis - Pattern-Mixture model 
Y 
 
 
 
 
Sensitivity Analysis - Tipping Point approach 
Y 
 
 
 
 
Exploratory Analysis    
Y  
Y 
 
 
 
Secondary Endpoints  - FAS 
Change from baseline in Peak FEV1 within 12 hours post-dose 
on Day 1 and Day 21 
Y[1] 
Y 
Y 
 
  
Change from baseline (Day 1) at Day 21 (Week 3) in trough 
FVC response at approximately 24 hours after the last dose 
(average of 23 hours 15 minutes and 23 hours 45 minutes 
post-dose measurements) 
Y[1] 
Y 
Y 
 
  
Change from baseline in time-normalized area under the curve 
for FEV1 measured over 12 hours on Day 1 and Day 21 
Y[1] 
Y 
Y 
 
  
Time to onset of response, defined as at least 12% and 200 
mL increase in FEV1 within 12 hours of dosing on Day 1 
 
 
Y 
Y 
 
Time to achieving steady state as measured by FEV1 trough 
assessments 
 
 
Y 
Y 
 
Time to achieving steady state as measured by FVC trough 
assessments 
 
 
Y 
Y 
 
 
NOTES : 
 
T = Table, F = Figure, L = Listing, Y = Yes display generated. 
 
Stats Analysis = Represents TF related to any formal statistical analyses (ie modeling) conducted. 


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 
Summary = Represents TF related to summaries (ie descriptive statistics) of the baseline, post-treatment and change 
from baseline for the primary pharmacodynamics analyses method. 
 
Individual = Represents L related to any displays of individual subject observed raw data. 
 
[1]: MMRM method applied  
 


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9.2. 
General Considerations 
All tests will be 2-sided and at 5% level of significance unless otherwise stated. 
In addition to the analyses described below, all endpoints will be summarized over time, by 
treatment, as appropriate. 
All endpoints will also be listed by treatment and subject. The interpretation of results from 
statistical tests will be based on the FAS. The PP population will be used to assess the robustness 
of the results from the statistical tests based on the FAS. Unless otherwise stated, ‘treatment’ 
refers to treatment group as randomized, rather than based on the actual treatment received.  
9.3. 
Testing Statistical Assumptions Including Comparability at Baseline 
All baseline data will be summarized by treatment group using descriptive statistics. No formal 
hypothesis testing will be conducted. Differences may occur by chance.  If there are any 
clinically meaningful differences identified, analyses may be adjusted to account for these 
imbalances through inclusion of additional covariates in the statistical models. 
The PD endpoints (FEV1, FVC) are assumed to be normally distributed and will be analyzed 
under this assumption.  The assumptions of normality and constant variance will be verified 
using diagnostic plots (normal quantile plots and scatter plots of residuals by treatment group).  
If assumptions are violated, either an appropriate transformation will be used or data will be 
analyzed using non-parametric methods. The methods use will be documented in the clinical 
study report. 
9.4. 
Statement of the Null and Alternate Hypotheses 
 
A significance test will be made for the primary pharmacodynamics endpoint in order to assess 
for superiority of GSP304 versus GSP304 placebo. Demonstration of superiority for this 
treatment comparison will be based on a hypothesis testing approach, whereby the null 
hypothesis is that there is no difference between treatment groups and the alternative hypothesis 
is that there is a difference between the treatment groups. 
A 2-sided 5% risk associated with incorrectly rejecting the null hypothesis (significance level) is 
considered acceptable for this study. 
9.5. 
Multiple Comparisons and Multiplicity 
As this is a phase 2 study, no adjustments for multiplicity are planned. The nominal p-values of 
all hypothesis tests will not be adjusted for multiplicity. 
 


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9.6. 
Analysis of the Primary Pharmacodynamics Endpoint 
9.6.1. 
Primary Pharmacodynamics Analysis 
 
The primary endpoint, change from baseline (Day 1) at Day 21 (Week 3) in trough FEV1 
response at approximately 24 hours after the last dose (average of 23 hours 15 minutes and 23 
hours 45 minutes post-dose measurements) will be analyzed using a mixed-effect repeated 
measures (MMRM) model. This model will assume that any missing data is Missing at Random 
(MAR). The model will include trough data from all visits (Days 1, 6, 13, 20 and Day 21),and 
fixed terms for treatment, visit, center, baseline, treatment by visit and baseline by visit 
interactions.  If an interaction term is significant, further ad-hoc analysis may be conducted. 
Subject will be included as a random term to account for the correlation between repeated 
measurements within a subject, and unstructured covariance structure will be used.   If the model 
fails to converge, alternative structures (VC, AR1, TOEP1, and CS) or removing terms will be 
investigated.  The covariance structure that provides the best fit (as determined by the smallest 
AIC value) will be used.   
The statements of a SAS® PROC MIXED analysis would be: 
PROC MIXED   data=dataset method= REML; 
    CLASS subject treatment center visit;  
    MODEL change = treatment center visit baseline treatment*visit   baseline*visit /s ddfm=kr;  
    REPEATED visit/subject=subject type=UN;  
    LSMEANS treatment*visit/at mean cl diff e;   
RUN; 
 
The adjusted means for each treatment and the estimated treatment differences for the treatment 
comparisons will be presented together with 95% confidence intervals, along with p-values for 
the treatment comparisons. The adjusted means and estimated treatment differences for the 
treatment comparisons (each GSP304 vs placebo, total GSP304 vs placebo, and Spiriva vs 
placebo) will also be plotted, with corresponding 95% confidence intervals. 
9.6.2. 
Sensitivity Analyses of the Primary Pharmacodynamics Results 
Sensitivity analyses will be performed on the FAS only. Subjects with at least one post-baseline 
assessment will be used in modeling.  
9.6.2.1. 
Pattern-Mixture Model 
 
The Mixed-effect Model Repeated Measure (MMRM) model will be fitted when some of the 
response values are missing by assuming that they are missing at random (MAR). This will be 
done computationally using Restricted Maximum-Likelihood (REML). However, this 


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assumption is unverifiable. It is necessary to perform sensitivity analyses under different 
assumptions regarding missing data. When the MAR assumptions do not hold, the data are 
assumed to be Missing Not At Random (MNAR). One possible way forward is to model a 
separate distribution for each pattern of missingness. A sensitivity analysis for missing data will 
be conducted based on multiple imputation-based methods with a form of pattern-mixture model 
(PMM).  
PMMs will be fitted based on multiple imputations method. In the multiple imputation approach, 
a model will be fitted to the incomplete data and a pseudo-independent sample drawn from the 
posterior distribution of parameters. Each member of the sample leads to a separate imputed 
dataset, in which the missing values will be replaced by values drawn randomly from their 
conditional distribution. This distribution is based on the observed data and the covariates for 
that subject using the imputation model and the sampled parameter values. Each dataset is then 
analyzed as if these were real data, leading to a series of estimates for a parameter. These are 
then combined to supply an overall estimate and standard error based on Rubin’s classic rules 
(Rubin, 1987) for combining across imputations. 
The primary endpoint will also be analyzed using a Jump to Reference (J2R) approach, that is, 
all the patterns have the same profile up to withdrawal (that estimated in the parameter 
estimation model), but after withdrawal the profile jumps to the estimated profile for the 
reference arm. Thisapproach is a multiple imputation technique and works under the assumption 
that data is missing not at random (MNAR).    
The J2R approach involves three distinct steps: 
1. The missing data are filled in m times to generate m complete data sets (m will be 
selected to provide sufficiently stable and reproducible results). 
 In J2R method, all the patterns have the same profile up to withdrawal (that 
estimated in the parameter estimation model), but after withdrawal the profile 
jumps to the estimated profile for the reference arm.  A new model is simulated 
from the posterior predictive distribution of the fitted model and missing values of 
the variable are imputed based on the new model.       
 The MNAR statement together with a MONOTON statement in PROC MI will be 
used. The variables that have missing values are imputed sequentially in each 
imputation. If the missing pattern is arbitrary, first the MCMC method will be 
used to partially impute data in order to obtain a monotone missing data pattern. 
2. The missing data are filled in m times to generate m complete data sets. The m complete 
data sets are analyzed by using a procedure. 
 ANCOVA analysis for change from baseline in trough FEV1 is performed using 
PROC MIXED with LSMEANS statement.  
3. Results of the ANCOVA analysis on m imputed datasets can be combined to derive an 
overall result. PROC MIANALYZE in SAS will be used to combine the results. 


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The adjusted means for each treatment and the estimated treatment differences for the treatment 
comparisons will be presented together with 95% confidence intervals for the differences and p-
values for the treatment comparisons. 
9.6.2.2. 
Tipping Point (Region) Approach  
The primary endpoint will also be analyzed using a special application of multiple imputation of 
missing values known as the tipping point method. The tipping point method assesses the 
possibility that subjects on active drug with missing values have worse outcomes than subjects 
on placebo. This sensitivity analysis involves multiple imputations and is also under the MNAR 
assumption in which one searches for a tipping point (region) that reverses the study conclusion.  
This approach is iterative in nature which tests how severe departures from MAR must be in 
order to overturn conclusions from the primary analysis.  If these departures from MAR in order 
to change the results from statistically significance (p<=0.05) to statistically insignificance 
(p>0.05) are deemed to be implausible, the results will be said to be robust to the departure from 
MAR assumption.   
The tipping point approach will be applied to the analysis of the primary endpoint using the 
MMRM.  In the MMRM, the dependent variable is change from baseline while the covariates are 
treatment, site, baseline value and study day as the within-subject effect. 
The imputation will be done on the missing cases of change from baseline values for GSP304 
treatment and Spiriva. Under the MNAR assumption, the imputed values for observations in the 
active treatment group and Spiriva, as well as placebo, will be adjusted directly using a shift 
parameter.  Missing values are imputed under the assumption that the distribution of the missing 
observations has a lower expected value than that of the observed only by a shift parameter 
value. The maximum shift parameter is set at 80 mL for being about 50% of treatment efficacy 
when assuming that a difference in mean change from baseline at the end of treatment in trough 
FEV1 between GSP304 and GSP304 placebo is 150 mL. The shift parameter will take on the 
values from -80 mL to 0 with increment of 20 mL as it is assumed that the tipping point that will 
reverse the study conclusion is those values.  If the tipping point is found to be between two 
increments on the given interval, a subsequent tipping point procedure will be performed using 
an interval on the neighborhood of the perceived tipping point finer increments for the shift 
parameter. If no tipping point is found, the shift parameter will be made more stringent and the 
process repeated.  
Implementing the tipping point approach includes the following steps with the first three steps 
being the standard multiple imputation (MI) steps using SAS:  
a) The missing data are filled in m times to generate m complete data sets using PROC MI.  
b) The m complete data sets are analyzed using PROC MIXED.  
c) The results from the m complete data sets are combined for the inference using PROC 
MIANALYZE.    


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d) Repeat the steps (a) to generate multiple imputed data sets with a specified shift 
parameter that adjusts the imputed values for observations in the active treatment and 
placebo groups. 
e) Repeat the step (b) for the imputed data sets with shift parameter applied. 
f) Repeat the step (c) to obtain the p-value to see if the p-value is still <=0.05. 
g) If needed, repeat the steps (d)-(f) with more stringent shift parameter applied until the p-
value >0.05. 
The iteration for each value of the shift parameter will be summarized in a table where the 
estimated treatment differences for the treatment comparisons will be presented together with 
95% confidence intervals for the differences and p-values for the treatment comparisons. 
9.6.3. 
Exploratory Analysis    
 
If appropriate, a dose response model will be fitted to the primary endpoint to estimate the dose 
response relationship.  Dose response models to be evaluated will include Emax (3-parameter) and 
linear models.  
 
The Emax model will be fitted as follows: 
 
 Endpoint = E0 + 
Emax Dose
Dose + ED50 +   𝜀 
 
where  E0  = Response at dose 0, Emax  = Maximum effect, ED50 = Dose at which 50% of the 
maximum effect is reached and  𝜀  = Residual error. 
 
The linear model will be fitted as follows: 
Endpoint = E0 +   βDose +   𝜀 
 
where E0 = Response at Dose 0, β  = slope and  𝜀  = Residual error 
 
Should these models not fit the data appropriately other models may be explored. For all of the 
models, baseline will be included as a covariate at E0. However, baseline may be fitted at ED50 
or Emax  for the Emax model depending on how the model fits the data best. Other covariates will 
be explored. Depending upon the adequacy of model fitting some parameters may need to be 
parameterized on the log scale (e.g. variance, ED50, Emax). The most appropriate model will be 
assessed visually, by evaluating the AIC and by looking at the residuals. To build confidence in 
the chosen model, the null model:  
Endpoint = E0  
 


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will also be fitted to the data and the p-value from a likelihood ratio test will be computed; i.e. 
the change in deviance (-2 Log Likelihood) between the chosen model and the null model will be 
compared to a chi-squared distribution with degrees of freedom equal to the difference in the 
number of parameters in the two models. 
 
Dose response model parameter estimates, along with corresponding 95% confidence intervals, 
from the final dose response model will be presented.   
9.7. 
Analysis of the Secondary Pharmacodynamics Endpoints 
 
The secondary endpoints are:  
 Change from baseline in peak FEV1 within 12 hours post-dose on Day 1 and 21 
 Change from baseline (Day 1) at Day 21 (Week 3) in trough FVC response at 
approximately 24 hours after the last dose (average of 23 hours 15 minutes and 23 
hours 45 minutes post-dose measurements) 
 Change from baseline in time-normalized area under the curve for FEV1 measured 
over 12 hours on Day 1 and 21 
 Time to onset of response, defined as at least 12% and 200 mL increase in FEV1 
within 12 hours of dosing on Day 1 
 Time to achieving steady state as measured by FEV1 trough assessments 
 Time to achieving steady state as measured by FVC trough assessments 
The change from baseline for the secondary pharmacodynamics endpoint of change from 
baseline (Day 1) at Day 21 (Week 3) in trough FVC response at approximately 24 hours after the 
last dose (average of 23 hours 15 minutes and 23 hours 45 minutes post-dose measurements) will 
be analysed using the same model as described above for the anlaysis of the primary endpoint.  
The change from baseline for the secondary pharmacodynamics endpoints of;  Change from 
baseline in peak FEV1 within 12 hours post-dose on Day 1 and 21 and change from baseline in 
time-normalized area under the curve for FEV1 measured over 12 hours on Day 1 and 21 will be 
analyzed using a mixed-effect repeated measures (MMRM) model. This model will assume that 
any missing data is Missing at Random (MAR). The model will include data from Day 1 and 
Day 21 and fixed terms for treatment, visit, center, baseline, treatment by visit and baseline by 
visit interactions.  If an interaction term is significant, further ad-hoc analysis may be conducted. 
Subject will be included as a random term to account for the correlation between repeated 
measurements within a subject, and unstructured covariance structure will be used.   If the model 
fails to converge, alternative structures (CS) or removing terms will be investigated.  The 
covariance structure that provides the best fit (as determined by the smallest AIC value) will be 
used.  The adjusted means for each treatment and the estimated treatment differences for the 


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treatment comparisons will be presented together with 95% confidence intervals, along with p-
values for the treatment comparisons. The adjusted means and estimated treatment differences 
for the treatment comparisons (each GSP304 vs placebo, total GSP304 vs placebo, and Spiriva 
vs placebo) will also be plotted, with corresponding 95% confidence intervals. 
For the secondary endpoint of time to onset of response of both a 12% and 200 mL increase from 
baseline in FEV1, the unadjusted mean change from baseline and unadjusted percent mean 
change from baseline will be summarized for day 1.  The unadjusted means will also be plotted 
over time, for day 1. For the secondary endpoints of time to steady state in FEV1 and FVC, the 
adjusted means from the MMRM model discussed above will be summarized by day (Days 1, 6, 
13, 20 and 21) and also plotted over time. 
 
9.8. 
Subgroup Analyses 
No subgroup analyses are planned for this study. 
9.9. 
Summary of Reasons for Efficacy Non-Evaluability /Exclusion from 
Efficacy Analyses 
The reasons for excluding subjects from the FAS and PP population will be listed by treatment 
and subject.  


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10. 
SAFETY AND TOLERABILITY 
 
10.1. 
Overall Summary of Tolerability 
The safety analyses will be based on the SAF, unless otherwise specified. 
Table 12 provides an overview of the planned analyses. 
Table 12: Overview of Planned Safety Analyses 
Display Type 
Data Displays Generated 
Table 
Figure 
Listing 
Adverse Events  
Overview  
Y 
 
 
Treatment Emergent AEs 
Y[1] 
 
Y 
Treatment-Related Emergent AEs 
Y 
 
Y 
Pre-Treatment Period AEs 
Y 
 
Y 
AEs Leading to Withdrawal 
 
 
Y 
SAEs 
Y 
 
Y 
Treatment Emergent SAEs 
Y 
 
Y 
Treatment-Related SAEs 
Y 
 
Y 
Laboratory  
Biochemistry 
Y[2]  
 
Y 
Hematology 
Y[2]  
 
Y 
Urinalysis 
Y[2]  
 
Y 
Pregnancy Test Results 
 
 
Y 
Other 
Vital Signs 
Y[3] 
 
Y 
ECGs 
Y[4] 
 
Y 
Physical Examination 
Y[5] 
 
Y 
 
NOTES : 
 
Y = Yes display generated. 
 
[1]: Display will also be produced by severity, by relationship to study treatment and leading to discontinuation  
 
[2]: Display will be produced separately for overall laboratory assessments (inc. change from baseline), 
potentially clinically significant laboratory results, and shift tables 
 
[3]: Display will be produced separately for overall summary (inc. change from baseline), potentially clinically 
significant results, and shift tables 
 
[4]: Display will be produced separately for overall summary (inc. change from baseline), potentially clinically 
significant ECGs, and shift tables 
 
[5]:Display will be produced separately for overall summary 
 
Safety will be assessed by evaluating AEs, SAEs, treatment related AEs and SAEs, vital signs, 
laboratory test results, ECG values, and physical examination findings.  The extent of exposure 
in each treatment group will be characterized according to the number of subjects exposed, the 
duration of exposure, and the dose to which they were exposed. All safety analyses will be 
performed on the SAF. 


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10.2. 
Adverse Event Preferred Term and Body/Organ System Summary 
Tables 
10.2.1. 
Summaries of Adverse Event for All Subjects 
 
For each AE, the following information is to be recorded; the start date, the stop date (or whether 
the AE is ongoing at study completion/discontinuation), the severity and the investigator 
relationship of the AE to study drug, the therapy for the AE, the action taken with study drug, 
and whether or not the AE is considered serious.  
Adverse events will be coded by system organ class (SOC) and preferred term (PT) using the 
Medical Dictionary for Regulatory Activities (MedDRA™) Version 18.0 or later.  
Treatment Emergent AEs (TEAEs) are defined as AEs (identified by PT) that begins or that 
worsens in severity after at least one dose of study treatment has been administered, and last upto 
the AE stop date or the follow-up visit or the last study participation day.  The number and 
percentage of subjects reporting at least one occurrence of a TEAE for each unique System 
Organ Class and Preferred Term will be tabulated by severity, and by the investigator 
relationship to study drug. For multiple occurrence of the same TEAE with the different severity, 
the TEAE with the highest severity will be tabulated. For multiple occurrences of the same 
TEAE with different relationship to study drug (related and not related), the TEAE will be 
tabulated as related. All TEAEs leading to discontinuation of treatment will also be tabulated. All 
AEs for all subjects will be presented in a data listing.  
Pre-Treatment AEs (PTAEs) are defined as AEs (identified by PT) that begin or that worsen in 
severity between study Day -14 and study drug administration, and last up to the AE stop date.    
 
The severity of AE is classified as follows:  
Mild 
The AE is a transient discomfort and does not interfere in a significant manner with the subject. 
The AE resolves spontaneously or may require minimal therapeutic intervention 
Moderate 
The AE produces limited impairment of function and may require therapeutic intervention. 
The AE produces no sequelae. 
Severe 
The AE results in a marked impairment of function and may lead to temporary inability to 
resume usual life pattern. 
  
The AE produces sequelae, which require (prolonged) therapeutic intervention. 
 
The relationship of AEs to study medication is classified as follows: 
 Not Related: A causal relationship between the study treatment and the AE is not a 
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 Related: A causal relationship between the study treatment and the AE is a reasonable 
possibility  
A COPD exacerbation is defined as worsening of the following 2 or more major symptoms for at 
least 2 consecutive days: dyspnea, sputum volume, and sputum purulence or a worsening of any 
1 major symptom together with an increase in any 1 of the following minor symptoms for at least 
2 consecutive days: sore throat, colds (nasal discharge and/or nasal congestion), fever without 
other cause, and cough. A COPD exacerbation shall be reported as an AE and may be considered 
serious if it meets the seriousness criteria for SAE reporting.  
All serious AEs that occur after administration of the first dose of study drug will be listed by 
System Organ Class, Preferred Term, and relationship to study drug as assessed by the 
investigator. In addition to three treatment levels, a GSP 304 total will be presented in AE/SAE-
related summary tables.  
10.2.2. 
Missing and Partial AE Onset Dates 
Refers to section 6.8.3  
10.2.3. 
Summaries of Serious Adverse Events (SAE), Adverse Event Dropouts, and 
Death 
For SAEs that are considered to be related to study drug, the number and percentage of subjects 
reporting at least one occurrence of an SAE for each unique System Organ Class will be 
tabulated. SAEs that lead to study discontinuation will be tabulated by unique System Organ 
Class, Preferred Term and relationship to study drug. All SAEs resulting in death will also be 
tabulated.  
All SAEs will be presented for individual subjects in data listings, as well as premature 
discontinuations due to all causality. Deaths of all causes, study-drug related (occurring during 
study participation and up to 30 days post-treatment) or not, will be presented in a separate 
listing. 
10.3. 
Concomitant and Other Medications 
Concomitant medication will be coded by system organ class (SOC) and preferred term (PT) 
using the Medical Dictionary for Regulatory Activities (MedDRA™) Version 18.0 or later. 
Medical history data will be listed by treatment and subject 
All concomitant medications taken since screening until the end of the study will be listed by 
treatment and subject.   
 


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10.4. 
Laboratory Data 
 Baseline and post-baseline clinical laboratory data (hematology, biochemistry, liver function,  
and urinalysis), will be summarized for Visit 4 to Visit 7 (the Final Visit).  Descriptive statistics 
(number of   subjects, mean, SD, median, minimum and maximum) will be presented for 
laboratory data as well as change from baseline by treatment and visit. In addition, values outside 
the respective normal range and values deemed as clinically significant by the Investigator will 
be listed.  
The number of subjects with values of potential clinical significance determined by the 
investigator will be tabulated by treatment group and visit. 
Shift tables will present changes from baseline in laboratory data (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) to end of treatment. 
All laboratory data will be listed by treatment and subject. 
Estimated Glomerular filtration rate (eGFR) will be estimated using the Cockcroft-Gault 
approach.  
10.5. 
Vital Signs 
The subject’s baseline and post-baseline vital signs will be recorded (pulse rates, sitting or lying 
down systolic and diastolic blood pressure) at Visits 3 to Visit 7.  Height and weight will also be 
recorded at Screening Visit (Day -28 to Day -15). Descriptive statistics (number of subjects, 
mean, SD, median, minimum and maximum) will be used to summarize vital sign results and 
changes from baseline by treatment group and visit.  
Values outside the respective normal range and values deemed as clinically significant by the 
Investigator will be listed.  
The number of subjects with values of potential clinical significance determined by the 
investigator will be tabulated by treatment group and visit. 
All vital sign data will be listed by treatment and subject. 
10.6. 
Electrocardiogram (ECG) 
Baseline and post-baseline electrocardiograms (12-lead ECG) will be performed at Visit 3 and 
Visit 6. The parameters to be reported are Heart Rate, PR Interval, QRS duration, QT interval, 
and QTc interval (QTcF and QTcB).   
Descriptive statistics for ECG parameters and changes from baseline will be presented by 
treatment group. Shift tables will present changes from baseline to end of treatment in ECG 
interpretation (categorized as normal; abnormal, not clinically significant; and abnormal, 
clinically significant). 


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The number of subjects with values of potential clinical significance determined by the 
investigator will be tabulated by treatment group and visit. 
All ECG data will be listed by treatment and subject. 
10.7. 
Physical Examination 
Baseline and post-baseline physical examinations will be performed at Visit 3 to Visit 6.   
Descriptive statistics (frequency and percentage) will be used to summarize physical 
examination results by body system, treatment group and visit. In addition, the number of 
subjects with values of potential clinical significance determined by the investigator will be 
tabulated.  
All physical examination data will be listed by treatment and subject. 
10.8. 
Study Termination Status 
 
If the Investigator or the Sponsor’s Medical Monitor becomes aware of conditions or events that 
suggest a possible hazard to subjects if the study continues, the study may be terminated after 
appropriate consultation between the relevant parties. The study may also be terminated early at 
the Sponsor’s discretion in the absence of such a finding. 
Conditions that may warrant termination include, but are not limited to: 
 The discovery of an unexpected, significant, or unacceptable risk to the subjects 
enrolled in the study; 
 Failure to enroll subjects at an acceptable rate; 
 A decision on the part of the Sponsor to suspend or discontinue development of the 
drug product.    
10.9. 
Changes from Protocol 
 
The following changes from the protocol were made in the SAP. 
 
1) The definition of the primary endpoint was clarified from change from baseline in trough 
forced expiratory volume in one second (FEV1) at 24 hours after the last dose of treatment on 
Day 21 in comparision with placebo to change from baseline (Day 1) at Day 21 (Week 3) in 
trough FEV1 response at approximately 24 hours after the last dose (average of 23 hours 15 
minutes and 23 hours 45 minutes post-dose measurements. 
 
2) The language used for definition of the secondary endpoint of change from baseline in trough 
FVC, and the associated analyses related to this endpoint, was modified to align it with the 
language that has been used for the primary endpoint. 


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3) The following secondary endpoints were added; 
 Time to onset of response, defined as at least 12% and 200 mL increase in FEV1 
within 12 hours of dosing on Day 1 
 Time to achieving steady state as measured by FEV1 trough assessments 
 Time to achieving steady state as measured by FVC trough assessments 
 
4) Spirometry Effort Start Time: will use the first effort (Test 1) regardless of whether this is an 
acceptable effort or not.  Instead of “start time of first spirometry effort” (per protocol), we are 
using the end time of the first spirometry effort. 
 


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11. 
REFERENCES 
 
Caillaud D, Le Merre C, Martinat Y et al. A dose-ranging study of tiotropium delivered via 
Respimat Soft Mist Inhaler or HandiHaler in COPD patients. Int J Chron Obstruct Pulmon Dis. 
2007; 2(4):559-65 
Rubin, DB (1987). Multiple Imputations for Nonresponse in Surveys, New York: John Wiley & 
Sons.  
Smith BP, Vandenhende FR, DeSante KA, Farid NA, Welch PA, Callaghan JT, Forgue ST. 
(2000). Confidence interval criteria for assessment of dose proportionality, Pharm Res 17:1278–
1283 
 


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12. 
APPENDIX 
12.1. 
Table of Contents for Data Display Specifications 
  
Tables and Figures 
Title 
Population 
Comment  
Study Population Section 
14.1.1 
Summary of   Disposition 
All Screened 
Subjects 
Unique 
14.1.2 
Summary of Subjects in Analysis Populations 
Randomized 
Subjects 
Unique 
14.1.3 
Summary of Protocol Deviations    
SAF 
Unique 
14.1.4 
Summary of Protocol Deviations    
PKAS 
Repeat 
14.1.8.1 
Summary of Demographic Characteristics   
FAS 
Unique 
14.1.8.2 
Summary of Demographic Characteristics   
SAF 
Repeat 
14.1.8.3 
Summary of Demographic Characteristics    
PP 
Repeat 
14.1.8.4 
Summary of Demographic Characteristics   
PKAS 
Repeat 
14.1.9 
Summary of Baseline Characteristics 
FAS 
Unique 
14.1.10 
Summary of Medical History per SOC and PT 
SAF 
Unique 
14.1.11 
Summary of Treatment Compliance 
SAF 
Unique 
14.1.12 
Summary of Prior Medication  
SAF 
Unique 
14.1.13 
Summary of Concomitant Medications 
SAF 
Repeat 
14.1.14 
Summary of Rescue Medication Use (Reported in eDiary) 
FAS 
Unique 
Pharmacodynamics Section 
14.2.1.1 
Summary of FEV1 Data  by  Visit, Time and Treatments   
FAS 
Unique 
14.2.1.2 
Statistical Analysis of Change from Baseline in Day 21Trough 
FEV1  
FAS  
Unique 
14.2.1.3 
Summary of FEV1 Data  by  Visit , Time and Treatments   
PP 
Repeat 
14.2.1.4 
Statistical Analysis of Change from Baseline in Day 21Trough 
FEV1   
PP 
Repeat 
14.2.1.5 
Sensitivity Statistical Analysis of Change from Baseline in 
Day 21 Trough FEV1 -: Pattern Mixture Model 
FAS 
Unique 
14.2.1.6 
Sensitivity Statistical Analysis of Change from Baseline in 
Day 21 Trough FEV1: Tipping Point Approach 
FAS 
Unique 
14.2.1.7 
Exploratory Statistical Analysis of Change from Baseline  in 
Day 21 Trough FEV1: Dose Response Modelling (Linear 
Model) 
FAS  
Unique 


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Title 
Population 
Comment  
14.2.1.8 
Exploratory Statistical Analysis of Change from Baseline in 
Day 21Trough FEV1: Dose Response Modelling (Non-Linear 
Model) 
FAS  
Unique 
14.2.2.1 
Summary of Peak FEV1 within 12 Hours Post Dose  by  Visit  
and Treatment 
FAS 
Repeat 
14.2.2.2 
Statistical Analysis of Change from Baseline in Peak FEV1 
within 12 Hours Post Dose on Day 1 and Day 21 
FAS 
Repeat 
14.2.2.3 
Summary of Trough FVC  Data by  Day, Time and Treatment 
FAS 
Repeat 
14.2.2.4 
Statistical Analysis of Change from Baseline of Trough FVC 
on Day  1 and Day 21 
FAS 
Repeat 
14.2.2.5 
Summary of Time-Normalized AUC for FEV1 Measured over 
12 Hours by Day and Treatment 
FAS 
Repeat 
14.2.2.6 
Statistical Analysis of Change from Baseline in Time-
Normalized AUC for FEV1 Measured over 12 Hours on Day 1 
and Day 21 
FAS 
Repeat 
14.2.3.1  
Summary of Plasma Concentrations (pg/mL) on  Day 1and 
Day 21 by Subject 
PKAS 
Unique (2) 
14.2.3.2 
Summary of Urine Concentrations  on Day1 and Day 21 by 
Subject 
PKAS 
Unique (2) 
14.2.4.1 
Summary of  Pharmacokinetic Parameters   on Day 1 and Day 
21 by Subject 
PKAS 
Unique (2) 
14.2.4.2 
Summary of Urine Pharmacokinetics Parameters on Day 1 
and Day 21 by Subject 
PKAS 
Unique 
14.2.5 
Relative Bioavailability of GSP304 Comparison to Spiriva 
PKAS 
Unique 
14.2.6 
Pharmacokinetics - Dose Proportionality Assessments of 
GSP304   
PKAS  
Unique  
Figures 
14.2.1.1 
Plot of LS Means of Change from Baseline in Trough FEV1  
by Day 
FAS  
Unique 
14.2.1.1.1 
Plot of Time to onset of action (Percent change in unadjusted 
mean FEV1 on Day 1) 
FAS 
Unique 
14.2.1.1.2 
Plot of Time to onset of action (Change in unadjusted mean 
FEV1 on Day 1) 
FAS 
Unique 
14.2.1.1.3 
Plot of Time to onset of action (Percent change in unadjusted 
mean FEV1 on Day 1) 
PP 
Repeat 
14.2.1.1.4 
Plot of Time to onset of action (Change in unadjusted mean 
FEV1 on Day 1) 
PP 
Repeat 
14.2.1.2 
Plot of LS Mean Treatment Differences of Change from 
Baseline in Day 21 Trough FEV1, in Comparion with Placebo 
FAS  
Unique 
14.2.1.2.1 
Time to Steady State in Unadjsuted Trough FEV1 
FAS 
Unique 
14.2.1.2.2 
Time to Steady State in Unadjsuted Trough FEV1 
PP 
Repeat 


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Title 
Population 
Comment  
14.2.1.3 
Plot of LS Means of  Change from Baseline in Trough FEV1 
PP 
Repeat 
14.2.1.4 
Plot of LS Mean Treatment Differences of Change from 
Baseline   in Day 21Trough (FEV1), in Comparison with 
Placebo 
PP 
Repeat 
14.2.1.5 
Plot of LS Means of Change from Baseline  in Day 21 Trough 
FEV1 t; Dose Response Modelling (Linear Model) 
FAS  
Unique 
14.2.1.6 
Plot of LS Means of Change from Baseline  in Day 21Trough 
FEV1 : Dose Response Modelling  (Non-Linear Model) 
FAS  
Unique 
14.2.2.1 
Plot of LS Means of Change from Baseline in Peak FEV1 
FAS  
Repeat 
14.2.2.2 
Plot of LS Mean Treatment Differences of Change from 
Baseline   in Peak FEV1 
FAS  
Repeat 
14.2.2.3 
Plot of LS Means of Change from Baseline in Trough FVC by 
Day 
FAS  
Repeat 
14.2.2.3.1 
Time to Steady State in Unadjsuted Trough FVC 
FAS 
Repeat 
14.2.3.3.2 
Time to Steady State in Unadjsuted Trough FVC 
PP 
Repeat 
14.2.2.4 
Plot of LS Mean Treatment Differences of Change from 
Baseline   in Day 21 Trough FVC in comparison with Placebo 
FAS  
Repeat 
14.2.2.5 
Plot of LS Means of Change from Baseline in Time-
Normalized AUC for FEV1 Measured over 12 Hours 
FAS  
Repeat 
14.2.2.6 
Plot of LS Mean Treatment Differences of Change from 
Baseline   in Time-Normalized AUC for FEV1 Measured over 
12 Hours 
FAS  
Repeat 
14.2.3.1 
Plot of Mean Plasma Concentrations by Day (Linear Scale) 
PKAS 
Unique 
14.2.3.2 
Plot of Mean   Plasma Concentrations by Day (Semi-Log 
Scale) 
PKAS 
Repeat 
14.2.4.1 
Plot of Mean Amount of Urine Excreted by Day (Linear 
Scale) 
PKAS 
Unique (2) 
14.2.4.2 
Plot of Combined Individual Concentrations – Plasma 
PKAS 
Unique 
14.2.5.1 
Plot of Dose Proportionality  - Plasma  
PKAS 
Unique 
14.2.5.2 
Plot of Dose Proportionality  - Urine 
PKAS 
Repeat 
 Safety Section 
14.3.1.1 
Overall Summary of  Adverse Events 
SAF 
Unique 
14.3.1.2 
Summary of Treatment Emergent Adverse  Events per  SOC 
and PT 
SAF 
Unique 
14.3.1.3 
Summary of Treatment-Related Emergent Adverse Events per  
SOC and PT 
SAF 
Repeat 
14.3.1.4 
Summary of Pre-Treatment Adverse Events   per  SOC and PT 
SAF 
Repeat 
14.3.1.5 
Summary of Serious Adverse Events per  SOC and PT 
SAF 
Repeat 


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Title 
Population 
Comment  
14.3.1.6 
Summary of Serious Adverse Events  Leading to Study 
Discontinuation per  SOC and PT 
SAF 
Repeat 
14.3.1.7 
Summary of Treatment-Related Treatment Emergent  Serious 
Adverse Events per  SOC and PT 
SAF 
Repeat 
14.3.1.8 
Summary of Treatment Emergent Adverse  Events Leading to 
Study Discontinuation  per  SOC and PT 
SAF 
Repeat 
14.3.1.9 
Summary of Treatment Emergent Adverse Events by Severity  
per  SOC and PT 
SAF 
Unique 
14.3.1.10 
Summary of Treatment Emergent Adverse Events by 
Relationship to Study Treatment  per  SOC and PT 
SAF 
Unique 
14.3.2 
Listing of Deaths for All Causes 
All Screened 
Subjects 
Unique 
14.3.4.1 
Summary of  Potentially Clinically Significant Laboratory 
Result  - Biochemistry     
SAF 
Unique 
14.3.4.2 
Summary of  Potentially Clinically Significant Laboratory 
Result  - Hematology   
SAF 
Repeat 
14.3.4.3 
Summary of  Potentially Clinically Significant Laboratory 
Result  - Urinalysis     
SAF 
Repeat 
14.3.5.1.1  
Summary of  Laboratory   Results - Biochemistry     
SAF 
Unique 
14.3.5.1.2 
Shift from Baseline to Day 21 in Biochemistry 
SAF 
Unique 
14.3.5.2.1 
Summary of  Laboratory Results - Hematology   
SAF 
Repeat 
14.3.5.2.2 
Shift from Baseline to Day 21 in Hematology 
SAF 
Repeat 
14.3.5.3.1 
Summary of   Laboratory  Results -  Urinalysis      
SAF 
Unique 
14.3.5.3.2 
Shift from Baseline to Day 21 in Urinalysis 
SAF 
Repeat 
14.3.5.4 
Summary of   Laboratory Results - Liver Function Test 
Elevation and Hy's Law Criteria 
SAF 
Unique 
14.3.6.1 
Summary of  Vital Signs   
SAF 
Repeat 
14.3.6.2 
Summary of Potentially Clinically Significant Vital Signs 
SAF 
Repeat 
14.3.6.3 
Shift from Baseline to Day 21 in Vital Signs 
SAF 
Repeat 
14.3.6.4 
Summary of Electrocardiogram Results 
SAF 
Repeat 
14.3.6.5 
Summary of Potentially Clinically Significant ECGs 
SAF 
Repeat 
14.3.6.6 
Shift from Baseline to Day 21 in ECG Interpretation  
SAF 
Repeat 
14.3.6.7 
Summary of Physical Examination  
SAF 
Unique 
 
Listings 
Title 
Population 
Comment 
16.2.1.1 
Listing of Subject Disposition  
All Screened 
Unique 


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Title 
Population 
Comment 
Subject 
16.2.1.2  
Listing of Study Completion/Withdrawal 
SAF 
Unique 
16.2.1.3 
Listing of Reason for Early Termination 
SAF 
Unique 
16.2.2  
Listing of Protocol Deviations   
SAF 
Unique 
16.2.3  
Listing of Subjects in Analysis Population  
FAS  
Unique 
16.2.4.1  
Listing of Demographics  and Baseline Characteristics 
SAF 
Unique 
16.2.4.2 
Listing of Medical History  
SAF 
Unique  
16.2.5.1 
Listing of Exposure to Study Medication  
SAF 
Unique 
16.2.5.2 
Listing of Treatment Compliance 
SAF 
Unique 
16.2.5.3 
Listing of Average Daily Dose and Time of Nebulization 
SAF 
Unique 
16.2.5.4 
Listing of Prior/Concomitant  Medications per Subject 
SAF 
Unique  
16.2.5.5 
Listing of Study Subjects – Unblinding  
SAF 
Unique 
16.2.5.6 
Lising of Rescue Medication per Subject 
SAF 
Unique 
16.2.6.1 
Listing of Change from Baseline in Primary and Secondary 
Pharmacodynamics Endpoints 
SAF 
Unique 
16.2.6.2.1 
Listing of Plasma Concentrations    
PKAS 
Unique 
16.2.6.2.2 
Listing of Urine Concentrations  on Day1 and Day 21 
PKAS 
Unique 
16.2.6.2.3 
Listing of Pharmacokinetic Parameters   
PKAS 
Unique 
16.2.6.2.4 
Listing of Pharmacokinetic Parameters  Excluded from Analysis 
PKAS 
Unique 
16.2.7.1 
Listing of Treatment Emergent Adverse Events     
SAF 
Unique 
16.2.7.2 
Listing of  Pre-Treatment Adverse Events   
All Screened 
Subjects 
Unique 
16.2.7.3 
Listing of Serious Adverse Events 
All Screened 
Subjects  
Unique 
16.2.8.1 
Listing of Laboratory Results  - Biochemistry  
SAF 
Unique 
16.2.8.2 
Listing of Laboratory Results  - Hematology   
SAF 
Unique 
16.2.8.3 
Listing of Laboratory Results  - Urinalysis 
SAF 
Unique 
16.2.8.4 
Listing of Test Results   
SAF 
Unique  
16.2.9.1 
Listing of Vital Signs per Subject 
SAF 
Unique  
16.2.9.2 
Listing of 12-Lead ECG per Subjext  
SAF 
Unique 
16.2.9.3 
Listing of Physical Examination per Subject 
SAF 
Unique 
 
 
 


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12.2. 
Data Display Specification 
 
Page XX of YY 
Table 14.1.1 
Summary of Disposition 
All Screened Subjects 
 
GSP304 
Spiriva R 
 
10 ug 
20 ug 
40 ug 
Placebo 
  
5 ug 
Total 
 
(N2= xxx) 
(N2=xxx) 
(N2=xxx) 
(N2=xxx) 
(N2=xxx) 
(N1=xxx; N2=xxx) 
Category  
n (.%)  
n (%)  
n (%)  
n (%)  
n (%)  
n (%)  
Total screened   
-- 
-- 
-- 
-- 
-- 
xxx 
Screen Failures [1] 
-- 
-- 
-- 
-- 
-- 
xx (xx.x) 
Reason for Screen Failure [1] 
 
 
 
 
 
 
Adverse Event   
--  
--  
--  
--  
--  
xx (xx.x) 
Did not Meet Inclusion/Exclusion Criteria  
--  
--  
--  
--  
--  
xx (xx.x) 
Lost to Follow-up  
--  
--  
--  
--  
--  
xx (xx.x) 
Physician Decision  
--  
--  
--  
--  
--  
xx (xx.x) 
Protocol Deviation   
--  
--  
--  
--  
--  
xx (xx.x) 
Withdrawal by Subject  
--  
--  
--  
--  
--  
xx (xx.x) 
Other  
--  
--  
--  
--  
--  
xx (xx.x) 
Completed Run-In Period [1] 
-- 
-- 
-- 
-- 
-- 
xx (xx.x) 
Randomized [2] 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xxx  
Completed Study [2] 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Terminated Early [2] 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Reason for Early Termination [2] 
 
 
 
 
 
 
Withdrawal of Consent by  
 
 
 
 
 
 
the Subject  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Adverse Event  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Investigator's Discretion  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Noncompliance with Study  
 
 
 
 
 
 
Procedures  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  


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Protocol Deviation  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
   Violation of Inclusion/Exclusion Criteria  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   Withdrawal Criteria   
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   Informed Consent   
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   Treatment Administration    
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   Prohibited Medications 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   Randomization Code Broken 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   Visit Schedule   
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   Procedure/Tests 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   AE/SAE 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Subject suffers from significant  
 
 
 
 
 
 
inter-current illness or undergoes 
 
 
 
 
 
 
surgery  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Subject requires concomitant 
 
 
 
 
 
 
medication, which may interfere with 
 
 
 
 
 
 
the PK of study medication  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Unable to comply with the spirometry 
 
 
 
 
 
 
washout criteria  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
COPD Exacerbation  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Lost To Follow-up  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Death  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Pregnancy  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Sponsor Decision  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Non- Compliance with Study 
 
 
 
 
 
 
Drug  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Other  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
[1] N1 is the number of screened subjects. Percentages are based on the number of screened subjects; [2] N2 is the number of randomized subjects. Percentages 
for all categories are based on the number of randomized subjects. n = Number of subjects with data in the summarized category  
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
 
Programming notes:  


Glenmark Specialty SA 
 
 
Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
67 
 
 
  
 
 
 
Page XX of YY 
Table 14.1.2 
Summary of Subjects in Analysis Population  
Randomized Subjects 
 
GSP304 
Spiriva R 
 
10 ug 
20 ug 
40 ug  
Placebo 
5 ug 
Total 
 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
Category  
n (%)  
n (%)  
n (%)  
n (%)  
n (%)  
n (%)  
Full Analysis Population  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Safety Population 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Per-protocol Population 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Pharmacokinetic Population 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Percentages are based on the total number of randomized subjects in each treatment group. N = Number of  randomized subjects; n = Number of subjects with 
data in the summarized category; Full analysis population includes all subjects who are randomized, have received at least 1 dose of study medication and have 
at least 1 post-baseline PD assessment;  Safety population  includes all subjects who are randomized and received at least 1 dose of study medication; Per-
protocol population includes all subjects who are randomized, received at least 1 dose of study medication, completed the study and do not have exclusionary 
major protocol deviations; Pharmacokinetic population  includes all subjects who are randomized, received at least 1 dose of study treatment and have at least 1 
quantifiable PK sample and do not have exclusionary major protocol deviations.  
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
 
Programming notes:   


Glenmark Specialty SA 
 
 
Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
68 
 
 
  
 
Page XX of YY 
Table 14.1.3 
Summary of Protocol Deviations  
Safety Set 
 
GSP304 
Spiriva R 
 
10 ug 
20 ug 
40 ug 
Placebo 
5 ug 
Total 
 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
 
n (%)  
n (%)  
n (%)  
n (%)  
n (%)  
n (%)  
Subjects with at least one PD  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Subjects with at least one Major PD [1] 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Category  
 
 
 
 
 
 
Violation of inclusion/exclusion Criteria  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Withdrawal Criteria   
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Informed Consent   
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Treatment Administration    
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Prohibited Medications  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Randomization Code Broken 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Visit Schedule   
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Procedure/Tests 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
AE/SAE 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Subjects with at least one Major PD leading to exclusion from PP 
 
 
 
 
 
 
Category 
 
 
 
 
 
 
Violation of inclusion/exclusion Criteria  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Withdrawal Criteria   
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Informed Consent   
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Treatment Administration    
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Prohibited Medications  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Randomization Code Broken 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Visit Schedule   
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Procedure/Tests 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
AE/SAE 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
[1] Deviations which require exclusion from per-protocol and/or PKAS population. The final MPD categories and decision on deviations to be decided during 
the blinded data review process. Subjects may have more than one significant protocol deviation; N = Number of safety sujects; n = Number of subjects with 
data in the summarized category.  


Glenmark Specialty SA 
 
 
Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
69 
 
 
  
 
 
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
 
Programming notes:   
Repeat for  
Table 14.1.4 Summary of Protocol Deviations 
PK Analysis Set 
 


Glenmark Specialty SA 
 
 
Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
70 
 
 
  
 
Page XX of YY 
Table 14.1.8.1 
Summary of Demographic Characteristics 
Full Analysis Set 
 
 
GSP304 
Spiriva R 
 
10 ug 
20 ug 
40 ug  
Placebo 
5 ug 
Total 
 
 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
 
Category/Statistics 
n (%)  
n (%)  
n (%)  
n (%)  
n (%)  
n (%)  
Age  
n  
xxx  
xxx  
xxx  
xxx  
xxx  
xxx  
(years)  
Mean (SD)  
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min; Max  
xx; xx 
xx; xx 
xx; xx 
xx; xx 
xx; xx 
xx; xx 
Age Category  
≥ 40, <65  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
(years)  
≥ 65, <85  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Sex  
Female  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
Male  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Race 
n 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
  
Asian  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
Black/  
 
 
 
 
 
 
 
African American 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
White  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
American Indian/  
 
 
 
 
 
 
 
Alaska Native 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Native Hawaiian/  
 
 
 
 
 
 
 
other Pacific Islander 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Multiple 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Not Stated  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Ethnicity  
Hispanic or Latino  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Not Hispanic or Latino  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Not Stated  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
N = Number of full analsyis subjects;  n = Number of subjects with data in the summarized category  
Program location/program name.sas/ddmmmyyyy/hh:mm 


Glenmark Specialty SA 
 
 
Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
71 
 
 
  
 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy  
 
Programming notes:  
Repeat for 
Table 14.1.8.2 Summary of Demographic Characteristics 
Safety Set 
Footnote: N = Number of safety subjects ;  n = Number of subjects with data in the summarized category  
 
 
Table 14.1.8.3 Summary of Demographic Characteristics 
Per-Protocol Set 
Footnote: N = Number of per-protocol subjects ;  n = Number of subjects with data in the summarized category  
 
 
Table 14.1.8.4 Summary of Demographic Characteristics 
PK Analysis Set 
Footnote: N = Number of PK analsyis subjects ;  n = Number of subjects with data in the summarized category  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Glenmark Specialty SA 
 
 
Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
72 
 
 
  
 
 
 
Page XX of YY 
Table 14.1.9 
Summary of  Baseline Characteristics 
Full Analysis Set 
 
 
GSP304 
Spiriva R 
 
10 ug 
20 ug 
40 ug 
Placebo 
5 ug 
Total 
 
 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
 
Category/Statistics 
n (%)  
n (%)  
n (%)  
n (%)  
n (%)  
n (%)  
Height (cm)  
n  
xxx  
xxx  
xxx  
xxx  
xxx  
xxx  
 
Mean (SD)  
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x( x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min; Max  
xx; xx  
xx; xx  
xx; xx  
xx; xx  
xx; xx  
xx; xx  
Weight (kg)  
n  
xxx  
xxx  
xxx  
xxx  
xxx  
xxx  
 
Mean (SD)  
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min; Max  
xx;xx  
xx; xx  
xx ;xx  
xx; xx  
xx; xx  
xx; xx  
BMI (kg/m2)  
n  
xxx  
xxx  
xxx  
xxx  
xxx  
xxx  
 
Mean (SD)  
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min; Max  
xx; xx  
xx;xx  
xx; xx  
xx; xx  
xx; xx  
xx; xx  
Smoking Status  
Yes  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
No  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Number of Cigarette Pack (years)  
n  
xxx  
xxx  
xxx  
xxx  
xxx  
xxx  
 
Mean (SD)  
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min; Max  
xx; xx  
xx; xx  
xx; xx  
xx; xx  
xx; xx  
xx; xx  
Time from COPD Diagnosis (years)  
n  
xxx  
xxx  
xxx  
xxx  
xxx  
xxx  
 
Mean (SD)  
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min; Max  
xx; xx  
xx; xx  
xx; xx  
xx; xx  
xx ;xx  
xx; xx  
 
 
 
 
 
 
 
 
Any COPD exacerbation  
Yes  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
in previous 3 months before screening  [1] 
No  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 


Glenmark Specialty SA 
 
 
Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
73 
 
 
  
 
 
 
 
 
 
 
 
 
Number of COPD if [1] =Yes 
n  
xxx  
xxx  
xxx  
xxx  
xxx  
xxx  
 
Mean (SD)  
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min; Max  
xx; xx  
xx; xx  
xx; xx  
xx; xx  
xx; xx  
xx; xx  
If [1] =Yes, was there any hospitalization? 
Yes 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
No 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
N = Number of full analsyis subjects;  n = Number of subjects with data in the summarized category  
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy  
 
Programming notes:   


Glenmark Specialty SA 
 
 
Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
74 
 
 
  
 
Page XX of YY 
Table 14.1.10 
Summary of Medical History per SOC and PT 
Safety Set 
 
GSP304 
Spiriva R 
 
10 ug 
20 ug 
40 ug  
Placebo 
5 ug 
Total 
System Organ Class  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
Preferred Term  
n (%) [#]  
n (%) [#]  
n (%) [#]  
n (%) [#]  
n (%) [#]  
n (%) [#]  
Any medical history 
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
SOC #1  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
PT #1  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
...  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
SOC #2  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
PT #2  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
...  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
...  
 
 
 
 
 
 
SOC = System Organ Class; PT = Preferred Term; N =  Number of safety subjects; n = Number of subjects reporting at least one medical history in that 
category; [#] = Number of individual occurrences of the medical history in that category 
 
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
 
Programming notes:   
Ordered in terms of decreasing frequency for SOC, and PT within SOC, in the treatment group, and then alphabetically for SOC, and PT within SOC. 


Glenmark Specialty SA 
 
 
Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
75 
 
 
  
 
Page XX of YY 
Table 14.1.11 
Summary of Treatment Compliance  
Safety Set 
 
 
GSP304 
Spiriva R 
 
10 ug 
20 ug 
40 ug  
Placebo 
5 ug 
Total 
 
 
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
Category  
Statistics 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Number of Subjects Exposed  
 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
 
 
 
 
 
 
 
  Average Daily Dose (ug) [1] 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
   
Mean (SD) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min; Max 
xx; xx 
xx; xx 
xx; xx 
xx; xx 
xx; xx 
xx; xx 
  Nebulization Time (minute) 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
   
Mean (SD) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min; Max 
xx; xx 
xx; xx 
xx; xx 
xx; xx 
xx; xx 
xx; xx 
   Number of Days on Treatment [2] 
n 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
    
Mean  (SD)  
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min; Max  
xx; xx 
xx; xx 
xx; xx 
xx; xx 
xx; xx 
xx; xx 
   Number of Days on Study [3] 
n 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
   
Mean  (SD)  
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min; Max  
xx; xx 
xx; xx 
xx; xx 
xx; xx 
xx; xx 
xx; xx 
 
Compliance Group (%)  
<80%  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
≥80% - ≤100%  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
>100% - <120%  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
≥120%  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
  Compliance (%) 
n 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
    
Mean  (SD)  
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min; Max  
xx; xx 
xx; xx 
xx; xx 
xx; xx 
xx; xx 
xx; xx 


Glenmark Specialty SA 
 
 
Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
76 
 
 
  
 
[1] Average dose = Add up all dose takend by the subject and divided by the number of days in the study ;[2] Total number of dosing days from first to last day 
of dose;  [3] Total number of days from study creening  through to end of study/follow-up. 
N = Number of safety subjects ;  n = Number of subjects with data in the summarized category  
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy  
 
Programming notes:   
SAP section 7.9  


Glenmark Specialty SA 
 
 
Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
77 
 
 
  
 
Page XX of YY 
Table 14.1.12 
Summary of Prior Medication  
Safety  Set 
 
GSP304 
Spiriva R 
 
WHODD September v2015  
10 ug 
20 ug 
40 ug 
Placebo 
5 ug 
Total 
WHO ATC Class  
 
 
 
 
 
 
                  Anatomical Main Group [level 1]  
 
 
 
 
 
 
Pharmacological Subgroup [Level 3]  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
Preferred Term  
n  (%)  
n  (%)  
n  (%)  
n  (%)  
n  (%)  
n  (%)  
Any medical history  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
            3-OXOANDROSTEN (4) DERIVATIVES, G03BA  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
GENITO URINARY SYSTEM AND SEX HORMONES, G 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
ANDROGENS, G03B  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
TESTOSTERONE  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
...  
 
 
 
 
 
 
N = Number of safety subjects; n = Number of subjects reporting at least one prior medication in that category  
 
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
 
Programming notes:   
Repeat for 
Table 14.1.13 Summary of Concomitant Medications  
Footnote:  
N = Number of safety subjects; n = Number of subjects reporting at least one concomitant medication in that category; [#] = Number of individual occurrences 
of the concomitant medication in that category 
 
 
 
 
 


Glenmark Specialty SA 
 
 
Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
78 
 
 
  
 
Page XX of YY 
Table 14.1.14 
Summary of Rescue Medication Use (Reported in eDiary) 
Full Analysis Set 
 
 
GSP304 
Spiriva R 
 
10 ug 
20 ug 
40 ug  
Placebo 
5 ug 
Total 
 
 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
 
Statistics 
n (%)  
n (%)  
n (%)  
n (%)  
n (%)  
n (%)  
Any Use 
 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
 
 
 
 
 
 
 
Number of Puffs 
n  
xxx  
xxx  
xxx  
xxx  
xxx  
xxx  
(years)  
Mean (SD)  
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
xx.x (x.xx) 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min; Max  
xx; xx 
xx; xx 
xx; xx 
xx; xx 
xx; xx 
xx; xx 
N = Number of full analsyis subjects;  n = Number of subjects with data in the summarized category  
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy  
 


Glenmark Specialty SA 
 
 
Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
79 
 
 
  
 
Page XX of YY 
Table 14.2.1.1 
Summary of FEV1 (L) Data  by Visit , Time and Treatments   
Full Analysis Set  
GSP304 
Spiriva R 
 
 
 
10 ug 
20 ug 
40 ug 
Placebo 
5 ug 
Visit  
Nominal Time  
Statistics 
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
Day 1 
   
-45 min 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   
 
Min; Max  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
 
-15 min  
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
 
Baseline [1]   
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
 
5 min  
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
 
 
 
 
 
 
 
 
 
Change from Baseline 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
 
 
 
 
 
 
 
 
 
30 min 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
 
 
 
 
 
 
 
 
 
Change from Baseline 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 


Glenmark Specialty SA 
 
 
Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
80 
 
 
  
 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
 
 
 
 
 
 
 
 
 
90 min 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
 
 
 
 
 
 
 
 
 
Change from Baseline 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
 
 
 
 
 
 
 
 
 
4 hours  
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
 
 
 
 
 
 
 
 
 
Change from Baseline 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
 
 
 
 
 
 
 
 
 
8 hours 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
 
 
 
 
 
 
 
 
 
Change from Baseline 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
 
 
 
 
 
 
 
 
 
12 hours 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
 
 
 
 
 
 
 
 
 
Change from Baseline 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 


Glenmark Specialty SA 
 
 
Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
81 
 
 
  
 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
 
 
 
 
 
 
 
 
 
23 hours 45 min 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
 
 
 
 
 
 
 
 
 
Change from Baseline 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
 
 
 
 
 
 
 
 
Insert Day 7 and Day 14 
-45 min;  -15 min; Trough [2] 
 
 
 
 
 
 
 
 
Day 21  
-45 min  
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
 
Change from Baseline 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
 
-15 min  
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
   
Change from Baseline 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
 
5 min  
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
   
Change from Baseline 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
 
15 min 
n  
xxx 
xxx 
xxx 
xxx 
xxx 


Glenmark Specialty SA 
 
 
Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
82 
 
 
  
 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
   
Change from Baseline 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
 
30 min 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
   
Change from Baseline 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
 
60 min 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
   
Change from Baseline 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
 
90 min 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
   
Change from Baseline 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
 
2 hours 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
   
Change from Baseline 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
 
4 hours  
n  
xxx 
xxx 
xxx 
xxx 
xxx 


Glenmark Specialty SA 
 
 
Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
83 
 
 
  
 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
   
Change from Baseline 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
 
6 hours 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
   
Change from Baseline 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
 
8 hours 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
   
Change from Baseline 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
 
10 hours 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
   
Change from Baseline 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
 
12 hours 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
   
Change from Baseline 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
 
23 hours 15 min 
n  
xxx 
xxx 
xxx 
xxx 
xxx 


Glenmark Specialty SA 
 
 
Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
84 
 
 
  
 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
   
Change from Baseline 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
 
23 hours 45 min 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
   
Change from Baseline 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
  
Trough  [2] 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
  
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx 
xx;xx 
xx;xx 
xx;xx 
xx;xx 
   
Change from Baseline 
n  
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Mean (SD)  
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
xx.x(xx.xx) 
 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
Min; Max  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
xx;xx  
[1] The baseline assessment for FEV1 is the average of the pre-dose FEV1 measured at -45 minutes and -15 minutes at Day 1.  
[2] Trough FEV1 is defined as the average of FEV1 obtained 23 hours 15 minutes and 23 hours 45 minutes post-morning dose of the previous day. 
N = Number of full analysis subjects;  n = Number of subjects with data in the summarized category  
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
 
 
Programming notes:  Include Day 7 and Day 14 before Day 21 
Repeat for  


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Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
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Table 14.2.1.3 Summary of FEV1  (L) Data byViist , Time and Treatment 
(Per-Protocol Set) 
Footnote: [1] The baseline assessment for FEV1 is the average of the pre-dose FEV1 measured at -45 minutes and -15 minutes at Day 1. 
[2] Trough FEV1 is defined as the average of FEV1 obtained 23 hours 15 minutes and 23 hours 45 minutes post-morning dose of the previous day. 
 
 
Table 14.2.2.1 Summary of Peak FEV1 (L) within 12 Hours Post Dose  by Visit  and Treatment  
(Full Analysis Set)  
Footnote: [1] The baseline assessment for Peak FEV1 is the average of the pre-dose FEV1 measured at -45 minutes and -15 minutes at Day 1. 
 
Programming note:  
Change  ‘Nominal Time’ to ‘Assessement’ and include ‘Actual Value’ in second column  
 
 
Table 14.2.2.3 Summary of FVC (L) Data  by Visit , Time and Treatment 
(Full Analysis Set)  
Footnote: [1] The baseline assessment for FVC is the average of the pre-dose FVC measured at -45 minutes and -15 minutes at Day 1. 
[2] Trough FVC is defined as the average of FVC obtained 23 hours 15 minutes and 23 hours 45 minutes post-morning dose of the previous day. 
 
 
Table 14.2.2.5 Summary of Time-Normalized AUC for FEV1 (L) Measured over 12 Hours  by  Visit, Time and Treatment 
(Full Analysis Set)  
Footnote: [1] The baseline assessment for Time-Normalized AUC for FEV1 (L) is the average of the pre-dose FEV1 measured at -45 minutes and -15 minutes at 
Day 1.  
Programming note:  
Change  ‘Nominal Time’ to ‘Assessement’ and include ‘Actual Value’ in second column   
 
 
 
 
 
 
 
 
 


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Page XX of YY 
Table 14.2.1.2 
Statistical Analysis of Change from Baseline in Day 21 Trough FEV1 (L)   
Full Analysis Set  
GSP304 
Spiriva R 
 
10 ug 
20 ug 
40 ug 
Placebo 
5 ug 
Statistics [1]  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
n  
xxx 
xxx 
xxx 
xxx 
xxx 
LS Mean(SE)  
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
LSMD (SE) 
xx.x (xx.xx) 
xx.x (xx.xx)  
xx.x (xx.xx) 
- 
xx.x (xx.xx)  
95% CI for LSMD   
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
- 
(xx.x, xx.x) 
p-value for LSMD 
x.xxx  
x.xxx  
x.xxx  
- 
x.xxx  
Trough FEV1 is defined as the average of FEV1 obtained 23 hours 15 minutes and 23 hours 45 minutes post-morning dose of the previous day; N = Number of 
full analysis subjects;  n = Number of subjects with at least one post baseline visit in the summarized category 
[1] LSMD = Least Square Mean Difference for each GSP304 vs placebo, and Spiriva vs placebo;  The model will include Troug FEV1 from all visits (Days 1, 6, 
13, 20 and Day 21) and fixed terms for treatment, visit, center, baseline, treatment by visit and baseline by visit interactions; Unstructured covariance structure is 
used. 
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
 
 
Programming notes: 
Repeat for  
Table 14.2.1.4  Statistical Analysis of Change from Baseline in Day 21 Trough FEV1  (L)   
Per-Protocol Set 
Footnote: Same as in 14.2.1.2 
Table 14.2.2.2 Statistical Analysis of Change from Baseline in Peak FEV1 (L) within 12 Hours Post Dose on Day 1 and Day 21  
Full Analysis Set  
Footnote: N = Number of full analysis subjects;  n = Number of subjects with at least one post baseline visit in the summarized category 
[1] LSMD = Least Square Mean Difference for each GSP304 vs placebo, and Spiriva vs placebo;  The model will include Peak FEV1 from Days 1 and 21 and  


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SEPT 12, 2017 
 
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fixed terms for treatment, visit, center, baseline, treatment by visit and baseline by visit interactions; Unstructured covariance structure is used. 
Table 14.2.2.4 Statistical Analysis of Change from Baseline of Trough FVC (L) on Day 1 and Day 21  
Full Analysis Set  
Footnote: Same as in 14.2.1.2 , but change FEV1 to FVC 
Table 14.2.2.6 Statistical Analysis of Change from Baseline in Time-Normalized AUC for FEV1 (L) Measured over 12 Hours on Day 1 and Day 21  
Full Analysis Set  
Footnote: N = Number of full analysis subjects;  n = Number of subjects with at least one post baseline visit in the summarized category 
[1] LSMD = Least Square Mean Difference for each GSP304 vs placebo, and Spiriva vs placebo;  The model will include AUC FEV1 from Days 1 and 21 and 
fixed terms for treatment, visit, center, baseline, treatment by visit and baseline by visit interactions; Unstructured covariance structure is used. 
 


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Page XX of YY 
Table 14.2.1.5 
Sensitivity Statistical Analysis of Change from Baseline in Day 21Trough FEV1 (L) :  
Pattern Mixture Model  
Full Analysis Set  
GSP304  
Spiriva R 
 
 
10 ug 
20 ug 
40 ug 
Placebo 
5 ug 
Model  
Statistics  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
 
n 
xxx 
xxx 
xxx 
xxx 
xxx 
MIPMM [1]  
LS Mean (SE)  
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
LSMD (SE) 
xx.x (xx.xx) 
xx.x (xx.xx)  
xx.x (xx.xx) 
- 
xx.x (xx.xx)  
 
95% CI for LSMD  
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
- 
(xx.x, xx.x) 
 
p-value for LSMD  
x.xxx  
x.xxx  
x.xxx  
- 
x.xxx  
MIPMM [2]  
LS Mean (SE)  
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
LSMD (SE) 
xx.x (xx.xx) 
xx.x (xx.xx)  
xx.x (xx.xx) 
- 
xx.x (xx.xx)  
 
95% CI for LSMD  
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
- 
(xx.x, xx.x) 
 
p-value for LSMD  
x.xxx  
x.xxx  
x.xxx  
- 
x.xxx  
Trough FEV1 is defined as the average of  FEV1 obtained 23 hours 15 minutes and 23 hours 45 minutes post-morning dose of the previous day;  N = Number of 
full analysis subjects; n = Number of subjects with at least one post baseline visit in the summarized category 
[1] Multiple Imputation Pattern Mixture Model (MIPMM) under Missing At Random (MAR) 
[2] Multiple Imputation Pattern Mixture Model (MIPMM) under Missing Not At Random (MNAR)(J2R) 
LSMD = Least Square Mean Difference for each GSP304 vs placebo, and Spiriva vs placebo; The model will include trough FEV1 from all visits (Days 1,  6, 
13, 20 and Day 21),  and fixed terms for treatment, visit, center, baseline, treatment by visit and baseline by visit interactions;  Unstructured covariance structure 
is used  LSMD = Least Square Mean Difference; N = Number of full analysis subjects;    
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
 
Programming notes: 


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SEPT 12, 2017 
 
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Page XX of YY 
Table 14.2.1.6  
Sensitivity Statistical Analysis of Change from Baseline in Day 21Trough FEV1(L) : 
 Tipping Point Approach 
Full Analysis Set  
Shift Parameter [1]  for 
GSP304 xx ug (n=xxx) 
 
Shift Parameter for GSP304 Placebo (n=xxx) 
 
Statistics 
0 mL 
-20 mL 
-40 mL 
-60 mL 
-80 mL 
0 mL 
LSMD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
95%CI 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
p-value 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
-20 mL 
LSMD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
95%CI 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
p-value 
x.xxx  
x.xxx  
x.xxx  
x.xxx  
x.xxx  
-40 mL 
LSMD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
95%CI 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
p-value 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
-60 mL 
LSMD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
95%CI 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
p-value 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
-80 mL 
LSMD 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
95%CI 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
p-value 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
Trough FEV1 is defined as the average of FEV1 obtained 23 hours 15 minutes and 23 hours 45 minutes post-morning dose of the previous day.; N = Number of 
full analysis subjects;  n = Number of subjects with at least one post baseline visit in the summarized category     
[1] LSMD = Least Square Mean Difference for each GSP304  vs GSP304 placebo:  Missing values are imputed under the assumption that the distribution of the 
missing observations has a low expected value than that of the observed only by a shift parameter value; The shift parameter is set at 80 mL for being about 50% 
of treatment efficacy when assuming that a difference in mean change from baseline at the end of treatment in trough FEV1 between GSP304 and GSP304 
placebo is 150 mL; Increment = 20 mL; If the tipping point is found to be between two increments on the given interval, a subsequent tipping point procedure 
will be performed using an interval on the neighborhood of the perceived tipping point finer increments for the shift parameter; The model will include trough 
FEV1 from all visits (Days 1, 6, 13, 20 and Day 21) and fixed terms for treatment, visit, center, baseline, treatment by visit and baseline by visit interactions 
Unstructured covariance structure is used ;  
program location/program name.sas/ddmmmyyyy/hh:mm 


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SEPT 12, 2017 
 
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Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
 
 
Programming notes: 
 


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SEPT 12, 2017 
 
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Table 14.2.1.7 
Exploratory Statistical Analysis of Change from Baseline  in Day 21Trough FEV1 (L)  
 Dose Response Modelling (Linear Model) 
Full Analysis Set  
GSP304 
 
 
10 ug 
20 ug 
40 ug 
Placebo 
 
 
Statistics  
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
 
 
n 
xxx 
xxx 
xxx 
xxx 
 
Mixed Model [1]  
LS Mean (SE)  
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
LSMD (SE) 
xx.x (xx.xx) 
xx.x (xx.xx)  
xx.x (xx.xx) 
- 
 
 
95% CI for LSMD 
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
- 
 
 
p-value for LSMD  
x.xxx  
x.xxx  
x.xxx  
- 
 
Slope [2]  
Estimate(SE)  
95% CI  
p-value  
 
 
 
 
xx.x (xx.xx)  
(xx.x, xx.x) 
x.xxx  
 
 
 
Trough FEV1 is defined as the average of FEV1 obtained 23 hours 15 minutes and 23 hours 45 minutes post-morning dose of the previous day; LSMD = Least 
Square Mean Difference for each GSP304 vs GSP304 placebo;  LSMD = Least Square Mean Difference;  N = Number of full analysis subjects;  n = Number of 
subjects with at least one post baseline visit in the summarized category 
[1] Change from baseline in FEV1 is modeled using a categorical dose as an explanatory variable with visit and visit by dose interaction as fixed effects.  
The model will include trough FEV1 from all visits (Days 1, 6, 13, 20 and Day 21) and fixed terms for treatment, visit, center, baseline, treatment by visit and 
baseline by visit interactions; Unstructured covariance structure is used. 
[2] Change from baseline in FEV1 is modeled using a continuous dose as an explanatory variable with visit and visit by dose interaction as fixed effects.  
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
 
Programming notes: 


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SEPT 12, 2017 
 
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Page XX of YY 
Table 14.2.1.8 
Exploratory Statistical Analysis of Change from Baseline in Day 21Trough FEV1 (L)  
 Dose Response Modelling (Non-Linear Model) 
Full Analysis Set  
 
Parameter  
Estimate(SE) 
CI 
E-Max Mode l [1]  
Intercept  
xx.x (xx.xx) 
(xx.x, xx.x) 
 
Parameter 1 
xx.x (xx.xx) 
(xx.x, xx.x) 
 
Parameter 2 
xx.x (xx.xx) 
(xx.x, xx.x) 
[1] Non-linear model using a continuous dose as an exploratory variable on  change from baseline in FEV1 will be analyzed using an E-max model with 3 
parameters; n = Number of subjects on Day 21. Trough FEV1 is defined as the average of FEV1 obtained 23 hours 15 minutes and 23 hours 45 minutes post-
morning dose of the previous day. 
 
Intercept = E0, the response at dose = 0 (placebo response)  
parameter 1 = Emax, the maximum change in the response compared to placebo 
parameter 2 = ED50,  the dose at 50% of maximum change in the response compared to placebo (ED50)  
The estimate of the ED50, the minimum effective dose has to be chosen close to twice the ED50 to obtain 100% of the maximum change in the response 
compared to placebo. 
 
 
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
 
Programming notes: 
 
 
 
 
 
 
 
 


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SEPT 12, 2017 
 
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Page XX of YY 
Table 14.2.3.1  
Summary of Plasma Concentration (pg/mL) on Day 1 and Day 21 by Subject 
PK Analysis Set 
Panel/Day/Treatment Group: <Day 1, Day 21> <treatment group>  
Subject ID 
pre-dose 
2 min 
4 min 
6 min 
10 min 
15 min 
30 min 
45 min 
60 min 
75 min 
90 min 
xxx-xxxx 
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xxx-xxxx 
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
.....  
 
 
 
 
 
 
 
 
 
 
 
n  
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD  
xx.xx  
xx.xx  
xx.xx  
xx.xx  
xx.xx  
xx.xx  
xx.xx  
xx.xx  
xx.xx  
xx.xx  
xx.xx  
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min; Max  
xx.x;xx.x  
xx.x;xx.x  
xx.x;xx.x  
xx.x;xx.x  
xx.x;xx.x  
xx.x;xx.x  
xx.x;xx.x  
xx.x;xx.x  
xx.x;xx.x  
xx.x;xx.x  
xx.x;xx.x  
%CV  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
GM  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
GM = Geometric Mean; n = Number of subjects with data in the summarized category 
The pre-dose sample on Day 1 should be collected within 30 minutes prior to dosing.  
The pre-dose sample on Day 21 should be collected within 10 minutes prior to the morning dose. 
 
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
 
 
Programming notes: Values will be reported to the same decimal place as in raw data (provided by bioanalytical lab); min and max values will be tabulated to 
the same precision as the source data, but with a maximum of 4 significant digits.   
 
 
 
 


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Page XX of YY 
Table 14.2.3.1  
Summary of Plasma Concentration (pg/mL) on Day 1 and Day 21 by Subject 
PK Analysis Set 
Panel/Day/Treatment Group: <Day 1, Day 21> <treatment group>  
Subject ID 
2 hr 
4 hr 
6 hr 
8 h 
12 hr 
16 hr 
20 hr 
24 hr 
xxx-xxxx 
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xxx-xxxx 
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
.....  
 
 
 
 
 
 
 
 
n  
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD  
xx.xx  
xx.xx  
xx.xx  
xx.xx  
xx.xx  
xx.xx  
xx.xx  
xx.xx  
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min; Max  
xx.x;xx.x  
xx.x;xx.x  
xx.x;xx.x  
xx.x;xx.x  
xx.x;xx.x  
xx.x;xx.x  
xx.x;xx.x  
xx.x;xx.x  
%CV  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
GM  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
GM = Geometric Mean; n = Number of subjects with data in the summarized category 
 
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
 
 
Programming notes: Values will be reported to the same decimal place as in raw data (provided by bioanalytical lab); min and max values will be tabulated to 
the same precision as the source data, but with a maximum of 4 significant digits.   
 
 
 
 
 


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SEPT 12, 2017 
 
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Page XX of YY 
Table 14.2.3.2 
Summary of Urine Concentration on Day 1 and Day 21 by Subject  
PK Analysis Set 
Panel/Day/Treatment Group: <Day 1, Day 21> <treatment group>  
 
 
predose 
 
 
0-6h 
 
 
6-12h 
 
   
Subject ID 
Conc(pg/mL) 
Vol(mL) 
Ae(mg) 
Conc(pg/mL) 
Vol(mL) 
Ae(mg) 
Conc(pg/mL) 
Vol(mL) 
Ae(mg) 
   
xxx-xxxx 
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
   
xxx-xxxx 
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
   
.....  
 
 
 
 
 
 
 
 
 
   
n  
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
   
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   
SD  
xx.xx  
xx.xx  
xx.xx  
xx.xx  
xx.xx  
xx.xx  
xx.xx  
xx.xx  
xx.xx  
   
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   
Min; Max  
xx.x;xx.x  
xx.x;xx.x  
xx.x;xx.x  
xx.x;xx.x  
xx.x;xx.x  
xx.x;xx.x  
xx.x;xx.x  
xx.x;xx.x  
xx.x;xx.x     
%CV  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   
GM  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   
GM = Geometric Mean; n = Number of subjects with data in the summarized category 
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
 
 
Programming notes: Conc and volume (from CRF) would be reported to the same decimal place as in raw data (provided by bioanalytical lab and sites) 
 
 
 
 
 
 
 
 


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Page XX of YY 
Table 14.2.3.2 
Summary of Urine Concentration on Day 1 and Day 21 by Subject 
PK Analysis Set 
Panel/Day/Treatment Group: <Day 1, Day 21> <treatment group>  
 
 
12-24h 
 
Cummulative amount 0-24h 
        
Subject ID 
Conc(pg/mL) 
Vol(mL) 
Ae(mg) 
Conc(pg/mL) 
Vol(mL) 
Ae(mg) 
            
xxx-xxxx 
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
            
xxx-xxxx 
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
            
.....  
 
 
 
 
 
 
      
n  
xx 
xx 
xx 
xx 
xx 
xx 
            
Mean  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
            
SD  
xx.xx  
xx.xx  
xx.xx  
xx.xx  
xx.xx  
xx.xx  
            
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
            
Min; Max  
xx.x;xx.x  
xx.x;xx.x  
xx.x;xx.x  
xx.x;xx.x  
xx.x;xx.x  
xx.x;xx.x  
            
%CV  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
            
GM  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
            
GM = Geometric Mean; n = Number of subjects with data in the summarized category 
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 14.2.4.1  
Summary of Pharmacokinetics Parameters on Day 1 and Day 21 by Subject   
PK Analysis Set 
Panel/Treatment Group/ Day: <treatment group>   <Day 1 >  
Subject ID 
CmaxSS 
(pg/mL); 
tmax 
(h) 
AUC0-tauSS  
(pg*hr/mL)  
t last 
(h) 
AUC 0-tauSS/Dose    
CmaxSS/Dose 
  
         
xxx-xxxx 
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
         
xxx-xxxx 
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
         
.....  
 
 
 
 
 
 
     
n  
xx 
xx  
xx 
xx 
xx 
xx 
         
Mean  
xx.x 
--  
xx.x 
xx.x 
xx.x 
xx.x 
         
SD  
xx.xx  
--   
xx.xx  
xx.xx  
xx.xx  
xx.xx  
         
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
         
Min; Max  
xx.x; xx.x  
xx.x; xx.x  
xx.x; xx.x  
xx.x; xx.x  
xx.x; xx.x  
xx.x; xx.x  
         
%CV  
xx.x 
--  
xx.x 
xx.x 
xx.x 
xx.x 
         
GM  
xx.x 
--  
xx.x 
xx.x 
xx.x 
xx.x 
         
GM%CV  
xx.x 
--  
xx.x 
xx.x 
xx.x 
xx.x 
         
GM = Geometric Mean; n = Number of subjects with data in the summarized category  
 
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
Programming notes: Values will be reported to the same decimal place as in raw data (provided by bioanalytical lab); min and max values will be tabulated to 
the same precision as the source data, but with a maximum of 4 significant digits.   
 
 
 
 
 
 


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Table 14.2.4.1  
Summary of Pharmacokinetics Parameters on Day 1 and Day 21 by Subject 
PK Analysis Set 
Panel/Treatment Group/ Day: <treatment group>   <Day 21 >  
Subject ID 
CmaxSS 
(pg/mL)  
       
tmax 
       (h) 
          AUC0-tauSS  
         (pg*hr/mL)  
tlast 
(h) 
AUC 0-tauSS/ 
Dose   
CmaxSS/ 
Dose 
  
CminSS 
(pg/mL) 
 CavSS 
(pg/mL) 
  t ½  
(h)    
 Rac 
    
 
xxx-xxxx 
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
 
xxx-xxxx 
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
xx.x  
 
.....  
 
 
 
 
 
 
 
 
 
 
 
n  
xx 
 xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
Mean  
xx.x 
 -- 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD  
xx.xx  
--   
xx.xx  
xx.xx  
xx.xx  
xx.xx  
xx.xx  
xx.xx  
xx.xx  
xx.xx  
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min; Max  
xx.x; xx.x  
xx.x; xx.x  
xx.x;xx.x   
xx.x; xx.x  
xx.x; xx.x  
xx.x;xx.x  xx.x; xx.x  xx.x; xx.x 
xx.x; xx.x  
xx.x;xx.x   
%CV  
xx.x 
--  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
GM  
xx.x 
--  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
GM%CV  
xx.x 
--  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
GM = Geometric Mean; n = Number of subjects with data in the summarized category 
 
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
Programming notes: Values will be reported to the same decimal place as in raw data (provided by bioanalytical lab); min and max values will be tabulated to 
the same precision as the source data, but with a maximum of 4 significant digits.   
 
 
 
 
 


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Table 14.2.4.2 
Summary of Urine Pharmacokinetics Parameters on Day 1 and Day 21 by Subject 
PK Analysis Set 
Panel/Treatment Group: <treatment group>     
Day 1 
Day 21 
Subject ID 
 Aetau 
(pg)  
 Aeta/Dose  
 Fe 
(%)  
  
Aetau 
(pg)  
Aeta/Dose  
Fe 
(%)   
  
xxx-xxxx 
xx.x  
xx.x  
xx.x  
  
xx.x  
xx.x  
xx.x  
   
xxx-xxxx 
xx.x  
xx.x  
xx.x  
   
xx.x  
xx.x  
xx.x  
   
.....  
 
 
 
 
 
 
 
 
n  
xx 
xx 
xx 
  
xx 
xx 
xx 
  
Mean  
xx.x 
xx.x 
xx.x 
  
xx.x 
xx.x 
xx.x 
  
SD  
xx.xx  
xx.xx  
xx.xx  
   
xx.xx  
xx.xx  
xx.xx  
   
Median  
xx.x 
xx.x 
xx.x 
  
xx.x 
xx.x 
xx.x 
  
Min; Max  
xx.x; xx.x  
xx.x; xx.x  
xx.x; xx.x  
  
 xx.x; 
xx.x 
xx.x; xx.x  
xx.x; xx.x  
   
%CV  
xx.x 
xx.x 
xx.x 
  
xx.x 
xx.x 
xx.x 
  
GM  
xx.x 
xx.x 
xx.x 
  
xx.x 
xx.x 
xx.x 
  
GM%CV  
xx.x 
xx.x 
xx.x 
  
xx.x 
xx.x 
xx.x 
  
GM = Geometric Mean; n = Number of subjects with data in the summarized category 
 
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
Programming notes: Values will be reported to the same decimal place as in raw data (provided by bioanalytical lab); min and max values will be 
tabulated to the same precision as the source data, but with a maximum of 4 significant digits.   
 
 
 
 


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Table 14.2.5 
  Relative Bioavailability of GSP304 Comparison to Spiriva 
PK Analysis Set 
GSP304  
Spiriva R 5 ug 
 
 
10 ug 
20 ug 
40 ug 
 
Parameter  
Statistics  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
CmaxSS 
n 
xxx 
xxx 
xxx 
xxx 
 
LS Mean (SE)  
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Ratio[1] (SE) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
  
 
90% CI for Ratio  
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
   
AUC0-tauSS  
n 
xxx 
xxx 
xxx 
xxx 
 
LS Mean (SE)  
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Ratio[1] (SE)  
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
  
 
90% CI for Ratio  
(xx.x, xx.x) 
(xx.x, xx.x) 
(xx.x, xx.x) 
 
An ANOVA is performed on the ln-transformed AUC 0-tauSS, and CmaxSS and includes treatment as fixed effect. The results from the model are back-transformed. 
[1] Ratio = GSP 304/ Spiriva; N = Number of PK subjects;  n = Number of subjects with data in the summarized category   
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
 
 
 
 
 
 
 
 
 
 
 


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Table 14.2.6 
Pharmacokinetics - Dose Proportionality Assessments of GSP304   
PK Analysis Set 
Power Model [1]  
Parameter  
Estimate(SE) 
CI 
CmaxSS  
Intercept  
xx.x (xx.xx) 
(xx.x, xx.x) 
 
Slope  
xx.x (xx.xx) 
(xx.x, xx.x) 
AUC 0-tauSS  
Intercept  
xx.x (xx.xx) 
(xx.x, xx.x) 
 
Slope  
xx.x (xx.xx) 
(xx.x, xx.x) 
Aetau  
Intercept  
xx.x (xx.xx) 
(xx.x, xx.x) 
 
Slope  
xx.x (xx.xx) 
(xx.x, xx.x) 
[1] Exploratory Analysis: Dose-proportionality of tiotropium C maxSS, AUC 0-tauSS and Aetau parameters is assessed using an ln-transformed power model. Dose 
proportionality will be declared if the estimate of slope lies between 0.5- 2.  
 
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
 
 
Programming notes: 
 
 
 


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Figure 14.2.1.1 
Plot of LS Means of Change from Baseline in Day 21 Trough FEV1  (L)  
Full Analysis Set  
Trough FEV1 is defined as the average of FEV1 obtained 23 hours 15 minutes and 23 hours 45 minutes post-morning dose of the previous day; LSM = Least 
Square Mean; n = Number of subjects with at least one post baseline visit in the summarized category; The model will include trough FEV1 from all visits (Days 
1, 6, 13, 20 and Day 21) and fixed terms for treatment, visit, center, baseline, treatment by visit and baseline by visit interactions; Unstructured covariance 
structure is used;   
Programming notes: Font for text/label number  = 10pt; Only for Day 21  
Repeat for  


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Figure 14.2.1.3. Plot of LS Means of  Change from Baseline in Day 21Trough FEV1(L)  
Per-Protocol set  
Similar to Figure 14.2.1.1; Only Day 21 
 
Figure 14.2.2.1 Plot of LS Means of Change from Baseline in Peak FEV1  (L) 
Full Analysis Set 
 
Footnote: LSM = Least Square Mean; n = Number of subjects with at least one post baseline visit in the summarized category; The model will include Peak 
FEV1 from Days 1 and 21 and fixed terms for treatment, visit, center, baseline, treatment by visit and baseline by visit interactions; Unstructured covariance 
structure is used;   
 
Plots for Day 1and Day 21: overlay with adding different symbols at mean value  
 
Figure 14.2.2.3 Plot of LS Means of Change from Baseline in Day 21 Trough FVC (L)  
Full Analysis Set 
 
Footnote: Same as 14.2.1.1 
 
 
Figure 14.2.2.5 Plot of LS Means of Change from Baseline in Time-Normalized AUC for FEV1 (L) Measured over 12 Hours  
Full Analysis Set 
Footnote: LSM = Least Square Mean; n = Number of subjects with at least one post baseline visit in the summarized category; The model will include Time-
Normalized AUC for FEV1 from Days 1 and 21 and fixed terms for treatment, visit, center, baseline, treatment by visit and baseline by visit interactions; 
Unstructured covariance structure is used;   
 
Plots for Day 1and Day 21: overlay with adding different symbols at mean value 
 
 
 
 
 
 
 
 
 
 


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Figure 14.2.1.1.1 
Plot of Time to onset of action (Percent change in unadjusted mean FEV1 (L) on Day 1) 
Full Analysis Set 
 
 
 
Programming notes: Font for text/label number  = 10 pt  
Change “Day” with “time” in hours, for the x-axis Add “Mean Percent Change in FEV1” to y-axis title Add a symbol for every point where there is change 
from baseline of >= 12 %. 
Add a horizontal reference line at 12% 
Please ensure that line and marker (line graph, means, standard error bars), significance symbols and colors are consistent within this figure and across figures 
  
 


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Figure 14.2.1.1.2 
Plot of Time to onset of action (Change in unadjusted mean FEV1 (L) on Day 1) 
Full Analysis Set 
 
 
 
 
 
Programming notes: Font for text/label number  = 10 pt  
Change “Day” with “time” in hours, for the x-axis  
Add “Mean Change in FEV1” to y-axis title  
Add a symbol for every point where there is change from baseline of >= 200mL 
Add a horizontal reference line at 200 ml.. 
 


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Please ensure that line and marker (line graph, means, standard error bars), significance symbols and colors are consistent within this figure and across figures 
 
Figure 14.2.1.1.3 Plot of Time to onset of action (Percent change in unadjusted mean FEV1 (L) on Day 1) 
Per Protocol Set 
Footnote: Same as in 14.2.1.1.1 
 
Figure 14.2.1.1.4 Plot of Time to onset of action (Change in unadjusted mean FEV1 (L) on  Day 1) 
Per Protocol Set 
Footnote: Same as in 14.2.1.1.1    
 
 


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Figure 14.2.1.2.1 
Time to Steady State in Trough FEV1 (L) 
Full Analysis Set 
 
 
 
 
Programming notes: Font for text/label number  = 10 pt  
1. Include Placebo,  
2. On the x-axis go from day 0 to day 21, There should be 5 time points (1, 6, 13, 20, 21). Use actual units of time on the x-axis  
3. Add “ Unadjusted Mean Trough FEV1” to y-axis title 
Please ensure that line and marker (line graph, means, standard error bars), significance symbols and colors are consistent within this figure and across figures 
 
Figure 14.2.1.2.2 Time to Steady State in Unadjsuted Trough FEV1(L) 
Per Protocol Set 
Footnote: Same as in 14.2.1.2.1   
 


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Figure 14.2.2.3.1 Time to Steady State in Unadjsuted Trough FVC (L) 
Full Analysis Set 
Footnote: Same as in 14.2.1.2.1    
 
Figure 14.2.2.3.2 Time to Steady State in Unadjsuted Trough FVC (L) 
Per Protocol Set 
Footnote: Same as in 14.2.1.2.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 14.2.1.2 
Plot of LS Mean Treatment Differences of Change from Baseline in Day 21 Trough FEV1 (L)  in Comparision with Placebo 
Full Analysis Set  
 
 
Trough FEV1 is defined as the average of FEV1 obtained 23 hours 15 minutes and 23 hours 45 minutes post-morning dose of the previous day; LSMD = Least 
Square Mean Differencefor each GSP304 vs GSP304 placebo, and Spiriva vs  GSP304 placebo n = Number of subjects with at least one post baseline visit in 
the summarized category;  The model will include trough FEV1 from all visits (Days 1, 6, 13, 20 and Day 21) and fixed terms for treatment, visit, center, 
baseline, treatment by visit and baseline by visit interactions; Unstructured covariance structure is used.   
 
Programming notes: Font for text/label number  = 10; Only for Day 21  
Repeat for  


Glenmark Specialty SA 
 
 
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SEPT 12, 2017 
 
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Figure 14.2.1.4 Plot of LS Mean Treatment Differences of Change from Baseline   in Day 21 Trough FEV1  (L) in Comparison with Placebo  
Per-Protocol set  
Footnote: Same as 14.2.1.2 
Similar to Figure 14.2.1.2; Only Day 21 
 
Figure 14.2.2.2 Plot of LS Mean Treatment Differences of Change from Baseline   in Peak FEV1 (L) 
Full Analysis Set 
Footnote: LSMD = Least Square Mean Differencefor each GSP304 vs GSP304 placebo, and Spiriva vs  GSP304 placebo n = Number of subjects with at least 
one post baseline visit in the summarized category;  The model will include peak FEV1 from  Days 1 and Day 21 and fixed terms for treatment, visit, center, 
baseline, treatment by visit and baseline by visit interactions; Unstructured 
 
Plots for Day 1 and Day21: overaly with adding different symbols at mean value  
 
Figure 14.2.2.4 Plot of LS Mean Treatment Differences of Change from Baseline   in FVC (L)  
Full Analysis Set 
Footnote: Trough FEV1 is defined as the average of FEV1 obtained 23 hours 15 minutes and 23 hours 45 minutes post-morning dose of the previous day; 
LSMD = Least Square Mean Differencefor each GSP304 vs GSP304 placebo, and Spiriva vs  GSP304 placebo n = Number of subjects with at least one post 
baseline visit in the summarized category;  The model will include trough FEV1 from all visits (Days 1, 6, 13, 20 and Day 21) and fixed terms for treatment, 
visit, center, baseline, treatment by visit and baseline by visit interactions; Unstructured 
Plots for Day 1 and Day21: overlay with adding different symbols at mean value 
 
Figure 14.2.2.6 Plot of LS Mean Treatment Differences of Change from Baseline   in Time-Normalized AUC for FEV1 (L) Measured over 12 Hours  
Full Analysis Set 
Footnote: LSMD = Least Square Mean Differencefor each GSP304 vs GSP304 placebo, and Spiriva vs  GSP304 placebo n = Number of subjects with at least 
one post baseline visit in the summarized category;  The model will include time normalized AUC for FEV1 from  Days 1 and Day 21 and fixed terms for 
treatment, visit, center, baseline, treatment by visit and baseline by visit interactions; Unstructured 
 
Plots for Day 1 and Day21: overlay with adding different symbols at mean value 
 


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Figure 14.2.1.5   
Plot of LS Means of Change from Baseline  in Day 21 Trough FEV1(L) :  
Dose Response Modelling (Linear Model) 
Full Analysis Set  
 
Trough FEV1 is defined as the average of FEV1 obtained 23 hours 15 minutes and 23 hours 45 minutes post-morning dose of the previous day; LSM = Least 
Square Mean; n = Number of subjects with at least one post baseline visit in the summarized category; The model will include trough FEV1 from all visits 
(Days 1, 6, 13, 20 and Day 21) and fixed terms for treatment, visit, center, baseline, treatment by visit and baseline by visit interactions; Unstructured 
covariance structure is used.   
 
Programming notes: Font for text/label number = 10 pt;  


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Figure 14.2.1.6 
Plot ofChange from Baseline  in Day 21Trough FEV1 (L)  
Dose Response Modelling (Non-Linear Model) 
Full Analysis Set  
 
Emax model with 3 parameters is used;  n = Number of subjects on Day 21; Trough FEV1 is defined as the average of FEV1 obtained 23 hours 15 minutes and 
23 hours 45 minutes post-morning dose of the previous day;   
 
Programming notes: Font for text/label number  = 10 pt  
 


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Figure 14.2.3.1 
Plot of Mean Plasma Concentrations by Day (Linear Scale) 
PK Analysis Set 
Panel/Day: <Day 1, Day 21>  
Programming notes: Font for text/label number  = 10 pt; 
Treatments (4 lines) should be overlaid. 
Repeat for 
Figure 14.2.3.2 Plot of Mean Plasma Concentrations by Day (Semi-Log Scale) 
Similar to Figure 14.4.1.1 
 


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Figure 14.2.4.1 
Plot of Mean Amount of Urine Excreted by Day (Linear Scale) 
PK Analysis Set 
Panel/Day: <Day 1, Day 21>  
 
 
Programming notes: Font for text/label number = 10 pt;   Treatments (4 lines) should be overlaid.  


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Figure 14.2.4.2 
Plot of Mean Amount of Urine Excreted by Day (Linear Scale) 
PK Analysis Set 
Panel/Day: <Day 1, Day 21>  
Programming notes: Font for text/label number = 10 pt;    
 
 
 


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Figure 14.2.4.2 
Plot of Combined Individual Concentrations – Plasma  
PK Analysis Set 
Panel/Day/Treatment Group: <Day 1, Day 21> <treatment group>  
Programming notes: Font for text/label number  = 10 pt; 
 
 
 


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Figure 14.2.5.1 
Plot of Dose Proportionality - Plasma  
Panel/Day/Parameter: <Day 1, Day 21> <parameter>  
 
Programming notes: Font for text/label number  = 10 pt; 
Y-axis = Parameter (unit) = CmaxSS (day 21 only) ;  AUC0-tauSS (day 21 only)   
Repeat for  
Figure 14.2.5.2  Plot of Dose Proportionality - Urine  


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Y-axis = Parameter (unit) = Aetau (day 1 and day 21)  
 
Page XX of YY 
Table 14.3.1.1 
Overall Summary of Adverse Events  
Safety Set 
 
GSP304 
Spiriva R 
 
10 ug 
20 ug 
40 ug 
Total 
Placebo 
5 ug 
Total 
 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
 
n (%) [#]  
n (%) [#]  
n (%) [#]  
n (%) [#]  
n (%) [#]  
n (%) [#]  
n (%) [#]  
TEAEs  
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
TEAEs Leading  
 
 
 
 
 
 
 
to Discontinuation [1]  
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
TEAEs Related  
 
 
 
 
 
 
 
to Study Drug  
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
AEs Leading  
 
 
 
 
 
 
 
to Withdrawal [2]  
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
SAE  
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
SAE Seriousness Reasons 
 
 
 
 
 
 
 
     Congenital Anomaly or Bith Defect 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
     Persistent or Significant Disability  
     or Incapacity 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
     Death 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
     Initial or Prolonged Hospitalization  
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
     Medically Important Event 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
     Life Threatening 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
SAEs Related  
 
 
 
 
 
 
 
to Study Drug  
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
AE = Adverse Events; SAE = Serious Adverse Events; TEAE = Treatment-Emergent Adverse Events; TEAEs are defined as AEs (identified by PT) that begins 
or that worsens in severity after at least one dose of study treatment has been administered, up to the last study visit; PT = Preferred Term;  n = Number of 
subjects reporting at least one TEAE in that category; [#] = Number of individual occurrences of the TEAE in that category 
[1] counts all TEAEs leading  to study discontinuation or treatment discontinuation during treatment period or follow-up period 


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[2] counts all AE leading to permanent discontinuation of study drug during treatment period or  leading to withdrawal (study or drug discontinuation) from 
study  during run-in, treatment period, or follow–up  period 
 
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
 
 
Programming notes:   
 
 
 


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Table 14.3.1.2 
Summary of Treatment Emergent Adverse Events per SOC and PT 
Safety Set 
 
GSP304 
Spiriva R 
 
10 ug 
20 ug 
40 ug 
Total 
Placebo 
5 ug 
Total 
 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
 
n (%) [#]  
n (%) [#]  
n (%) [#]  
n (%) [#]  
n (%) [#]  
n (%) [#]  
n (%) [#]  
Any TEAE  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
SOC #1  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
PT #1  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
...  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
SOC #2  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
PT #2  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
...  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
...  
 
 
 
 
 
 
 
SOC = System Organ Class; PT = Preferred Term; Treatment Emergent AEs (TEAEs) are defined as AEs (identified by PT) that begins or that worsens in 
severity after at least one dose of study treatment has been administered, up to the last study visit; PT = Preferred Term; N = Number of safety subjects; n = 
Number of subjects reporting at least one TEAE in that category; [#] = Number of individual occurrences of the TEAE in that category 
 
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
 
Programming notes:   
Ordered in terms of decreasing frequency for SOC, and PT within SOC, in the treatment group, and then alphabetically for SOC, and PT within SOC. 
Repeat Table for: 
Table 14.3.1.3 Summary of Treatment-Related Emergent Adverse Events per  SOC and PT 
Programming note: In the first row:  Any Treatment-Related AE 
 
 
Table 14.3.1.4 Summary of Pre-Treatment Adverse Events  per  SOC and PT 
Footnote:  Pre-Treatment AEs (PTAEs)are defined as AEs (identified by PT) that begin or that worsen in severity between study Day -14 and study drug 
 


Glenmark Specialty SA 
 
 
Statistical Analysis Plan - Protocol #GSP304-201 
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121 
 
 
  
 
administration, and last up to the AE stop date 
Programming note: In the first row:  Any Pre-Treatment AE 
 
Table 14.3.1.5 Summary of Serious Adverse Events per  SOC and PT 
Programming note: In the first row:  Any  Serious AE 
 
 
Table 14.3.1.6 Summary of Serious Adverse Events Leading to Study Discontinuation  per  SOC and PT 
Programming note: In the first row:  Any  Serious AE Leasing to Study Discontinuation  
 
 
Table 14.3.1.7 Summary of Treatment-Related Emergent Serious Adverse Events per  SOC and PT  
Programming note: In the first row:  Any Treatment-Related Serious AE 
 
 
Table 14.3.1.8 Summary of Treatment Emergent Adverse Events Leading to Study Discontinuation  per  SOC and PT 
Programming note: In the first row:  Any TEAE Leading to Study Discontinuation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 14.3.1.9 
Summary of Treatment Emergent Adverse Events by Severity per SOC and PC 
Safety Set 
 
 
GSP304 
Spiriva R 
 
10 ug 
20 ug 
40 ug 
Total 
Placebo 
5 ug 
Total 
 
 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
 
Category  
n (%) [#]  
n (%) [#]  
n (%) [#]  
n (%) [#]  
n (%) [#]  
n (%) [#]  
n (%) [#]  
Any TEAE  
Any  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
 
Mild 
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
 
Moderate 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
 
Severe 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
SOC #1  
Any  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
 
Mild 
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
 
Moderate 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
 
Severe 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
PT #1  
Any  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
 
Mild 
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
 
Moderate 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
 
Severe 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
...  
 
 
 
 
 
 
 
 
SOC #2  
Any  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
 
Mild 
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
 
Moderate 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
 
Severe 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
PT #2  
Any  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
 
Mild 
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
 
Moderate 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
 
Severe 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
xx (xx.x) [#] 
...  
 
 
 
 
 
 
 
 
...  
 
 
 
 
 
 
 
 
SOC = System Organ Class; PT = Preferred Term; TEAE = Treatment-Emergent Adverse Events; TEAEs are defined as AEs (identified by PT) that begins or 
that worsens in severity after at least one dose of study treatment has been administered, up to the last study visit; PT = Preferred Term; N = Number of safety 
subjects; n = Number of subjects reporting at least one TEAE in that category;[#] = Number of individual occurrences of the TEAE in that category;  


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Each subject is counted once within each System Organ Class and Preferred Term according to the maximum intensity for all TEAEs within that System Organ 
Class, High Level Term or Preferred Term. 
 
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
 
Programming notes:   
Ordered in terms of decreasing frequency for SOC, and PT within SOC, in the treatment group, and then alphabetically for SOC, and PT within SOC. 


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124 
 
 
  
 
Page XX of YY 
Table 14.3.1.10 
Summary of Treatment Emergent Adverse Events by Relationship to Study Treatment per SOC and PC 
Safety Set 
 
 
GSP304 
Spiriva R 
 
10 ug 
20 ug 
40 ug 
Total 
Placebo 
5 ug 
Total 
 
 
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
 
Category  
n (%) [#]  
n (%) [#]  
n (%) [#]  
n (%) [#]  
n (%) [#]  
n (%) [#]  
n (%) [#]  
Any TEAE  
Not Related  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
 
Related 
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
SOC #1  
Not Related  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
 
Related 
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
PT #1  
Not Related  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
 
Related 
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
xx (xx.x) [#]  
...  
 
 
 
 
 
 
 
 
SOC = System Organ Class; PT = Preferred Term; TEAE = Treatment-Emergent Adverse Events; TEAEs are defined as AEs (identified by PT) that begins or 
that worsens in severity after at least one dose of study treatment has been administered, up to the last study visit; PT = Preferred Term; N = Number of safety 
subjects; n = Number of subjects reporting at least one TEAE in that category;[#] = Number of individual occurrences of the TEAE in that category  
 
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
 
Programming notes:   
 
 
 
 
 
 
 
 
 


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Page XX of YY 
Table 14.3.2 
Listing of Deaths for All Causes  
All Screened Subjects  
Site/Subject ID 
 Study Period  
Treatment  Treatment Start Date Date of Death Reason for Death 
xxxxxx   
 Screening 
 NA  
 NA  
 ddmmmyyyy  xxx 
  
NA =  Not Applicable  
program location/program name.sas/ddmmmyyyy/hh:mm 
 
Programming notes: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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126 
 
 
  
 
 
 
 
Page XX of YY 
Table 14.3.4.1  
Summary of Potentially Clinically Significant Laboratory Results - Biochemistry  
Safety Set 
Panel/Parameter: <parameter>  
 
 
GSP304 
Spiriva R 
 
10 ug 
20 ug 
40 ug 
Total 
Placebo 
5 ug 
Total 
 
 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
Visit  
Category  
n (%)  
n (%)  
n (%)  
n (%)  
n (%)  
n (%)  
n (%)  
Baseline[1]  
Normal 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
   
ANCS  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
ACS  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
UE  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Total  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Day 7  
Normal 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
ANCS  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
ACS  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
UE  
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Total  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Continue  
 
 
 
 
 
 
 
 
for other visits  
 
 
 
 
 
 
 
 
[1] Baseline = Screening (Day -28 to Day -15); Percentages are based on the number of subjects with a non-missing measurement for that variable in each 
corresponding visit; N = Number of safety subjects;  n = Number of subjects with data in the summarized category 
ANCS = Abnormal, not clinically significant; ACS = Abnormal, clinically significant; UE = Un-evaluable  
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
 
 
 


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Programming notes:   
Parameter = Blood Glucose, Total Protein, Albumin, Albumin to Globulin Ratio, Serum Cholesterol(total), Serum Triglycerides, Serum Creatinine, Blood Urea 
Nitrogen(BUN), Sodium, Potassium, Bicarbonate   
 
 
Repeat table for:  
 
Table 14.3.4.2 'Summary of Potentially Clinically Significant Laboratory Result - Hematology' 
Panel/Parameter: <Parameter> (<Units>) 
Parameter = Erythrocyte Count, Hemoglobin, Packed Cell Volumne, Activated Partial Thromboplastin Time and Prothrombin Time, Mean Corpuscular 
Volumne, Mean Corpuscular Hemoglobin, Mean Corpuscular Hemoglobin Concentration,Red Cell Distribution Width, Total Leucocyte Count (absolute and 
percent),Differential Leucocyte Count (absolute and percent), Platelet Count  
 
Table 14.3.4.3  Summary of Potentially Clinically Significant Laboratory Result - Urinalysis  
Panel/Parameter: <Parameter> (<Units>)  
Parameter = Color, appearance, pH, Microscopy, Specific gravity, Glucose, Protein, Ketones, Blood, Billirubin, Leukocyte Esterase, Nitrite  
Table 14.3.6.2  Summary of Potentially Clinically Significant Vital Signs 
Panel/Parameter: <Parameter> (<Units>) 
Parameter = Systolic Blood Pressure (mmHg), Diastolic Blood Pressure (mmHg), Pulse rate (beats per minute), Respiratory rate (per minute) 
Footnote: [1] Baseline = Day 1 (1hr pre-dose); N = Number of safety subjects; ANCS = Abnormal, not clinically significant; 
ACS = Abnormal, clinically significant; UE = Un-evaluable. 
Pre-dose = within 1 hour before study drug administration in the morning (prior to pre-dose spirometry and PK procedure) on Day1 (Baseline) and Day14; 
Post-dose = within 1 hour after study drug administration in the morning; on Day1 and Day14; 
Trough = approximately 24 hours after study drug administration in the morning Day1. 
Percentages are based on the number of subjects with a non-missing measurement for that variable in each corresponding visit. 


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Page XX of YY 
Table 14.3.5.1.1 
Summary of Laboratory Results - Biochemistry  
Safety Set 
Panel/Parameter: <Parameter> (<Units>) 
 
 
GSP304 
Spiriva R 
 
10 ug 
20 ug 
40 ug 
Total 
Placebo 
5 ug 
Total 
Visit  
Statistic  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
Baseline 
n 
         xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Mean (SD) 
xx.x (xx.xx)  
xx.x (xx.xx)  
xx.x (xx.xx)  
xx.x (xx.xx)  
xx.x (xx.xx)  
xx.x (xx.xx)  
xx.x (xx.xx)  
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min; Max 
xx; xx  
xx; xx  
xx; xx  
xx; xx  
xx; xx  
xx; xx  
xx; xx  
Day 7  
n  
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min; Max 
xx; xx 
xx; xx 
xx; xx 
xx; xx 
xx; xx 
xx; xx 
xx; xx 
Change from Baseline  
n  
xxx  
xxx  
xxx  
xxx  
xxx  
xxx  
xxx  
 
Mean (SD)  
xx.x (xx.xx)  
xx.x (xx.xx)  
xx.x (xx.xx)  
xx.x (xx.xx)  
xx.x (xx.xx)  
xx.x (xx.xx)  
xx.x (xx.xx)  
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Min; Max  
xx; xx  
xx; xx  
xx; xx  
xx; xx  
xx; xx  
xx; xx  
xx; xx  
Continue  
 
 
 
 
 
 
 
 
for other  
 
 
 
 
 
 
 
 
visits  
 
 
 
 
 
 
 
 
[1] Baseline = Screening (Day -28 to Day -15) ; N = Number of safety subjects;  n = Number of subjects with data in the summarized category 
 
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
 
Programming notes: 
Refer to SAP section 6.1 for Days 
Parameter = Blood Glucose, Total Protein, Albumin, Albumin to Globulin Ratio, Serum Cholesterol (total), Serum Triglycerides, Serum Creatinine, Blood Urea 


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Nitrogen (BUN), Sodium, Potassium, Bicarbonate, GFR   
Parameter= AST(SGOT),ALT(SGPT),Gamma-glutamyl transferase, Alkaline Phosphatase, Total Bilirubin,Direct Bilirubin 
Repeat table for:  
Table 14.3.5.2.1 'Summary of  Laboratory Results - Hematology' 
Panel/Parameter: <Parameter> (<Units>) 
Parameter = Erythrocyte Count, Hemoglobin, Packed Cell Volume, Activated Partial Thromboplastin Time and Prothrombin Time, Mean Corpuscular Volume, 
Mean Corpuscular Hemoglobin, Mean Corpuscular Hemoglobin Concentration, Red Cell Distribution Width, Total Leucocyte Count (absolute and percent), 
Differential Leucocyte Count (absolute and percent), Platelet Count 
 
Table 14.3.6.1  Summary of Vital Signs 
Panel/Parameter: <Parameter> (<Units>) 
Parameter = Systolic Blood Pressure (mmHg), Diastolic Blood Pressure (mmHg), Pulse rate (beats per minute), Respiratory rate (per minute) 
Change (next day) to (trough)  
Change ‘Visit’ to ‘Visit [1]’ 
 
Footnote: [1] Pre-dose = within 1hour before study drug administration in the morning (prior to pre-dose spirometry and PK procedure) on Day 1 (Baseline) 
and Day 14;  Post-dose = within 1 hour after study drug administration in the morning;on Day 1 and Day 21;  Trough = approximately 24 hours after study drug 
administration in the morning on Day 1 
 
 
Table 14.3.6.4  Summary of Electrocardiogram Results 
Panel/Parameter: <Parameter> (<Units>) 
Parameter= Heart Rate (beats/minute), PR(msec), QRS(msec), QTcB(msec), QTcF(msec)  
Footnote: [1] Baseline = Day 1 (pre-dose); N = Number of safety subjects;n = Number of subjects with data in the summarized category  


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Table 14.3.5.1.2  
Shift Summary from Baseline to Day 21 in Biochemistry 
Safety Set 
Panel/Treatment Group/Parameter: <Placebo>(<N=xxx>); < Parameter> (<Units>) 
 
Number of Subjects 
 Subject Status at Day 21 
Baseline  
Day 21  
Day 21 and Baseline 
Normal 
Abnormal 
ANCS 
ACS   
Baseline [1] 
N1 
N2 
N3  
n/N3 (%)  
n/N3 (%)  
n/N3 (%)  
n/N3 (%)  
Total 
xx 
xx 
yy  
xx/yy (xx.x) [2]   
xx/yy (xx.x)   
xx/yy (xx.x)   
xx/yy (xx.x)   
     Normal 
xx 
xx 
yy  
xx/yy (xx.x) [3]  
xx/yy (xx.x)   
xx/yy (xx.x)   
xx/yy (xx.x)   
    Abnormal 
xx 
xx 
yy  
xx/yy (xx.x) [4]  
xx/yy (xx.x)   
xx/yy (xx.x)   
xx/yy (xx.x)   
        ANCS  
xx 
xx 
yy  
xx/yy (xx.x)   
xx/yy (xx.x)   
xx/yy (xx.x)   
xx/yy (xx.x)   
        ACS  
xx 
xx 
yy 
xx/yy (xx.x)   
xx/yy (xx.x)   
xx/yy (xx.x)   
xx/yy (xx.x)   
[1] Baseline: Screening (Day -28 to Day -15); N1 = Number of safety subjects with baseline data;  N2 = Number of safety subjects with Date 21 data; N3 = 
Number of safety subjects with baseline and Day 21data; n = Number of subjects with data in the summarized category  
Percentages are based on the number of subjects with a non-missing measurement for that variable in each corresponding visit. 
[2] Percentages are based on total subjects with baseline and Day 21 data 
[3] Percentages are based on subjects with normal status at baseline that have Day 21 data 
[4] Percentages are based on subjects with abormal status at baseline that have Day 21 data; similar for ANCS, ACS. 
ANCS = Abnormal, not clinically significant; ACS = Abnormal, clinically significant  
 
 
program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
 
Programming notes:   
For each laboratory parameter, subjects are included only once,  
in the maximum post-baseline severity, for that laboratory parameter.  
Subjects without any post-baseline results are not included in the shift summary 


Glenmark Specialty SA 
 
 
Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
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Parameter = Blood Glucose, Total Protein, Albumin, Albumin to Globulin Ratio, Serum Cholesterol (total), Serum Triglycerides, Serum Creatinine, Blood Urea 
Nitrogen (BUN), Sodium, Potassium, Bicarbonate  
 
AST(SGOT), ALT(SGPT), Gamma-glutamyl transferase, Alkaline Phosphatase, Total Bilirubin, Direct Bilirubin, 
Repeat this table for  
Table 14.3.5.2.2 'Shift Summary from Baseline to Day 21 in Hematology' 
Panel/Treatment Group/Parameter: <Placebo>(<n=xxx>); < Parameter> (<Units>) 
Parameter = Erythrocyte Count, Hemoglobin, Packed Cell Volumne, Activated Partial Thromboplastin Time and Prothrombin Time, Mean Corpuscular 
Volumne, Mean Corpuscular Hemoglobin, Mean Corpuscular Hemoglobin Concentration, Red Cell Distribution Width, Total Leucocyte Count (absolute and 
percents), Differential Leucocyte Count (absolute and percents), Platelet Count 
 
Table 14.3.5.3.2 ' Shift Summary from Baseline to Day 21 in Urinalysis'  
Panel/Treatment Group/Parameter: <Placebo>(<n=xxx>); < Parameter> (<Units>) 
Parameter=Color, appearance, pH, Microscopy, Specific gravity, Glucose, Protein, Ketones, Blood, Billirubin, Leukocyte Esterase, Nitrite 
Table 14.3.6.3  ' Shift Summary from Baseline to Day 21 in Vital Signs'  
Panel/Treatment Group/Parameter: <Placebo>(<n=xxx>); < Parameter> (<Units>) 
Parameter = Systolic Blood Pressure (mmHg), Diastolic Blood Pressure (mmHg), Pulse rate (beats per minute), Respiratory rate (per minute) 
Footnote: [1] Baseline = Day 1 (1hr pre-dose) 
Table 14.3.6.6   ' Shift Summary from Baseline to Day 21 in ECG Interpretation '  
Panel/Treatment Group/Pl acebo ( <n=xxx>) 
Footnote: [1] Baseline = Day 1 (pre-dose)  


Glenmark Specialty SA 
 
 
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SEPT 12, 2017 
 
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Page XX of YY 
Table 14.3.5.3.1  
Summary of Laboratory Results - Urinalysis  
Safety Set 
Panel/Parameter: <Parameter> (<Units>) 
 
 
GSP304 
Spiriva R 
 
10 ug 
20 ug 
40 ug 
Total 
Placebo 
5 ug 
Total 
 
 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
(N=xxx) 
Visit  
Category  
n (%)  
n (%)  
n (%)  
n (%)  
n (%)  
n (%)  
n (%)  
Baseline [1]  
None 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
Trace 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
+1 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
+2 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
+3 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
+4 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
+5 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
No Result 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
Not Done 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Day 7  
None 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
Trace 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
+1 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
+2 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
+3 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
+4 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
+5 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
No Result 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
Not Done 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Continue  
 
 
 
 
 
 
 
 
for other visits  
 
 
 
 
 
 
 
 
[1] Baseline = Screening (Day -28 to Day -15);  N = Number of safety subjects;  n = Number of subjects with data in the summarized category; 
NEG (negative) = not present or none seen; +(few) = The structure is present but not in all fields examined, a specific structure is occasionally found in a field; 
++(moderate) = The structure is present in all fields examined but quantification is still low; +++(many) = The structure is present in all fields examined. 
Percentages are based on the number of subjects with a non-missing measurement for that variable in each corresponding visit.  
 


Glenmark Specialty SA 
 
 
Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
133 
 
 
  
 
 
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
 
Programming notes:   
Parameter = Color, appearance, pH, Microscopy, Specific gravity, Glucose,  
Protein, Ketones, Blood, Billirubin, Leukocyte Esterase, Nitrite  


Glenmark Specialty SA 
 
 
Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
134 
 
 
  
 
Page XX of YY 
Table 14.3.5.4 
Summary of Laboratory Results - Liver Function Test Elevation and Hy's Law Criteria Summary 
Safety Set 
 
GSP304 
Spiriva R 
 
10 ug 
20 ug 
40 ug 
Total 
Placebo 
5 ug 
Total 
 
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
Elevation Criteria 
n (%)  
n (%)  
n (%)  
n (%)  
n (%)  
n (%)  
n (%)  
Hy's Law[1] 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
AST(SGOT) 
 
 
 
 
 
 
 
2xULN elevations 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
3xULN elevations 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
5xULN elevations 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
10xULN elevations 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
ALT(SGPT)  
 
 
 
 
 
 
 
2xULN elevations 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
3xULN elevations 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
5xULN elevations 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
10xULN elevations 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Gamma-glutamyl transferase  
 
 
 
 
 
 
 
2xULN elevations 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
3xULN elevations 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
5xULN elevations 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
10xULN elevations 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Alkaline Phosphatase  
 
 
 
 
 
 
 
2xULN elevations 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
3xULN elevations 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
5xULN elevations 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
10xULN elevations 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
Total Bilirubin  
 
 
 
 
 
 
 
2xULN elevations 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
3xULN elevations 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
5xULN elevations 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
10xULN elevations 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  


Glenmark Specialty SA 
 
 
Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
135 
 
 
  
 
Direct Bilirubin  
 
 
 
 
 
 
 
2xULN elevations 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
3xULN elevations 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
5xULN elevations 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
10xULN elevations 
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
[1] Hy's Law criteria are based on the following: ≥2 x ULN elevation of Bilirubin and 3 x ULN elevation of either ALT or AST. In order to meet the above 
criteria, a subject must experience the elevation in bilirubin and ALT or AST at the same visit. N = Number of safety subjects;  n = Number of subjects with data 
in the summarized category 
 
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
 
Programming notes:   


Glenmark Specialty SA 
 
 
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SEPT 12, 2017 
 
136 
 
 
  
 
Page XX of YY 
Table 14.3.6.7  
Summary of Physical Examination by Treatment  
Safety Set 
Panel/Parameter: <Parameter>  
 
 
GSP304 
Spiriva R 
 
10 ug 
20 ug 
40 ug 
Total 
Placebo 
5 ug 
Total 
Visit  
Category  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
(N=xxx)  
 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Baseline[1]  
n  
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
  
Normal  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
Abnormal  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
Not Done 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Day 7  
n  
xxx  
xxx  
xxx  
xxx  
xxx  
xxx  
xxx  
 
Normal  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
Abnormal  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
xx (xx.x)  
 
Not Done 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
Continue  
 
 
 
 
 
 
 
 
for other visits 
 
 
 
 
 
 
 
 
[1] Baseline = Day -1; N = Number of safety subjects;  n = Number of subjects with data in the summarized category 
Percentages are based on the number of subjects with a non-missing measurement for that variable in each corresponding visit. 
 
Program location/program name.sas/ddmmmyyyy/hh:mm 
Source Data: Listing xxxxxxx Database Extract Date: ddmmmyyyy 
 
Programming notes:  
Parameter = General Appearance; Skin/subcutaneous Tissue; Head and Neck (including thyroid gland); Eyes, Ears,  
Nose and Throat; Gastrointestinal System; Lymph Nodes; Musculoskeletal System;  
Heart/Cardiovascular; Respiratory System; Urogenital System; Ano-rectal; Extremities; Neurological System  
 


Glenmark Specialty SA 
 
 
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SEPT 12, 2017 
 
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Page XX of YY 
Listing 16.2.1.1 
Listing of Subject Disposition  
All Screened Subjects 
Panel/Treatment Group: <GSP304 10 ug> 
Site/Subject ID/Sex/Age(years)/Race/Baseline Weight(kg): <xxxx/xxxx/M/25/WHITE/75> 
Subject 
Status 
Date of Informed Consent/ Date of 
Randomization 
Date of First Study Medication/ Last Study 
Medication 
Date of Early 
Termination 
Reason for Premature Study 
Termination 
Screen 
Failure 
ddmmmyyyy/ddmmmyyyy 
ddmmmyyyy/ddmmmyyyy 
ddmmmyyyy 
Adverse Event  
program location/program name.sas/ddmmmyyyy/hh:mm 
 
 
Programming notes: If the subject status is screen failure, the info past informed consent should show as N/A 


Glenmark Specialty SA 
 
 
Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
138 
 
 
  
 
Page XX of YY 
Listing 16.2.1.2  
Listing of Study Completion/Withdrawal  
Safety Set 
Site/Subject ID 
Treatment 
Subject Status 
Date of Completion/Withdrawn 
Reason for Withdrawn 
 Study Day    
xxxx/xxx-xxxx  
xxxx 
Complete 
ddmmmyyyy/ddmmmyyy 
Adverse Event 
56 
Study day = date of interest – randomization date + 1 if the date of interest occurs on or after the randomization date: Study day = date of interest – 
randomization date if the date of interest occurs on or before the randomization date 
program location/program name.sas/ddmmmyyyy/hh:mm 
 
 
Programming notes: 


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Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
139 
 
 
  
 
Page XX of YY 
Listing 16.2.1.3 
Listing of Reason for Early Termination 
Safety Set 
Site/Subject ID  
Treatment 
Date of Early Termination 
Reason for Early Termination 
Failed to Inclusion/Exclusion [#] 
xxx/xxx-xxxx  
xxxx 
ddmmmyyyy 
Adverse Event 
 
xxx/xxx-xxxx  
xxxx 
ddmmmyyyy 
 
Exclusion [2] 
program location/program name.sas/ddmmmyyyy/hh:mm 
 
 
Programming notes: 


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Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
140 
 
 
  
 
Page XX of YY 
Listing 16.2.2 
Protocol Deviations 
Full Analysis Set  
Site/Subject ID 
Subject Status 
PD Status Classification 
PD Occur Date 
Description Final Decision 
Action to be Taken  
BDRM Comment 
  
xxx/xxx-xxxx  
Completed 
Closed 
Inc/Excl Criteria 
ddmmmyyyy 
xxxx 
Major 
Exclude from PP 
xxxx 
  
PD = Protocol Deviation  
  
program location/program name.sas/ddmmmyyyy/hh:mm 
 
 
Programming notes: 


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SEPT 12, 2017 
 
141 
 
 
  
 
Page XX of YY 
Listing 16.2.3 
Listing of Subjects in Analysis Population  
Full Analysis Set  
Site/Subject ID FAS 
FAS-Exclusion 
Reason 
SAF 
SAF Exclusion 
Reason 
PP  
PP-Exclusion 
Reason 
PKAS 
PKAS-Exclusion 
Reason 
Completed 
Study 
Latest 
Visit 
Protocol 
Deviation 
xxxxxx   
xxx xxx 
xxx xxx 
xxx xxx 
xxx 
xxx 
xxx 
xxx 
xxx  
FAS = Full Analysis Set; SAF = Safety Set; PP = Per-Protocol Set; PKAS = Pharmacokinetic Set  
FAS will include all subjects who are randomized, have received at least 1 dose of study medication and have at least 1 post-baseline PD assessment; SAF will 
include all subjects who are randomized and received at least 1 dose of study medication; PP will include all subjects who are randomized, received at least 1 
dose of study medication, completed the study and do not have any major protocol deviations; PKAS will include all subjects who are randomized, received at 
least 1 dose of study treatment and have at least 1 quantifiable PK sample and do not have any major protocol deviations. 
 
program location/program name.sas/ddmmmyyyy/hh:mm 
 
 
Programming notes: 


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SEPT 12, 2017 
 
142 
 
 
  
 
Page XX of YY 
Listing 16.2.4.1 
Listing of Demographic and Baseline Characteristics   
Safety Set  
Panel/Site/Subject ID/Treatment/Age/Sex/Race/Ethnicity: <xxx/xx-xxxx/Placebo/45/F/Other/WHITE > 
Height(cm)  Weight(kg)  BMI(kg/m2) Smoking Status (Y/N) 
 
X-Ray Interpretation 
  
Any COPD exacerbation in 
previous 3 months before  
screening? (Y/N) [1] 
 
If [1] =Yes, COPD Hosptalization? (Y/N)  
xxx  
xxx  
xxx 
Y 
xxxx 
xxxx 
xxxx 
     
Y =Yes; N =No; ANCS = Abnormal, not clinically significant; ACS = Abnormal, clinically significant; UE = Un-evaluable  
program location/program name.sas/ddmmmyyyy/hh:mm 
 
 
Programming notes: 


Glenmark Specialty SA 
 
 
Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
143 
 
 
  
 
Page XX of YY 
Listing 16.2.4.2 
Listing for Medical History  
Safety Set  
Site/Subject ID 
Body 
System    Medical History Term 
LLT/LLT Code 
PT/PT Code 
HLT 
HLT Code HLGT/HLGT Code 
SOC/SOC code 
xxxx 
xxxx 
xxxx 
xxx/xxx 
xxx/xxx 
xxx/xxx xxx/xxx 
xxx/xxx 
xxx/xxx 
MH = Medical History; LLT = Lowest Term; PT = Preferred Term; HLT =High Level Term; HLGT = High Level Group Term; SOC = System Organ Class 
program location/program name.sas/ddmmmyyyy/hh:mm 
 
 
Programming notes: 


Glenmark Specialty SA 
 
 
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SEPT 12, 2017 
 
144 
 
 
  
 
Page XX of YY 
Listing 16.2.5.1 
Listing of Exposure to Study Medication  
Safety Set  
Site/Subject ID 
Treatment 
Date of First Dose 
Date of Last Dose 
Study Medication Duration (days)  
xxx/xxx-xxxx  
GSP304 10 ug 
ddmmmyyyy 
ddmmmyyyy 
42 
Duration = Last dose date – First dose date +1 
program location/program name.sas/ddmmmyyyy/hh:mm 
 
 
Programming notes: 


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Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
145 
 
 
  
 
Page XX of YY 
Listing 16.2.5.2 
Listing of Treatment Compliance 
Safety Set  
Site/Subject ID 
Treatment 
Number of Received/Number of Expected  
Compliance (%)  
xxx/xxx-xxxx  
Placebo 
9/9  
100% 
 
program location/program name.sas/ddmmmyyyy/hh:mm 
 
 
Programming notes: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Glenmark Specialty SA 
 
 
Statistical Analysis Plan - Protocol #GSP304-201 
SEPT 12, 2017 
 
146 
 
 
  
 
 
 
Page XX of YY 
Listing 16.2.5.3 
Listing of Average Daily Dose and Nebulization Time 
Safety Set  
Site/Subject ID 
Visit 
 Treatment                        Average Daily Dose (ug) 
  
 Nebulization Time in Miniute  
 
xxx-xxxx  
xxxxx 
GSP304 10 ug                         xxxx 
  
 xxx 
 
program location/program name.sas/ddmmmyyyy/hh:mm 
  
 
Programming notes:       
 


Glenmark Specialty SA 
 
 
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SEPT 12, 2017 
 
147 
 
 
  
 
Page XX of YY 
Listing 16.2.5.4 
Listing for Prior/Concomitant Medication per Subject 
Safety Set  
Panel/Site/Subject ID/Sex/Age(years)/Race/Baseline Weight(kg): <xxxx/M/25/WHITE/75> 
Treatment 
Drug Class/Preferred 
Term/Medication Reported 
Flag Start Date/End Date   
 
Study Day 
Start/End  
On-
going 
Dose Unit 
Route Frequency 
Indication 
Placebo  
xxxxx/xxxx/xxxx 
P/C 
Ddmmmyyyy/ddmmmyyyy    
 12/15 
Y 
xxx  xxxx xxx 
xxxx 
xxxx  
Study day = date of interest – randomization date + 1 if the date of interest occurs on or after the randomization date: Study day = date of interest – 
randomization date if the date of interest occurs on or before the randomization date;   
Prior and concomitant meditations were coded with the WHO Drug dictionary dated September, 2015; Flag: P = Prior medication if both the start and stop date 
exist and are before the first dose date of study drug , C = Concomitant medication if the start date is on or after the first dose date of study drug,  P/C = if the 
start date is before the first dose date of study drug and the stop date is after the first dose date of study drug or the medication is continuing,    
program location/program name.sas/ddmmmyyyy/hh:mm 
 
 
Programming notes:       
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 16.2.5.5 
Listing of Study Subjects – Unblinding  
Safety  Set  
Site/Subject ID  
Randomization Number   
Randomization  Date 
Treatment Randomized  
Treatment Received  
xxxx/xxx-xxxx  
xxxxxx  
ddmmmyyyy 
GSP304 10 ug 
GSP304 10 ug  
program location/program name.sas/ddmmmyyyy/hh:mm 
 
 
 
 
Programming notes: 
 
 
 
 
 
 
 
 


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Listing 16.2.5.6 
Listing of Rescue Medication per Subject 
Safety Set  
Panel/Site/Subject ID/Sex/Age(years)/Race/Baseline Weight(kg): <xxxx/M/25/WHITE/75> 
Treatment 
Medication Reported 
 
 
  
  
 
 
 
 
Placebo  
xxxx 
 
 
  
  
  
 
 
 
Rescue meditations were collected on patient eDiarries.    
program location/program name.sas/ddmmmyyyy/hh:mm 
 
 
Note To Programmer:  List data as collected/ reported from eDiary. Add columns based on data collected.


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Listing 16.2.6.1 
Listing of Change from Baseline in Primary and Secondary Pharmacodynamics Endpoints 
Safety Set  
Panel/Site/Subject ID/Sex/Age(years)/Race/Baseline Weight(kg): <xxxx/M/25/WHITE/75> 
Treatment 
Endpoints 
Value at Baseline 
Value at Day 1/Day 21 
Change from Baseline at Day 1/Day 21 
GSP304 10 ug 
[1] 
xxxx 
xxxx/xxx 
xxxxx /xxx 
[1] Primary Endpoint: Change from baseline in trough FEV1 at 24 hours after the last dose of treatment on Day 21  
[2] Secondary Endpoint: Change from baseline in peak FEV1 within 12 hours post dose on Day 1 and Day 21  
[3] Secondary Endpoint: Change from baseline in FVC on Day 1 and Day 21  
[4] Secondary Endpoint: Change from baseline in time-normalized area under the curve for FEV1 measured over 12 hours on Day 1 and Day 21  
program location/program name.sas/ddmmmyyyy/hh:mm 
 
 
Programming notes: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Page XX of YY 
Listing 16.2.6.2.1   
Listing of  Plasma Concentrations  
PK Analysis Set  
 
Site/Subjec
t ID  
 Treatment  Visit Sample Collection Date 
Hour  
 Nominal 
Time 
 Actual 
Time 
 
Deviations 
Time   
Plasma Concentration 
(unit) 
Commen
t  
  xx/xxxx 
xxx      
xxx 
ddmmmyyyy 
Pre-dose  
xxxx     
xxx 
 
xxxx 
xxxx 
xxxxx  
Lower Limit of Quantification (LLOQ) = XX:XX (unit); BLQ = Below the Limit of Quantification; NA = Not Applicable; NS = Not Sampled  
program location/program name.sas/ddmmmyyyy/hh:mm 
 
 
 
Programming notes: Add comment if sample collected outside of allowed window (reason) and or reason sample excluded 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 16.2.6.2.2  
Listing of  Urine Concentrations on Day1 and Day 21  
PK Analysis Set  
Panel/ Site/Subject ID /Visit/Study Day: <Day 1/12 >  
Treatment 
Last Dose Date/Time 
Scheduled 
Time(unit) 
Sample Date/Time(start) 
Sample Date/Time(end)  
Concentration  
(unit) 
Volumne 
(unit) 
Comment  
GSP304 10 ug ddmmmyyyy/hh:mm 
hh:mm(sec) 
ddmmmyyyy/hh:mm 
ddmmmyyyy/hh:mm 
xxxx  
xxxx  
xxxx  
Study day = date of interest – randomization date + 1 if the date of interest occurs on or after the randomization date: Study day = date of interest – 
randomization date if the date of interest occurs on or before the randomization date 
Lower Limit of Quantification (LLOQ) = XX (pg/mL); BLQ = Below the Limit of Quantification; NA = Not Applicable; NS = Not Sampled  
program location/program name.sas/ddmmmyyyy/hh:mm 
 
 
 
Programming notes: Add comment if sample collected outside of allowed window and or reason sample excluded 
 
 
 
 
 
 
 
 
 
 
 


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Listing 16.2.6.2.3  
Listing of Pharmacokinetic Parameters  
PK Analysis Set  
Panel/ Site/Subject ID/Sex/Age(years)/Race/Baseline Weight(kg): <xxxx/xxx-xxx//M/25/WHITE/75> 
Treatment 
Visit 
Hour 
Parameter(unit) 
Value 
Comment  
GSP304 10 ug 
Day 1 
Pre-dose  
AUC(ng.h/mL) 
xxx 
xxxxx 
program location/program name.sas/ddmmmyyyy/hh:mm 
 
 
 
Programming notes:  Add comment if sample collected outside of  allowed window and or reason sample excluded 
Include all PK parameters  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Listing 16.2.6.2.4  
Listing of Pharmacokinetic Parameters Excluded from Analysis 
PK Analysis Set  
Site/Subject ID 
Treatment                Visit 
 Sequence 
Period 
Parameter(unit) 
Value 
Reason  
xxx-xxxx  
GSP304 10 ug         xxx 
 
 xxxxx 
xxxx  
AUC(ng.h/mL) 
xxx 
Not be determined 
program location/program name.sas/ddmmmyyyy/hh:mm 
 
 
 
 
Programming notes:    
   
 


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Listing 16.2.7.1 
Listing of Treatment Emergent Adverse Events  
Safety Set  
Panel/Site/Subject ID/Treatment/AE/Stat Date/End Date/Study Day/Ongoing: <xxxx/xxxx/xxx/xxx/Y/ddmmmyyyy/ddmmmyyyy/xx/Y > 
Severity SAE? 
SAE-
Seriousness 
Reasons 
Relationship to 
Study Medication 
Action 
Taken 
with IP 
Outcome 
LLT/LLT 
Code 
PT/PT 
Code 
HLT 
HLT Code 
HLGT/HLGT 
Code 
SOC/SOC 
code  
xxxx 
Y 
death 
xxxx 
xxxx 
xxxx 
xxxx/xxxx 
xxxx/xxxx 
xxxx/xxxx xxxx/xxxx xxxx/xxxx  
xxxx/xxxx  
Treatment Emergent AEs are defined as AEs (identified by PT) that begins or that worsens in severity after at least one dose of study treatment has been 
administered, up to the last study visit; AE = Adverse Events; SAE = Serious Adverse Event; LLT = Lowest Term; PT = Preferred Term; HLT =High Level 
Term; HLGT = High Level Group Term; SOC = System Organ Class; AEs were coded using MedDRA v19.1;   Study day = date of interest – randomization 
date + 1; Treatment Emergent AEs are defined as AEs (identified by PT) that begins or that worsens in severity after at least one dose of study treatment has 
been administered, up to the last study visit; PT = Preferred Term  
program location/program name.sas/ddmmmyyyy/hh:mm 
 
 
Programming notes: 
Repeat for  
Table 16.2.7.2 Listing of Pre-Treatment Adverse Events 
All Screened Subjects 
Footnote:  Pre-Treatment AEs (PTAEs)are defined as AEs (identified by PT) that begin or that worsen in severity between study Day -14 and study drug 
administration, and last up to the AE stop date 
 
 
 
 
 
 
 


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Listing 16.2.7.3 
Listing of Serious Adverse Events  
All Screened Subjects  
Panel/Site/Subject ID/Treatment/AE/Stat Date/End Date/Study Day/Ongoing: <xxxx/xxxx/xxx/xxx/Y/ddmmmyyyy/ddmmmyyyy/xx/Y > 
Severity 
SAE-
Seriousness 
Reasons 
Relationship to 
Study Medication 
Action 
Taken with 
IP 
Outcome 
LLT/LLT 
Code 
PT/PT Code HLT 
HLT Code 
HLGT/HLGT 
Code 
SOC/SOC 
code  
xxxx 
 death 
xxxx 
xxxx 
xxxx 
xxxx/xxxx 
xxxx/xxxx 
xxxx/xxxx xxxx/xxxx xxxx/xxxx  
xxxx/xxxx  
Treatment Emergent AEs are defined as AEs (identified by PT) that begins or that worsens in severity after at least one dose of study treatment has been 
administered, up to the last study visit; SAE = Serious Adverse Event; LLT = Lowest Term; PT = Preferred Term; HLT =High Level Term; HLGT = High Level 
Group Term; SOC = System Organ Class; AEs were coded using MedDRA v19.1;   Study day = date of interest – randomization date + 1; Treatment Emergent 
AEs are defined as AEs (identified by PT) that begins or that worsens in severity after at least one dose of study treatment has been administered, up to the last 
study visit; PT = Preferred Term  
program location/program name.sas/ddmmmyyyy/hh:mm 
 
 
 
Page XX of YY 


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Listing 16.2.8.1 
Listing of Laboratory Results per Subject - Biochemistry  
Safety Set  
Panel/Site/Subject ID/Sex/Age(years)/Race/Baseline Weight(kg): <xxxx/M/25/WHITE/75> 
Treatment Parameter(unit) 
Normal 
Range 
Day 
number 
Lab Not Done 
(Y/N) 
Scheduled Visit 
(Y/N) 
Data Sample 
Taken 
Lab Result 
[1] 
Change from Baseline 
[2]  
Placebo 
Basophil(10^9/L) xxx-xxx 
Day 1 
N 
Y 
ddmmmyyyy 
0.2 N 
0.06   
[1] N = Normal; ANCS = Abnormal, not clinically significant; ACS = Abnormal, clinically significant; UE = Unevaluable; NA = Not Applicable  
[2] Baseline = Screening (Day -28 to Day -15) 
program location/program name.sas/ddmmmyyyy/hh:mm 
 
 
Programming notes: 
Repeat for  
Listing 16.2.8.2 Listing of Laboratory Results per Subject - Hematology  
Footnote: 
[1] N = Normal; ANCS = Abnormal, not clinically significant; ACS = Abnormal, clinically significant; UE = Unevaluable; NA = Not Applicable 
[2] Baseline = Screening (Day -28 to Day -15) 
 
 
Listing 16.2.8.3 Listing of Laboratory Results per Subject – Urinalysis 
Footnote: 
[1] N = Normal; ANCS = Abnormal, not clinically significant; ACS = Abnormal, clinically significant; UE = Unevaluable; NA = Not Applicable 
 
[2] Baseline = Screening (Day -28 to Day -15) 
NEG(negative) = not present or none seen; +(few) = The structure is present but not in all fields examined. A specific structure is occasionally found in a field; 
++(moderate) = The structure is present in all fields examined but quantification is still low.; +++(many) = The structure is present in all fields examined. 
 
 


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Listing 16.2.8.4 
Listing of Test Results    
Safety Set  
Site/Subject ID 
  Visit 
  Test 
Done?  
Results 
xxx/xxxxxx  
  Screening 
  Pregnancy/xxxx/xxx 
Yes 
xxxx 
program location/program name.sas/ddmmmyyyy/hh:mm 
 
 
Programming notes:  Test = Chest XRay, CT Scan, FSH test and Serum Pregnancy Test, Blood Alcohol Test,  Urinalysis, Serology Test  
Thyroid stimulating hormone; Follicle stimulating hormone; HBsAg and HCV antibody; 
The list should be ordered by Site/Subject ID, then Visit   
 


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Listing 16.2.9.1  
Listing of Vital Signs Data per Subject 
Safety Set  
Subject ID/Sex/Age(years)/Race/Baseline Weight(kg): <xxxx/M/25/WHITE/75> 
Treatment 
Visit 
Scheduled Visit (Y/N) 
Date 
Parameter(unit) 
Result 
Abnormality 
Clinically Significant?  
Placebo 
Screening 
xxxx 
ddmmmyyyy 
Heart Rate (bpm) 
xxxx 
No 
No  
program location/program name.sas/ddmmmyyyy/hh:mm 
 
 
Programming notes: 
Repeat for 
Listing 16.2.9.2 Listing of 12-Lead ECG Measurement per Subject 
Listing 16.2.9.3  Listing of Physical Examinations  per Subject