Conditions: Chronic Obstructive Pulmonary Disease
Keywords: COPD
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 377
Healthy volunteers: no

Brief summary:
The purpose of this study is to show bioequivalence of test product to reference product based on baseline-adjusted forced expiratory volume in one second (FEV1).

Detailed description:

Arms:
arm 1: Once daily administration of test product (tiotropium bromide inhalation powder), 18 mcg for open-label extension (device robustness). arm 2: Single dose of reference product (Spiriva®) 18 mcg arm 3: Single dose of placebo inhalation powder

Interventions: intervention 1: Placebo intervention 2: Test Product (tiotropium bromide inhalation powder) intervention 3: Reference Product (Spiriva®)
Intervention descriptions: intervention 1: Single dose of placebo inhalation powder administered by test and reference dry powder inhalers. intervention 2: Double-Blind: Single dose of test product 18 mcg of test product Open-Label: once daily administration of test product (tiotropium bromide inhalation powder) 18 mcg administered by test dry powder inhaler. intervention 3: Reference product (Spiriva®) 18 mcg.

Protocol document:
Prot_001.pdf: 
Page 1 of 174 
 
CLINICAL STUDY PROTOCOL 
Protocol No. TB-DPI-301 
A Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Crossover, 
Multicenter Clinical Study to Assess the Efficacy and Safety of Once Daily Administration 
of Lupin Tiotropium Bromide Inhalation Powder Compared to SPIRIVA® 
HANDIHALER® and Placebo in Patients with COPD including a 12-Week Open-Label 
Extension to Assess Inhaler Robustness 
 
 
Protocol Version (Date): 
1.0 (18-Nov-2016) 
Amendment (Date):   
Amendment 1 (11-May-2017) 
Sponsor:  
 
 
Lupin Inc. 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
This study will be conducted in accordance with the ethical principles that have their origin 
in the Declaration of Helsinki and clinical research guidelines established by the Code of 
Federal Regulations (Title 21, CFR Parts 50, 56, and 312) and ICH Guidelines.  All 
Investigators will agree to comply with US Federal Regulations concerning written 
informed consent and the rights of human patients as outlined in CFR Part 50.  Essential 
study documents will be archived in accordance with applicable country regulations. 
 
CONFIDENTIAL 
This document contains trade secrets and proprietary information of Lupin Inc. This 
information is the confidential property of Lupin Inc. and is subject to confidentiality 
agreements entered into with Lupin Inc.  No information contained herein should be 
disclosed or reproduced without prior written approval from Lupin Inc. 
. 
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PROTOCOL NUMBER: TB-DPJ-301 
Version: Amendment 1 (1 l-May-2017) 
SPONSOR SIGN A TORY 
Signed 
Lupin Inc. 
 
Lupin Inc. 
Page 2of 174 
Date: // 
CONFIDENTIAL 
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PROTOCOL NUMBER: TB-DPI-301 
Version: Amendment I (ll-May-2017) 
Page 3of1 74 
INVESTIGATOR AGREEMENT 
A Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Crossover, 
Multicenter Clinical Study to Assess the Efficacy and Safety of Once Daily Administration 
of Lupin Tiotropium Bromide Inhalation Powder Compared to SPIRIV A® 
HANDIHALER® and Placebo in Patients with COPD including a 12-Week Open-Label 
Extension to Assess Inhaler Robustness 
IND/EudraCT number: NA 
I have carefully read the foregoing protocol including all appendices and agree that it contains all 
the necessary information for conducting the study safely. 
I will conduct this study in strict accordance with this protocol and according to the current GCP 
guidelines and will attempt to complete the study within the time designated. 
I will provide copies of the protocol and all other information submitted by the Sponsor relating 
to pre-clinical and prior clinical experience to all personnel for whom I am responsible that 
participate in the study. I will discuss this information with them to assure that they are 
adequately infonned regarding the drug and conduct of the study. 
I agree to keep records on all subject infonnation (case report fonns, shipment and drug return 
forms and all other infonnation collected during the study) in accordance with the current GCP 
and local regulations. 
Site Principal Investigator's name 
Lupin Inc. Representative's name 
Signature 
Signature .M 
Date (dd-Mmm-yyyy) 
Date (dd-Mrnm-yyyy) 
Institution 
Lupin Inc. 
CO NFIDENTIAL 
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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT.................................................................................................. 3 
TABLE OF CONTENTS ................................................................................................................ 4 
1 
SYNOPSIS .............................................................................................................................. 8 
2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.......................................... 19 
3 
INTRODUCTION ................................................................................................................. 21 
3.1 
Background .................................................................................................................... 21 
3.2 
Clinical Experience with Tiotropium Bromide Inhalation Powder Administered by a    
Dry Powder HANDIHALER (DPI) ............................................................................... 22 
3.3 
Study Purpose ................................................................................................................. 23 
4 
STUDY OBJECTIVES ......................................................................................................... 24 
4.1 
Primary Objective .......................................................................................................... 24 
4.2 
Secondary Objectives ..................................................................................................... 24 
4.3 
Other Objectives ............................................................................................................. 24 
4.4 
STUDY ENDPOINTS ................................................................................................... 24 
4.4.1 
Primary Efficacy Endpoint ..................................................................................... 24 
4.4.2 
Safety Endpoints ..................................................................................................... 24 
4.4.3 
Other Endpoints ...................................................................................................... 25 
5 
INVESTIGATIONAL PLAN ............................................................................................... 26 
5.1 
Overall Design and Plan of the Study ............................................................................ 26 
5.1.1 
Part 1: Double-Blind Treatment Period .................................................................. 26 
5.1.2 
Part 2: Open-Label Extension ................................................................................. 28 
5.2 
Dose Rationale ............................................................................................................... 29 
6 
SELECTION OF STUDY POPULATION ........................................................................... 30 
6.1 
Inclusion Criteria ............................................................................................................ 30 
6.2 
Exclusion Criteria ........................................................................................................... 32 
6.3 
RANDOMIZATION CRITERIA .................................................................................. 34 
6.4 
CONTINUATION CRITERIA ...................................................................................... 34 
6.5 
Withdrawal Criteria ........................................................................................................ 35 
6.6 
Replacement of Patients Who Withdraw or are Discontinued ....................................... 36 
7 
TREATMENTS ..................................................................................................................... 37 
7.1 
Treatments Administered ............................................................................................... 37 
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7.2 
Identity of Investigational Product ................................................................................. 37 
7.3 
Identity of Comparators ................................................................................................. 38 
7.4 
Ancillary Supplies .......................................................................................................... 38 
7.5 
Supply of Study Medication ........................................................................................... 39 
7.6 
Method of Assigning Patients to Treatment SEQUENCES .......................................... 39 
7.7 
Blinding .......................................................................................................................... 40 
7.7.1 
Part 1 ....................................................................................................................... 40 
7.7.2 
Part 2 ....................................................................................................................... 41 
7.8 
Treatment Compliance ................................................................................................... 41 
7.9 
Dosing Procedures.......................................................................................................... 42 
7.10 
Study Medication Accountability................................................................................... 42 
7.11 
Retention ........................................................................................................................ 43 
7.12 
Emergency Code Breaking............................................................................................. 43 
8 
PROHIBITED AND RESTRICTED MEDICATIONS AND PROCEDURES ................... 44 
8.1 
Prohibited Concomitant Medications ............................................................................. 44 
8.1.1 
Washout Restrictions during Part 1 of the Study Only ........................................... 45 
8.1.2 
Permitted Medication with Restrictions during Part 1 of the Study Only .............. 46 
8.1.3 
Permitted Concomitant Medication/Therapy during Part 2 of the Study Only ...... 47 
8.2 
General and Dietary Restrictions ................................................................................... 47 
9 
STUDY PROCEDURES ....................................................................................................... 48 
9.1 
Schedule of Events ......................................................................................................... 48 
9.2 
Study Procedures ............................................................................................................ 54 
9.2.1 
Efficacy Procedures ................................................................................................ 54 
9.2.2 
Safety Procedures.................................................................................................... 56 
9.2.3 
Other Procedures ..................................................................................................... 58 
9.3 
Study Visits .................................................................................................................... 59 
9.3.1 
Screening Period ..................................................................................................... 60 
9.3.2 
Run-in Period .......................................................................................................... 62 
9.3.3 
Double-blind Treatment Period (Part 1) ................................................................. 62 
9.3.4 
Open-Label Treatment Period (Part 2) ................................................................... 66 
9.3.5 
Early Termination (ET) Visit .................................................................................. 69 
9.3.6 
Retest Visits ............................................................................................................ 69 
9.3.7 
Rescreening ............................................................................................................. 70 
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10 
SAFETY AND PHARMACOVIGILANCE ..................................................................... 71 
10.1 
Definition of an Adverse Event ...................................................................................... 71 
10.2 
Intensity of Adverse Events ........................................................................................... 71 
10.3 
Relationship of Adverse Events to Study Medication ................................................... 71 
10.3.1 
Definition of “No Reasonable Possibility” ............................................................. 71 
10.3.2 
Definition of “Reasonable Possibility” ................................................................... 72 
10.4 
Recording of Adverse Events ......................................................................................... 72 
10.4.1 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as AE: ...... 73 
10.5 
Definition of a Serious Adverse Event ........................................................................... 73 
10.6 
Serious Adverse Event Reporting .................................................................................. 74 
10.7 
Reporting to the United States Food and Drug Administration (US FDA) ................... 76 
11 
DATA COLLECTION AND ANALYSIS ........................................................................ 77 
11.1 
Data Collection Methods ................................................................................................ 77 
11.2 
Sample Size Calculations ............................................................................................... 77 
11.3 
Populations for Analysis ................................................................................................ 78 
11.3.1 
Intent-to-Treat (ITT) Population ............................................................................. 78 
11.3.2 
Per-Protocol (PP) Population .................................................................................. 78 
11.3.3 
Safety Population .................................................................................................... 78 
11.3.4 
Part 2 of the Study (Open-Label) ............................................................................ 79 
11.4 
INTERIM ANALYSIS .................................................................................................. 79 
11.5 
METHODS OF STATISTICAL ANALYSES .............................................................. 79 
11.5.1 
Multiplicity ............................................................................................................. 79 
11.5.2 
Summarization of Data ........................................................................................... 79 
11.5.3 
Missing Data ........................................................................................................... 80 
11.5.4 
Primary Variable ..................................................................................................... 80 
11.5.5 
Establishing Superiority of Test (T) and Reference (R) to Placebo ....................... 81 
11.5.6 
Establishing Bioequivalence between Test (T) and Reference (R) products ......... 81 
11.5.7 
Safety Analyses ....................................................................................................... 81 
11.5.8 
Safety Spirometry ................................................................................................... 83 
11.5.9 
EXACT/ER-S Scores .............................................................................................. 83 
11.5.10 
Albuterol/Salbutamol Usage ............................................................................... 83 
11.5.11 
Inhaler Robustness (Part 2) ................................................................................. 83 
12 
STUDY ADMINISTRATION........................................................................................... 85 
12.1 
Regulatory and Ethical Considerations .......................................................................... 85 
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12.1.1 
Regulatory Authority Approval .............................................................................. 85 
12.1.2 
Ethics Approval ...................................................................................................... 85 
12.1.3 
Patient Informed Consent ....................................................................................... 85 
12.1.4 
Investigator Reporting Requirements ..................................................................... 86 
12.2 
Protocol Amendments .................................................................................................... 86 
12.3 
Declaration of the End of the Clinical Trial ................................................................... 86 
12.4 
Study Monitoring ........................................................................................................... 86 
12.5 
Quality Assurance .......................................................................................................... 87 
12.6 
Study Termination and Site Closure .............................................................................. 87 
12.7 
Site Termination ............................................................................................................. 88 
12.8 
Records Retention .......................................................................................................... 88 
12.9 
Confidentiality of Information ....................................................................................... 89 
12.10 Payment to Patients ........................................................................................................ 89 
12.11 Clinical Trial Registration .............................................................................................. 89 
13 
REFERENCES .................................................................................................................. 90 
14 
APPENDICES ................................................................................................................... 91 
Appendix A: Study Medication Instructions For Use…………………………………………92 
Appendix B: Inhalation Training With In-Check Dial……………………………..………..107 
Appendix C: Exact Daily Diary……………………………………………………………...110 
Appendix D: Protocol Amendment 1 Summary of Changes .................................................. 113 
 
LIST OF TABLES 
Table 7-1. Randomization Scheme ............................................................................................... 39 
Table 8-1. Prohibited Medications (Part 1 and Part 2) ................................................................. 44 
Table 8-2. Permitted Medications with Restrictions..................................................................... 46 
Table 9-1. Schedule of Events 1…………………………………………………………………48 
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1 
SYNOPSIS 
Protocol Number 
TB-DPI-301 
Title of Study 
A 
Randomized, 
Double-Blind, 
Double-Dummy, 
Placebo-Controlled, 
Crossover, Multicenter Clinical Study to Assess the Efficacy and Safety of 
Once Daily Administration of Lupin Tiotropium Bromide Inhalation Powder 
Compared to SPIRIVA® HANDIHALER® and Placebo in Patients with 
COPD including a 12-Week Open-Label Extension to assess Inhaler 
Robustness 
Name of Active Ingredients 
Tiotropium bromide 
IND/EudraCT No. 
Not applicable 
Indication 
Chronic Obstructive Pulmonary Disease (COPD) 
Phase of Clinical Development 
3 
Study Centers 
The study is planned to be conducted at approximately 40 investigational 
centers in the United States of America (USA).  Additional centers in the 
USA may be added as needed. 
Objectives 
Primary Objective 
The primary objective of this study is to show clinical bioequivalence (BE) in 
the efficacy of the Lupin Tiotropium Bromide Inhalation Powder, 18 mcg 
administered as a single dose versus SPIRIVA HANDIHALER, 18 mcg 
based on the adjusted mean change in forced expiratory volume in the first 
second (FEV1) area under the curve from time zero to 24 hours postdose 
(AUC0-24h) on day 1. 
Secondary Objectives 
The secondary objectives of this study are to evaluate the safety and 
tolerability of Lupin Tiotropium Bromide Inhalation Powder and SPIRIVA 
HANDIHALER in patients 40 years of age and older with COPD. 
Other Objectives 
For a subset of the Lupin tiotropium dry powder inhalers (DPIs), 
LUPINHALER™, used during the open-label extension (Part 2) the following 
objectives will be assessed: 
• 
ruggedness of the LUPINHALER during 72 days of in-patient use 
• 
in vitro performance post 72 days of in-patient use 
Study Design Overview 
This is a 2-part clinical study.  Part 1 is a randomized, double-blind, 
double-dummy, placebo-controlled, 3-period, single-dose crossover study that 
will evaluate the clinical BE of single-dose treatment of Lupin Tiotropium 
Bromide Inhalation Powder, 18 mcg and SPIRIVA HANDIHALER, 18 mcg 
in patients 40 years of age and older with established COPD.  Part 2 is a 
12-week open-label extension of Part 1, which will enroll a subset of patients 
(approximately 120 patients) at select investigational centers who have 
successfully completed Part 1 of the study, to assess robustness of the 
LUPINHALER over 72 days of treatment.  The duration of patient 
participation for Part 1 is approximately 14 weeks and for patients 
participating in both Part 1 and Part 2, the duration of patient participation is 
approximately 26 weeks. 
Part 1 of the study consists of a screening period up to 30 days, followed by a 
single-blind placebo run-in period of 14 (+2) days and 3 single-dose, 
double-blind treatment periods (visits 2-4) each separated by a 21-day 
(+3 days) washout period.  Each double-blind treatment period begins with 
administration of the study medication at the investigational center, followed 
by lung function assessments collected over a 24-hour period.  For patients 
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ending participation in the study after completing Part 1 and not enrolling into 
the open-label extension (Part 2), a follow-up visit via phone contact will be 
conducted 7 days (±3 days) after the completion of treatment period 3 
(visit 4). 
The screening period, of up to 30 days, allows for adequate washout of the 
following COPD therapies, along with other prohibited medications per 
protocol: 
• 
long-acting anti-muscarinic agent (LAMA) medications (including 
mono products and combination products containing LAMAs [eg, 
LAMA/LABA]) will not be permitted within 21 days of the 
screening visit (visit 1) 
• 
long-acting beta agonist (LABA) mono products will not be 
permitted within 7 days of the screening visit (visit 1) 
• 
inhaled corticosteroid (ICS) mono products and ICS/LABA 
combination products will not be permitted within 30 days of the 
screening visit (visit 1) 
If a patient is washing out of ICS (monotherapy) or ICS/LABA combination 
therapy as stated above, an additional 3 day window is permitted to complete 
the assessments for the screening visit (visit 1). 
If the patients were formerly taking LAMA, LABA, or ICS/LABA therapy, 
the medications will need to be discontinued and may be replaced at the 
discretion of the Investigator with the short-acting anti-muscarinic agent 
(SAMA) medication, ipratropium bromide, for use during the course of the 
study.  Patients who have not taken LAMA, LABA or ICS/LABA 
combination products within the time period specified above, or who are not 
on medications that are restricted according to the protocol criteria, and who 
have met the selection criteria (eg, reversibility and baseline safety measures) 
at the screening visit (visit 1) will begin the 14 (+2) day single-blind placebo 
run-in period.   
All patients enrolled in the screening/run-in periods will be supplied with the 
following; ediary/electronic flow meter to measure lung function for 
monitoring disease stability during the screening and run-in periods; 
short-acting bronchodilator (SABA), ie, albuterol/salbutamol metered dose 
inhaler (MDI); 90 mcg ex-actuator or equivalent, for use during the course of 
the study.  Dispensation of the albuterol/ salbutamol MDI is not required 
during the screening period if the patient is taking this medication as part of 
their current COPD therapy.  Once the patient is enrolled in the run-in period, 
dispensation/administration of the study albuterol/salbutamol MDI is required 
and the patient will discontinue the use of their own albuterol/salbutamol 
MDI.  Patients enrolled in the run-in period will also be supplied with placebo 
Lupin Tiotropium Bromide Inhalation Powder (placebo LUPINHALER) for 
once daily administration (2 inhalations from one capsule) in the morning 
throughout the single-blind run-in period.  Patients will be required to 
measure FEV1 prior to dosing in the morning at approximately the same time 
each 
day. 
 
The 
FEV1 
results 
and 
usage 
of 
study 
medication/albuterol/salbutamol MDI will be monitored and recorded in the 
ediary.  Patients will also complete the Exacerbations of Chronic Pulmonary 
Disease Tool (EXACT®) Patient Reported Outcome (PRO) within the ediary, 
once daily, each evening before bedtime, during the screening and run-in 
periods. 
Patients will present at the investigational center for visit 2 on day 0 between 
0600 and 1000 having withheld the prohibited/restricted medications for the 
prescribed protocol-defined period and without conducting lung function 
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measurements on the electronic flow meter (home device).  Patients will 
record albuterol/salbutamol MDI usage in their diaries on the mornings prior 
to this visit.  Patients meeting all of the randomization criteria will be 
randomly assigned to 1 of the following 6 treatment sequences in a double-
dummy manner using a Williams design Latin Square: 
Treatment 
sequence 
Treatment period 
1 
Treatment period 
2 
Treatment period 
3 
A (TRP) 
Lupin Tiotropium 
Bromide 
Inhalation 
Powder 18 mcg 
SPIRIVA 
HANDIHALER 
18 mcg 
Placebo 
B (RPT) 
SPIRIVA 
HANDIHALER 
18 mcg 
Placebo  
Lupin Tiotropium 
Bromide 
Inhalation 
Powder 18 mcg 
C (PTR) 
Placebo  
Lupin Tiotropium 
Bromide 
Inhalation 
Powder 18 mcg 
SPIRIVA 
HANDIHALER 
18 mcg 
D (PRT) 
Placebo  
SPIRIVA 
HANDIHALER 
18 mcg 
Lupin Tiotropium 
Bromide 
Inhalation 
Powder 18 mcg 
E (TPR) 
Lupin Tiotropium 
Bromide 
Inhalation 
Powder18 mcg 
Placebo  
SPIRIVA 
HANDIHALER 
18 mcg 
F (RTP) 
SPIRIVA 
HANDIHALER 
18 mcg 
Lupin Tiotropium 
Bromide 
Inhalation 
Powder 18 mcg 
Placebo 
In order to maintain the patient blind, a specified member of the 
investigational center (ie, unblinded administrator) will load and dispense the 
study medication to the patient and instruct the patients to take 2 full 
inhalations from each of 2 inhalers.  The unblinded administrator will also 
apply an opaque covering to the chamber windows prior to patient 
administration to obstruct capsule identification in each inhaler. 
Patients will undertake 2 baseline FEV1 measurements at 0 hours (-30 
and -15 minutes before study medication administration) followed by serial 
FEV1 measurements at 5 and 30 minutes postdose, and at 1, 2, 4, 6, 8, 10, 12, 
23, and 24 hours postdose.  The 23 and 24 hour FEV1 measurements will be 
taken on the 2nd day of the visit (day 1) in the morning at the investigational 
center.  Prior to and for the duration of the FEV1 measurements at the 
investigational center visits (day 0 and day 1), patients should refrain from 
using albuterol/salbutamol MDI and other prohibited medication; patients 
should not smoke for at least 1 hour prior to lung function assessments during 
the visit; and patients should adhere to the dietary restrictions as per protocol. 
After completion of all assessments at visit 2, the patients will enter a 21-day 
(+3 days) washout phase where the patients may continue to use 
albuterol/salbutamol MDI and other medications permitted per protocol 
(eg, SAMA).  Patients will continue to measure lung function for monitoring 
disease stability during the double-blind treatment period.  On days of 
non-investigational center visits, patients will be required to measure FEV1 
once daily prior to dosing in the morning at approximately the same time each 
day.  The FEV1 will be recorded in the ediary/electronic flow meter.  Patients 
will also complete the EXACT once daily, each evening before bedtime 
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within the ediary.  On days of investigational center visits, patients will 
perform the FEV1 measurements and administer the study medication at the 
investigational center, and the EXACT will be collected at home in the 
evening before bedtime.  Usage of albuterol/salbutamol MDI will also be 
recorded in the ediary. 
Prior to visit 3 (days 21 and 22) and visit 4 (days 42 and 43) patients should 
observe the same smoking, dietary and medication restrictions as visit 2.  
Patients will record albuterol/salbutamol MDI usage in their diaries on the 
mornings prior to these visits; however, no FEV1 measurements will be 
performed in the morning using the electronic flow meter (home device).  
Patients should present at the investigational center so that the start of lung 
function testing will be within ±1 hour from the lung function testing at 
visit 1.  Patients will then undertake 2 baseline FEV1 measurements at 0 hours 
(-30 and -15 minutes before study medication administration), followed by 
serial FEV1 measurements at 5 and 30 minutes postdose, and at 1, 2, 4, 6, 8, 
10, 12, 23, and 24 hours postdose.  After completion of all assessments at 
visit 3 (days 21 and 22), the patient will enter a 21-day (+3 days) washout 
phase where the patient may continue to use albuterol/salbutamol MDI and 
other medications permitted per protocol (eg, SAMA). 
After completion of visit 4 (days 42 and 43), a subset of patients 
(approximately 120 patients) at select investigational centers who 
successfully completed Part 1 and continue to meet the continuation criteria 
will be eligible for enrollment into a 12-week open-label extension to 
examine the robustness of the LUPINHALER.  Patients who successfully 
completed the 3 single-dose treatments in Part 1 and who are not enrolled into 
the open-label extension (Part 2) will be contacted via phone 7 days (±3 days) 
after the visit for a final safety check and then formally discharged from the 
study. 
The open-label extension (Part 2) will consist of 7 visits (visit 5 through 
visit 10, and follow-up), and will begin on the last day of visit 4 (Part 1).  
Visits 6 and 8 will be conducted via telephone contact.  The final safety 
follow-up for those patients participating in Part 2 will be conducted via 
telephone 7 days (±3 days) after the last active treatment of the open-label 
extension (ie, visit 10).   
Patients participating in the open-label extension will begin study activities 
on the same day as the final visit in the double-blind treatment period 
(visit 4), which will be considered the first day of the open-label extension 
(visit 5).  Patients will be issued a 90-day supply of the Lupin Tiotropium 
Bromide Inhalation Powder, 18 mcg for once-daily administration (to be 
taken at home each morning) during a 72-day treatment phase.  Treatment 
with the Lupin Tiotropium Bromide Inhalation Powder will begin on visit 5 
after all FEV1 assessments and study activities were completed for Part 1.  
Patients will be permitted to resume other non-study medications and 
albuterol/salbutamol MDI as permitted per protocol.  LAMA medications 
(mono and combination therapies), other than the study medication, are 
prohibited in Part 2 of the study.  Patients will assess functionality of the 
LUPINHALER daily and record this data in the ediary. 
Patients will measure lung function to monitor disease stability via the 
ediary/electronic flow meter during the open-label extension.  Patients will be 
required to measure FEV1 twice daily: upon awakening in the morning 
immediately prior to dosing with the study medication and at 2 (+2) hours 
after 
study 
medication 
administration. 
 
The 
FEV1 
results 
and 
albuterol/salbutamol MDI/study medication usage will be monitored and 
recorded in the ediary/electronic flow meter.  Patients will also complete the 
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EXACT once daily, each evening before bedtime within the ediary.  
At visit 6 and visit 8, patients will be contacted via telephone by 
investigational center personnel to monitor AEs and any issues regarding the 
inhaler function.  
The patients will return to the investigational center on visit 7 and visit 9 for 
an overall assessment of safety and tolerability, to verify inhaler technique, 
and to assess any inhaler issues/malfunctions.   
On visit 10, patients will return for a final treatment visit, in which vital signs 
will 
be 
assessed, 
inhaler 
issues/malfunctions 
assessed, 
and 
the 
ediary/electronic flow meter, albuterol/salbutamol MDI, and study medication 
collected and stored appropriately.  The patient should be contacted via phone 
7 ±3 days after the final treatment visit (visit 10) for a final safety check and 
to be formally discharged from the study. 
If at any time patients experience a perceived issue with their inhaler, the 
ediary system will alert the investigational center who will arrange the 
necessary corrective action, if required.  The investigational center should 
endeavor to complete the electronic case report form (eCRF) within 24 hours 
of notification of an issue.  
Safety will be monitored throughout Part 1 and Part 2 of the study by vital 
signs measurements, albuterol/salbutamol MDI and concomitant medication 
usage, physical examinations, head, ears, eyes, nose, throat (HEENT)/chest 
examinations, 
spirometry 
(FEV1) 
measurements, 
electrocardiography 
(ECGs), ER-S: COPD scores (derived from the EXACT), COPD 
exacerbations, and adverse events (AEs).  During the screening and run-in 
periods, safety will be assessed via FEV1 measurements, ER-S: COPD scores, 
and monitoring of AEs and COPD exacerbations. 
Number of Patients Planned 
For Part 1 of the study, in order to have 180 completed per-protocol (PP) 
patients, approximately 240 male and female patients 40 years of age and 
older with established COPD will be randomly assigned in order to account 
for a potential withdrawal rate of 30% from the PP population.  Patients will 
be assigned to 1 of 6 treatment sequences as described in section 7.6.  No 
estimates of within-patient variability for the primary variable were available 
in the public domain.  As this is necessary for sample size estimation, a 
blinded interim analysis will be performed in order to assess this variability 
compared to the estimate used to initially estimate sample size.  The blinded 
interim analysis has the potential to increase the sample size if necessary to 
maintain 90% power. 
For Part 2, a subset of patients (approximately 120 patients) who successfully 
completed Part 1 will be enrolled into the open-label extension to ensure that 
at least 100 inhalers are returned to Lupin for evaluation of pharmaceutical 
performance. 
Diagnosis and Main Criteria for 
Enrollment 
Inclusion Criteria 
1. Patient is able to give signed written informed consent prior to study entry.  
2. Male or female patients 40 years of age and older, inclusive, as of the 
screening visit (visit 1). 
3. Patient has a diagnosis of COPD according to the Global Initiative 
Chronic Obstructive Lung Disease (GOLD) guidelines 2016. 
4. Ability to perform acceptable and repeatable spirometry according to the 
American Thoracic Society (ATS)/European Respiratory Society (ERS) 
2005 criteria and/or protocol defined criteria. 
Note: If the patient cannot meet the criterion, the visit may be rescheduled 
as per the retest criteria (section 9.3.6). 
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5. Patient is able to achieve an inspiratory flow rate of ≥40 L/min using the 
In-Check DIAL at the screening visit (visit 1). 
6. Patient is able to demonstrate proper inhalation technique using the DPI. 
7. Post-bronchodilator FEV1 of <80% of the predicted value during the 
screening visit (visit 1).  National Health and Nutrition Examination 
Survey (NHANES) III normative values will be used for all patients with 
adjustments to these values made for African American patients.  All 
spirometry tests should be carried out in accordance with the ATS/ERS 
2005 criteria (Miller et al 2005). 
Note: If the patient cannot meet the criterion, the visit may be rescheduled 
as per the retest criteria (section 9.3.6). 
8. Post-bronchodilator FEV1/FVC ratio of ≤0.70 at the screening visit 
(visit 1). 
Note: If the patient cannot meet the criterion, the visit may be rescheduled 
as per the retest criteria (section 9.3.6). 
9. Patient has demonstrated ≥15% reversibility of FEV1 within 30 or 
60 minutes following 68 mcg of ipratropium bromide inhalation (pMDI) at 
the screening visit (visit 1).  If required, spacers are permitted for use 
during reversibility testing for ipratropium administration.  Patients who 
do not demonstrate a positive improvement of at least 15% in FEV1 
measured at 30 or 60 minutes post inhalation will not be eligible to 
participate in the study.  However, based on Investigator judgment, 
patients will be allowed to retest once no sooner than 24 hours and no later 
than 2 weeks after the initial failure (see section 9.3.6).  Reversibility 
values of 14.50-14.99 will be rounded to 15. 
10. Patient is a current smoker or non-smoker with a minimum 10 pack-years 
of historical use (the equivalent of one pack per day for 10 years). 
11. Patient is able to withhold all inhaled SABAs for at least 6 hours and 
SAMAs for at least 8 hours prior to lung function assessments on study 
visit days. 
12. Patient is medically able to tolerate permitted medications without a 
significant adjustment of dosage, formulation, dosing interval for the 
duration of the study, and judged able by the Investigator to withhold them 
for the specified minimum time intervals prior to each clinic visit.  
13. Patient is free of any concomitant conditions or treatments that could 
interfere with study conduct, influence the interpretation of study 
observations/results, or put the patient at increased risk during the study 
(eg, patient is not able to self-administer study medication or self-complete 
the ediary). 
14. Patient did not experience an AE that in the opinion of the Investigator 
would result in failure to meet the inclusion/exclusion criteria during the 
screening period. 
15. If female, is currently not pregnant, breast feeding, or attempting to 
become pregnant (for 4 weeks before the screening visit (visit 1) and 
throughout the duration of the study), and is of 
• 
nonchildbearing potential, defined as:  
− 
≥1 year post-menopausal 
− 
surgically 
sterile 
(tubal 
ligation, 
oophorectomy, 
or 
hysterectomy) 
− 
diagnosed as infertile and not undergoing treatment to reverse 
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infertility 
or is of 
• 
childbearing potential, has a negative serum pregnancy test at the 
screening visit (visit 1), and willing to commit to using a consistent 
and acceptable method of birth control as defined below for the 
duration of the study or exclusively has same-sex partners:   
− 
systemic contraception used for ≥1 month prior to screening, 
including birth control pills, transdermal patch (EVRA® or 
equivalent), vaginal ring (NUVARING® or equivalent), 
levonorgestrel implant (NORPLANT® or equivalent), or 
injectable progesterone (DEPO-PROVERA® or equivalent)  
− 
double barrier methods (condoms, cervical cap, diaphragm, and 
vaginal contraceptive film with spermicide)  
− 
intrauterine device (IUD) with a low failure rate <1% per year 
− monogamous with a vasectomized male partner or exclusively 
has same-sex partners  
or is of 
• 
childbearing potential and not sexually active, has a negative serum 
pregnancy test at the screening visit (visit 1), and willing to commit 
to using a consistent and acceptable method of birth control as 
defined above for the duration of the study, in the event the patient 
becomes sexually active 
If male and sexually active, the patient is willing to commit to an 
acceptable method of birth control for the duration of the study or 
exclusively has same-sex partners. 
Exclusion Criteria 
1. Known respiratory disorder other than COPD, including but not limited to 
the following: alpha-1-antitrypsin deficiency, cystic fibrosis, significant 
asthma, active bronchiectasis, sarcoidosis, lung fibrosis, pulmonary 
hypertension, pulmonary edema, or interstitial lung disease. 
2. Evidence or history of other clinically significant disease or abnormality 
(such as congestive heart failure, uncontrolled hypertension, uncontrolled 
coronary artery disease, myocardial infarction, stroke, glaucoma or cardiac 
dysrhythmia), sleep apnea, malignancy (excluding basal cell carcinoma).  
In addition, historical or current evidence of significant hematologic, 
hepatic, neurologic, psychiatric, renal, pulmonary, or other diseases that in 
the opinion of the Investigator, would put the patient at risk through study 
participation, or would affect the study analyses if the disease exacerbated 
during the study. 
3. Known active tuberculosis. 
4. Hospitalization for a COPD exacerbation or pneumonia within 12 weeks 
prior to the screening visit (visit 1).   
5. History of frequent COPD exacerbations of moderate to severe severity 
averaging 2 or more per year, or 2 or more exacerbations per year which 
resulted in hospitalization, averaged over the last 3 years. 
6. Treatment for a non-hospitalized COPD exacerbation or pneumonia 
requiring antibiotics and/or systemic corticosteroids within 12 weeks prior 
to the screening visit (visit 1).   
7. History of paradoxical bronchospasm, narrow-angle glaucoma, prostatic 
hypertrophy or bladder neck obstruction, which, in the Investigator’s 
opinion, would contraindicate the use of an anticholinergic agent. 
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8. The patient is pregnant or lactating, or plans to become pregnant or donate 
gametes (ova or sperm) during the study period or for 30 days after the 
patient’s last study-related visit (for eligible patients only, if applicable). 
Eligible female and male patients unwilling to employ appropriate 
contraceptive measures to ensure that pregnancy will not occur during the 
study will be excluded.  Any patient becoming pregnant during the study 
will be withdrawn from the study. 
9. Treatment with any protocol prohibited medications during the prescribed 
washout period before the screening visit (visit 1). 
10. Inability to discontinue COPD medications during the screening, run-in, 
and treatment periods. 
11. Documented or suspected viral or bacterial, upper respiratory infection 
(URI) or lower respiratory infection (LRI), sinusitis, sinus infection, 
rhinitis, pharyngitis, middle ear infection, urinary tract infection, or illness 
within 6 weeks prior to the screening visit (visit 1). 
12. History of allergy or hypersensitivity to anticholinergic/muscarinic 
receptor antagonist agent, beta-2 agonists, lactose/milk proteins, or 
specific intolerance to aerosolized tiotropium bromide containing 
products, or known hypersensitivity to any of the proposed ingredients or 
components of the delivery system. 
13. Factors (eg, infirmity, disability, or geographic location) that the 
Investigator feels would likely limit the patient's compliance with the 
study protocol or scheduled clinic visits. 
14. Current evidence or known history of alcohol or substance abuse within 
2 years of the screening visit (visit 1). 
15. Positive urine drug screen at the screening visit (visit 1).  If a patient has a 
positive urine drug screen for a class of drug which is consistent with a 
medication that the patient is currently prescribed (excluding inhaled 
marijuana), the patient can be considered eligible for the study after the 
prescription is confirmed by the Investigator. 
16. Clinically significant abnormalities as judged by the Investigator on the 
12-lead ECG at the screening visit (visit 1). 
17. History of a positive test for infection with human immunodeficiency virus 
(HIV), hepatitis B, or hepatitis C. 
18. Patient is either an employee of the investigational center or an immediate 
relative of an employee of the investigational center. 
19. History of lung volume reduction surgery, lung resection or on active 
phase of pulmonary rehabilitation within the previous 12 months prior to 
the screening visit (visit 1). 
20. Chronic oxygen use for >12 hours/day. 
21. Patient does not maintain regular day/night waking/sleeping cycles 
(eg. night shift workers).  
Randomization Criteria 
1. Patient continues to be in general good health, and continues to meet all 
study entry criteria. 
2. Patient has not experienced an AE that would result in failure to continue 
to meet selection criteria. 
3. Patient has had no significant changes in COPD medications or taken any 
prohibited medication during the screening and run-in period. 
4. Patient has had no COPD exacerbation during the screening and run-in 
period as defined in section 6.5. 
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5. Patient has withheld all inhaled SABAs for at least 6 hours and SAMAs 
for at least 8 hours prior to lung function assessments at visit 2. 
6. Patient has not had a viral/bacterial URI or LRI during the screening and 
run-in period.  A patient who develops symptoms of a URI or LRI during 
the screening and run-in period may rescreen once no sooner than 
6 weeks after resolution of symptoms, and at the discretion of the 
Investigator (see section 9.3.7).  
7. Patient has not had clinically significant abnormalities as judged by the 
Investigator on the 12-lead ECG at visit 2. 
8. Patient has no clinically significant laboratory abnormality as judged by 
the Investigator at the screening visit (visit 1). 
9. Patient has demonstrated ediary compliance to placebo run-in medication 
within the margins of at least ≥75% and ≤125% of projected use.  
10. Patient has completed diary data on a minimum of 5 days out of the last 
7 days prior to randomization (not including the day of randomization) 
and has achieved a minimum of 75% compliance with the ediary during 
the run-in period. 
Continuation Criteria 
1. Patient continues to be in general good health, and continues to meet 
study eligibility criteria. 
2. Patient has not had a moderate to severe COPD exacerbation during the 
double-blind period in Part 1 as defined in section 6.5. 
3. Patient has not had a viral/bacterial URI or LRI during the double-blind 
treatment in Part 1.  See section 6.5. 
4. Patient’s pre-bronchodilator FEV1 at visits 3 through 4 does not vary by 
more than ±10% of the value obtained at the randomization visit (visit 2).  
Retests will be permitted at discretion of the Investigator and per the 
retest criteria is section 9.3.6. 
Note: The pre-bronchodilator FEV1 value constitutes the average of the 
2 values taken at 30 and 15 minutes before dosing with study medication. 
5. Patient has not had clinically significant abnormalities as judged by the 
Investigator on the 12-lead ECG at visits 3-4.  
6. Patient has not experienced an AE that would result in failure to continue 
to meet the selection/continuation criteria. 
Study Endpoints 
Primary Endpoint 
The primary endpoint is the change from baseline in FEV1AUC0-24h on day 1. 
Safety Endpoints 
Safety will be assessed throughout Part 1 and Part 2 of the study by 
monitoring the following: 
• 
AEs 
• 
SABA (albuterol/salbutamol MDI) and concomitant medication use 
• 
vital signs measurements 
• 
physical examinations  
• 
HEENT and chest examinations 
• 
COPD exacerbations 
• 
12-lead ECGs  
Other Endpoints 
For a subset of the LUPINHALERs used during the open-label extension 
(Part 2), the following endpoints will be assessed: 
• 
ruggedness of the LUPINHALER during 72 days of in-patient use: 
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• 
percent (%) of overall inhalers with reported problems or 
malfunctions; comprised of problems/malfunctions encountered 
with the device (eg, lack of efficacy, mechanical problems, 
problems with device after it has been dropped) during 72 days 
of in-patient use 
• 
in vitro performance of 100 inhalers post 72 days of in-patient use 
Test Product, Dose, and Mode 
of Administration 
Test product: Tiotropium bromide inhalation powder, 18 mcg 
Manufacturer: Lupin Limited 
Mode of Administration: Oral inhalation via LUPINHALER 
Dose: Part 1: Single-dose of 2 inhalations from one capsule at visits 2-4, per 
the treatment sequence 
Part 2: Two inhalations from one capsule, once daily in the morning for 
72 days of treatment 
Reference Product, Dose, and 
Mode of Administration 
Reference product: SPIRIVA HANDIHALER (tiotropium bromide 
inhalation powder), 18 mcg 
Manufacturer: Boehringer Ingleheim 
Mode of Administration: Oral inhalation 
Dose: (Part 1 only), Single-dose of 2 inhalations from one capsule at 
visits 2-4, per the treatment sequence  
Test Placebo Product, Dose, 
and Mode of Administration 
Placebo product: Identical to Lupin test product with no active ingredient 
(placebo LUPINHALER) 
Manufacturer: Lupin Limited 
Mode of Administration: Oral inhalation 
Dose: (Part 1 only), Single-dose of 2 inhalations from one capsule at 
visits 2-4, per the treatment sequence  
Reference Placebo, Dose, and 
Mode of Administration 
Placebo product: SPIRIVA HANDIHALER reference product with no 
active ingredient using the Lupin placebo capsule (placebo SPIRIVA 
HANDIHALER) 
Manufacturer: Boehringer Ingleheim 
Mode of Administration: Oral inhalation 
Dose: (Part 1 only), Single-dose of 2 inhalations from one capsule at 
visits 2-4, per the treatment sequence 
Statistical Methods 
Sample Size Determination 
The sample size estimation was determined based on demonstrating 
equivalence between the Test (T) product (Lupin Tiotropium Bromide 
Inhalation 
Powder) 
and 
the 
Reference 
(R) 
product 
(SPIRIVA 
HANDIHALER) for the primary endpoint change from baseline in FEV1 
AUC0-24 on the treatment day, and to demonstrate that both the Test (T) and 
Reference (R) products are superior to the placebo.  Bioequivalence (BE) will 
be demonstrated if the 90% confidence interval (CI) on the T to R ratio for 
the endpoint is contained within the interval (0.80, 1.25).  Superiority will be 
demonstrated by showing that each active treatment’s response for the 
endpoint is greater than, and statistically different from (p<0.05, two-sided), 
that of the placebo (P).  For the equivalence evaluation, the results in the PP 
analysis set will be considered definitive and for the superiority evaluations, 
those in the Intent-to-Treat (ITT) population will be considered definitive. 
A review of the literature did not yield any estimates of within-patient 
variability of baseline-adjusted FEV1 AUC0-24 from a crossover study using a 
similar patient population with similar objectives.  From a review of studies 
on clinicaltrials.gov, there were a number of estimates available of 
between-patient variability for baseline-adjusted FEV1 AUC0-24.  From the 
12 studies reviewed, the mean coefficient of variation (CV) for the variable 
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was 121%.  Within-patient variability is generally much less than between-
patient variability.  As a starting point for the sample size estimation it was 
assumed that the within-patient variability would be about 50% of the 
between-patient variability, or a CV of 60%.  
The goal of the study is to complete 180 patients per protocol.  With a sample 
size in each of the 6 sequence groups of 30, for a total sample size of 180, a 
crossover design will have 90% power to reject both the null hypothesis that 
the ratio of the test mean to the standard mean is below 0.80 and the null 
hypothesis that the ratio of test mean to the standard mean is above 1.25 (ie, 
that the test and standard are not equivalent), in favor of the alternative 
hypothesis that the means of the 2 treatments are equivalent, assuming that 
the expected ratio of means is 1.00, the between-patient coefficient of 
variation is 1.21, the intra-patient coefficient of variation is 0.60.  In order to 
allow for a potential 30% premature withdrawal rate or loss from the PP 
population due to protocol deviations, 240 patients will be randomized in 
total, 40 to each of the 6 treatment sequences. . 
As no estimates of within-patient variability were available in the public 
domain, a blinded interim analysis will be conducted in order to assess the 
within-patient variability.  The blinded interim analysis will be done to 
ascertain if an increase in sample size is necessary maintain 90% power to 
complete the study with a 90% CI for the relative bioavailability of the Test 
(T) to the Reference (R) product inside of the pre-specified interval 0.80-1.25. 
Analysis of Primary Endpoints This crossover study will follow a Williams design with 6 treatment 
sequences balanced for first order carryover effects.  A mixed model analysis 
consisting of fixed effects of treatment, visit, and sequence, and the random 
effect of patient will be carried out. 
The analysis of primary endpoints for BE will be performed with this model 
on the PP population which will include all patients in the PP population who 
have generated FEV1 data over 24 hours. 
The 90% CI on the ratio of the T-to-R means will be constructed using 
Fieller’s method.  Bioequivalence (BE) will be declared if the 90% CI is 
entirely contained within the BE interval, 0.800 to 1.250.  
Adequate study sensitivity will be demonstrated if the Test (T) and Reference 
(R) products are shown to be statistically superior to placebo (two-sided, 
p<0.05, by applying the mixed model analysis to the ITT population. 
Analysis of Safety Endpoints 
All safety endpoints will be tabulated by treatment on the safety analysis set 
without formal inferential statistics. AEs will be mapped using Medical 
Dictionary for Regulatory Activities (MedDRA) with respect to the system 
organ class and preferred term.  Incidence of treatment-emergent AEs and 
serious adverse events (SAEs) will be tabulated.  Observed and change from 
baseline in vital signs, physical examinations, HEENT and chest 
examinations, COPD exacerbations, and ECGs will be tabulated by study 
medication. 
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2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Abbreviation 
Definition 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ATS 
American Thoracic Society 
AUC0-24 
area under the curve from time zero to 24 hours postdose 
CDER 
Center for Drug Evaluation and Research 
CDMS 
clinical data management system 
CFR 
Code of Federal Regulation 
CI 
confidence interval 
CRF 
case report form 
CRO 
Contract research organization 
COPD 
chronic obstructive pulmonary disease 
CV 
coefficient of variation 
CYP3A4 
cytochrome P450 3A4 
DALYS 
Disability Adjusted Life Years 
DPI 
dry powder inhaler 
ECG 
Electrocardiogram 
ERS 
European Respiratory Society 
ER-S 
Evaluating Respiratory Symptoms 
ET 
early termination 
EU 
European Union 
eCRF 
electronic case report form 
EXACT PRO (EXACT) 
Exacerbations of Chronic Pulmonary Disease Tool Patient Reported 
Outcome 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in the first second 
GCP 
Good Clinical Practice 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
HEENT 
head, ears, eyes, nose, and throat 
HIPAA 
Health Insurance Portability and Accountability Act Authorization 
HIV 
human immunodeficiency virus 
 
 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
IUD 
intrauterine device 
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Iv 
Intravenous 
LABA 
long-acting beta agonist 
LAMA 
long-acting anti-muscarinic agent 
LCM 
Local Clinical Management 
LLT 
lowest level term 
LRI 
lower respiratory infection 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDI 
metered dose inhaler 
NHANES III 
National Health and Nutrition Examination Survey III 
OTC 
over-the-counter 
P 
Placebo 
PD 
pharmacodynamics(s) 
PFTs 
pulmonary function tests 
PK 
Pharmacokinetic 
PT 
preferred term 
pMDI 
pressurized metered dose inhaler 
PP 
per-protocol 
PRN 
as needed 
R 
Reference 
RLD 
reference listed drug 
SABA 
short-acting beta agonist 
SAMA 
short-acting anti-muscarinic agent 
SAE(s) 
serious adverse event(s) 
SAP 
statistical analysis plan 
sNDA 
Supplemental New Drug Application 
SOC 
system organ class 
SUSAR 
serious unexpected adverse reactions 
T 
Test 
tmax 
time to maximum bronchodilator response 
URI 
upper respiratory infection 
USA 
United States of America 
USC 
United States Code 
 
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3 
INTRODUCTION 
3.1 
BACKGROUND 
Chronic obstructive pulmonary disease (COPD) is a common preventable and treatable 
disease which is characterized by persistent airflow limitation that is usually progressive 
and is associated with an enhanced chronic inflammatory response in the airways and the 
lung to noxious particles or gases (Global Initiative for Chronic Obstructive Lung 
Disease [GOLD] 2016).  Exacerbations and associated co-morbidities contribute to the 
overall severity in individual patients and present targets for treatment (GOLD 2016). 
Chronic obstructive pulmonary disease (COPD) is the 4th leading cause of mortality 
globally (GOLD 2016) and this is set to increase in prevalence partially in response to 
historical smoking trends over past decades, although outdoor, occupational and indoor 
pollutants are also a major risk factor in development of COPD. 
In the United States of America (USA) the estimated direct costs of COPD are around 
$29.5 billion annually with indirect costs of $20.4 billion; in Europe the burden of COPD 
makes up around 6% of the total healthcare budget.  Fewer than 6% of the adult 
population have been diagnosed with COPD although there is a significant level of under 
diagnosis and the overall incidence is likely to be higher than this (van den Boom 1998).  
Disease progression is generally associated with increasing levels for disability.  The 
overall impact of disability and mortality can be quantified by Disability Adjusted Life 
Years (DALYs) which represent the sum of years lost due to premature mortality plus the 
sum of years lived with disability.  Chronic obstructive pulmonary disease (COPD) is set 
to rise from the twelfth highest driver for DALYs in 1990 to the seventh highest by 2030 
(Mathers 2006).  
The goals of COPD therapy are focused initially on smoking cessation for subjects who 
continue to smoke followed by relief of symptoms, moderation of exacerbation frequency 
and severity and improvement in health quality and exercise tolerance (GOLD 2016).  
Initial treatments for intermittent symptoms tend to be short-acting bronchodilators 
(SABAs) which are generally either beta-agonists (eg, albuterol) or anticholinergics (eg, 
ipratropium).  The duration of action of SABAs is limited and as symptoms progress 
these are largely substituted by long-acting bronchodilators (LABAs), which include a 
variety of beta-agonists or anticholinergic medications.  Long-acting bronchodilators 
(LABAs) can be used in isolation or as a combination of mechanisms for greater 
symptom control, or with the addition of broad spectrum anti-inflammatory medications 
such as inhaled corticosteroids for patients with more severe disease or at increased risk 
of exacerbations.  The anticholinergic medications work by blocking the effect of 
acetylcholine on muscarinic receptors which results in smooth muscle relaxation and 
bronchodilation, which opens the airways and lowers airway resistance. 
Tiotropium bromide is one of a number of long-acting anticholinergic medications 
approved for use with COPD.  Tiotropium bromide under the trade name SPIRIVA® was 
approved by the Food and Drug Administration (FDA) in 2004 as a single-dose dry 
powder device delivered by the HANDIHALER® device for the long-term, once daily 
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maintenance treatment of bronchospasm associated with COPD.  In 2009, a 
supplementary New Drug Application (sNDA) was granted for the indication to be 
expanded to include COPD exacerbation reduction.  Tiotropium has been shown to 
reduce exacerbations and related hospitalization, improve health status (Barr 2005) and 
increase the effectiveness of pulmonary rehabilitation (Cheyne 2013), in addition to 
providing a maintenance therapy for bronchospasm.  
Lupin Inc. is developing Tiotropium Bromide Inhalation Powder, equivalent to 18 mcg 
tiotropium/capsule (hereinafter referred to Lupin Tiotropium Bromide Inhalation Powder) 
as a substitutable product for SPIRIVA HANDIHALER.  The strategy for the proposed 
clinical development of Lupin Tiotropium Bromide Inhalation Powder includes a total of 
2 pivotal clinical studies: one assessing pharmacokinetic (PK) bioequivalence (BE) and 
one assessing pharmacodynamics (PD) BE of Lupin Tiotropium Bromide Inhalation 
Powder and SPIRIVA HANDIHALER.  In addition, pilot studies are planned to examine 
the PK endpoints of Lupin Tiotropium Bromide Inhalation Powder compared to 
SPIRIVA HANDIHALER.  Refer to section 3.2 regarding recent clinical experience with 
Tiotropium Bromide Inhalation Powder. 
3.2 
CLINICAL EXPERIENCE WITH TIOTROPIUM BROMIDE 
INHALATION POWDER ADMINISTERED BY A DRY POWDER 
HANDIHALER (DPI) 
SPIRIVA is marketed in 2 different delivery formats: as a single-dose DPI delivering 
18 mcg of tiotropium from a capsule via the HANDIHALER device and as a multiple 
dose aqueous solution aerosolized mist inhaler delivering 1.25 or 2.5 mcg tiotropium per 
actuation via the RESPIMAT® device.  These devices are marketed in the USA, Europe 
and, Japan under the same SPIRIVA trade name.  
SPIRIVA has been found to the well tolerated with the most common side effect of dry 
mouth.  Uncommon potential side effects include constipation, increased heart rate, 
blurred vision, glaucoma, urinary deficiency and urinary retention.  Because Lupin 
Tiotropium Bromide Inhalation Powder is designed to be a substitutable product for 
SPIRIVA HANDIHALER, the safety profile is expected to be similar to SPIRIVA. 
To date, 2 clinical studies (Study LBC-P-055-15 and LBC-P-006-15) with Lupin 
Tiotropium Bromide Inhalation Powder have been conducted. 
Study LBC-P-055-15 was a randomized, open-label, single-dose, 3-period Phase 1, PK 
crossover study being conducted in healthy male subjects 18-45 years of age under 
fasting conditions.  The primary objective of the study was to assess the systemic levels 
and relative bioavailability of a single orally-administered dose of tiotropium (36 mcg), 
administered as 2 inhalations from 1 batch of Lupin tiotropium capsules 18 mcg 
(×2 capsules) via both the LUPINHALER and HANDIHALER, and 1 batch of SPIRIVA 
capsules 18 mcg (×2 capsules) via the HANDIHALER. 
Preliminary safety results from this study indicate that Tiotropium Bromide Inhalation 
Powder was well tolerated by the healthy subjects, ages 18 to 45 years.  No SAEs were 
reported.  The final statistical analyses and PK results are not available at this time.  
Because this was a pilot study used to screen a formulation of test product which is not 
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representative of the exhibit batch to be used in the pivotal BE in vivo studies, data is on 
file and not presented in this section.  
Study LBC-P-0006-15 was a randomized, open-label, single-dose, 3-period Phase 1, PK 
crossover study being conducted in healthy male subjects 18-45 years of age under 
fasting conditions.  The primary objective of the study was to assess the systemic levels 
and relative bioavailability of a single orally-administered dose of tiotropium (18 mcg), 
from 2 different batches of Lupin tiotropium capsules 18 mcg (×1 capsule) via the 
LUPINHALER, and 1 batch of SPIRIVA capsules 18 mcg (×1 capsule) via the 
HANDIHALER. 
Preliminary safety results from this study indicate that Tiotropium Bromide Inhalation 
Powder was well tolerated by the healthy subjects, ages 18 to 45 years.  No SAEs were 
reported.  The final statistical analyses and PK results are not available at this time. 
3.3 
STUDY PURPOSE 
Lupin Inc. is developing Tiotropium Bromide Inhalation Powder as a substitutable 
product for SPIRIVA HANDIHALER.  This study is designed to show BE in terms of 
efficacy between the Lupin Tiotropium Bromide Inhalation Powder, 18 mcg administered 
as a single dose versus SPIRIVA HANDIHALER, 18 mcg.  This study will also assess 
device robustness of the LUPINHALER. 
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4 
STUDY OBJECTIVES 
4.1 
PRIMARY OBJECTIVE 
The primary objective of this study is to show clinical BE in the efficacy of the Lupin 
Tiotropium Bromide Inhalation Powder, 18 mcg administered as a single dose versus 
SPIRIVA HANDIHALER, 18 mcg based on the adjusted mean change in forced 
expiratory volume in the first second (FEV1) area under the curve from time zero to 24 
hours postdose (AUC0-24h) on day 1. 
4.2 
SECONDARY OBJECTIVES 
The secondary objectives of this study are to evaluate the safety and tolerability of the 
Lupin Tiotropium Bromide Inhalation Powder and SPIRIVA HANDIHALER following 
single doses of 18 mcg in patients 40 years of age and older with COPD. 
4.3 
OTHER OBJECTIVES  
For a subset of the Lupin tiotropium DPIs (LUPINHALER™) used during the open-label 
extension (Part 2) the following objectives will be assessed: 
• ruggedness of the LUPINHALER during 72 days of in-patient use 
• in vitro performance post 72 days of in-patient use 
4.4 
STUDY ENDPOINTS 
4.4.1 Primary Efficacy Endpoint 
The primary endpoint is the change from baseline in FEV1 AUC0-24h on day 1.  On each 
study day in Part 1, baseline is defined as the average of the FEV1 values recorded at 
approximately 30 minutes and 15 minutes before dosing. 
4.4.2 Safety Endpoints 
Safety will be assessed throughout Part 1 and Part 2 of the study by monitoring the 
following: 
• adverse events (AEs) 
• SABA (albuterol/salbutamol MDI) and concomitant medication use 
• vital signs measurements 
• physical examinations  
• head, ears, eyes, nose, and throat (HEENT) and chest examinations 
• COPD exacerbations 
• 12-lead electrocardiograms (ECGs) 
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4.4.3 Other Endpoints 
For a subset of the LUPINHALERs used during the open-label extension (Part 2), the 
following endpoints will be assessed: 
• ruggedness of the LUPINHALER during 72 days of in-patient use 
• 
percent (%) of overall inhalers with reported problems or malfunctions; 
comprised of misuse episodes (eg, impact and moisture) and issues identified 
(eg, mechanical problems and COPD worsening/seems ineffective) during 
72 days of in-patient use 
• in vitro pharmaceutical performance of 100 inhalers post 72 days of in-patient use 
The data resulting from the in vitro evaluation of the pharmaceutical performance 
will be presented in a separate report. 
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5 
INVESTIGATIONAL PLAN 
5.1 
OVERALL DESIGN AND PLAN OF THE STUDY 
This is a 2-part clinical study:   
• Part 1 is a randomized, double-blind, double-dummy, placebo-controlled, 
3-period, single-dose crossover study that will evaluate the clinical BE of 
single-dose treatment of Lupin Tiotropium Bromide Inhalation Powder, 18 mcg 
and SPIRIVA HANDIHALER, 18 mcg in patients 40 years of age and older with 
established COPD.   
• Part 2 is a 12-week open-label extension of Part 1, which will enroll a subset of 
patients at select investigational centers who successfully completed Part 1 of the 
study, to assess robustness of the LUPINHALER over 72 days of treatment. 
The duration of patient participation for Part 1 is approximately 14 weeks and for patients 
participating in both Part 1 and Part 2, the duration of patient participation is 
approximately 26 weeks. 
5.1.1 Part 1: Double-Blind Treatment Period 
Part 1 of the study consists of a screening period up to 30 days, followed by a 
single-blind placebo run-in period of 14 (+2) days and 3 single-dose, double-blind 
treatment periods (visits 2-4) each separated by a 21-day (+3 days) washout period.  Each 
double-blind treatment period begins with administration of the study medication at the 
investigational center, followed by lung function assessments collected over a 24-hour 
period.  For patients ending participation in the study after completing Part 1 and not 
enrolling into the open-label extension (Part 2), a follow-up visit via phone contact will 
be conducted 7 days (±3 days) after the completion of treatment period 3 (visit 4). 
The screening period, of up to 30 days, allows for adequate washout of the following 
COPD therapies, along with other prohibited medications per protocol: 
• long-acting anti-muscarinic agent (LAMA) medications (including mono products 
and combination products containing LAMAs [eg, LAMA/LABA]) will not be 
permitted within 21 days of the screening visit (visit 1) 
• long-acting beta agonist (LABA) mono products will not be permitted within 7 
days of the screening visit (visit 1) 
• inhaled corticosteroid (ICS) mono products and ICS/LABA combination products 
will not be permitted within 30 days of the screening visit (visit 1) 
If a patient is washing out of ICS (monotherapy) or ICS/LABA combination therapy as 
stated above, an additional 3 day window is permitted to complete the assessments for the 
screening visit (visit 1). 
If the patients were formerly taking LAMA, LABA, or ICS/LABA therapy, the 
medications will need to be discontinued and may be replaced at the discretion of the 
Investigator with the short-acting anti-muscarinic agent (SAMA) medication, ipratropium 
bromide, for use during the course of the study.  Patients who have not taken LAMA, 
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LABA or ICS/LABA combination products within the time period specified above, or 
who are not on medications that are restricted according to the protocol criteria, and who 
have met the selection criteria (eg, reversibility and baseline safety measures) at the 
screening visit (visit 1) will begin the 14 (+2) day single-blind placebo run-in period. 
All patients enrolled in the screening/run-in periods will be supplied with the following; 
ediary/electronic flow meter to measure lung function for monitoring disease stability 
during the screening and run-in periods; short-acting bronchodilator (SABA), ie, 
albuterol/salbutamol metered dose inhaler (MDI); 90 mcg ex-actuator or equivalent, for 
use during the course of the study.  Dispensation of the albuterol/ salbutamol MDI is not 
required during the screening period if the patient is taking this medication as part of their 
current COPD therapy.  Once the patient is enrolled in the run-in period, 
dispensation/administration of the study albuterol/salbutamol MDI is required and the 
patient will discontinue the use of their own albuterol/salbutamol MDI.  Patients enrolled 
in the run-in period will also be supplied with a placebo Lupin Tiotropium Bromide 
Inhalation Powder (placebo LUPINHALER) for once daily administration (2 inhalations 
from one capsule) in the morning throughout the single-blind run-in period.  Patients will 
be required to measure FEV1 prior to dosing in the morning at approximately the same 
time each day.  The FEV1 results and usage of study medication/albuterol/salbutamol 
MDI will be monitored and recorded in the ediary.  Patients will also complete the 
Exacerbations of Chronic Pulmonary Disease Tool (EXACT®) Patient Reported Outcome 
(PRO) within the ediary, once daily, each evening before bedtime during the screening 
and run-in periods. 
Patients will present at the investigational center for visit 2 on day 0 between 0600 and 
1000 having withheld the prohibited/restricted medications for the prescribed protocol 
period and without conducting lung function measurements on the electronic flow meter 
(home device).  Patients will record albuterol/salbutamol MDI usage in their diaries on 
the mornings prior to this visit.  Patients meeting all of the randomization criteria will be 
randomly assigned to 1 of 6 treatment sequences in a double-dummy manner using a 
Williams design Latin Square as described in section 7. 
In order to maintain the patient blind, a specified member of the investigational center (ie, 
unblinded administrator) will load and dispense the study medication to the patient and 
instruct the patients to take 2 full inhalations from each of 2 inhalers.  The unblinded 
administrator will also apply an opaque covering to the chamber windows prior to patient 
administration to obstruct capsule identification in each inhaler. 
Patients 
will 
undertake 
2 baseline 
FEV1 
measurements 
at 
0 
hours (-30 
and -15 minutes before study medication administration) followed by serial FEV1 
measurements at 5 and 30 minutes postdose, and at 1, 2, 4, 6, 8, 10, 12, 23, and 24 hours 
postdose.  The 23 and 24 hour FEV1 measurements will be taken on the 2nd day of the 
visit (day 1) in the morning at the investigational center.  Prior to and for the duration of 
the FEV1 measurements at the investigational center visits (day 0 and day 1), patients 
should refrain from using albuterol/salbutamol MDI and other prohibited medication; 
patients should not smoke for at least 1 hour prior to lung function assessments during the 
visit; and patients should adhere to the dietary restrictions as per protocol. 
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After completion of all assessments at visit 2, the patients will enter a 21-day (+3 days) 
washout phase where the patients may continue to use albuterol/salbutamol MDI and 
other medications permitted per protocol (eg, SAMA).  Patients will continue to measure 
lung function for monitoring disease stability during the double-blind treatment period.  
On days of non-investigational center visits, patients will be required to measure FEV1 
once daily prior to dosing in the morning at approximately the same time each day.  The 
FEV1 will be recorded in the ediary/electronic flow meter.  Patients will also complete 
the EXACT once daily, each evening before bedtime within the ediary.  On days of 
investigational center visits, patients will perform the FEV1 measurements and administer 
the study medication at the investigational center, and the EXACT will be collected at 
home in the evening before bedtime.  Usage of albuterol/salbutamol MDI will also be 
recorded in the ediary. 
Prior to visit 3 (days 21 and 22) and visit 4 (days 42 and 43) patients should observe the 
same smoking, dietary and medication restrictions as visit 2.  Patients will record 
albuterol/salbutamol MDI usage in their diaries on the mornings prior to these visits; 
however, no FEV1 measurements will be performed in the morning using the electronic 
flow meter (home device).  Patients should present at the investigational center so that the 
start of lung function testing will be within ±1 hour from the lung function testing at 
visit 1.  Patients will then undertake 2 baseline FEV1 measurements at 0 hours (-30 
and -15 minutes before study medication administration), followed by serial FEV1 
measurements at 5 and 30 minutes postdose, and at 1, 2, 4, 6, 8, 10, 12, 23, and 24 hours 
postdose.  After completion of all assessments at visit 3 (days 21 and 22), the patient will 
enter a 21-day (+3 days) washout phase where the patient may continue to use 
albuterol/salbutamol MDI and other medications permitted per protocol (eg, SAMA). 
After completion of visit 4 (days 42 and 43), a subset of patients (approximately 
120 patients) at select investigational centers who successfully completed Part 1 and 
continue to meet the continuation criteria will be eligible for enrollment into a 12-week 
open-label extension to examine the robustness of the LUPINHALER.  Patients who 
successfully completed the 3 single-dose treatments in Part 1 and who are not enrolled 
into the open-label extension (Part 2) will be contacted via phone 7 days (±3 days) after 
the visit for a final safety check and then formally discharged from the study. 
5.1.2 Part 2: Open-Label Extension 
The open-label extension (Part 2) will consist of 7 visits (visit 5 through visit 10, and 
follow-up), and will begin on the last day of visit 4 (Part 1).  Visits 6 and 8 will be 
conducted via telephone contact.  The final safety follow-up for those patients 
participating in Part 2 will be conducted via telephone 7 days (±3 days) after the last 
active treatment of the open-label extension (ie, visit 10). 
Patients participating in the open-label extension will begin study activities on the same 
day as the final visit in the double-blind treatment period (visit 4), which will be 
considered the first day of the open-label extension (visit 5).  Patients will be issued a 90-
day supply of the Tiotropium Bromide Inhalation Powder, 18 mcg for once-daily 
administration (to be taken at home each morning) during a 72-day treatment phase.  
Treatment with the Lupin Tiotropium Bromide Inhalation Powder will begin on visit 5 
after all FEV1 assessments and study activities were completed for Part 1.  Patients will 
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be permitted to resume other non-study medications and albuterol/salbutamol MDI as 
permitted per protocol.  LAMA medications (mono and combination therapies), other 
than the study medication, are prohibited in Part 2 of the study.  Patients will assess 
functionality of the LUPINHALER daily and record this data in the ediary. 
Patients will measure lung function to monitor disease stability via the ediary/electronic 
flow meter during the open-label extension.  Patients will be required to measure FEV1 
twice daily: upon awakening in the morning immediately prior to dosing with the study 
medication and at 2 (+2) hours after study medication administration.  The FEV1 results 
and albuterol/salbutamol MDI/study medication usage will be monitored and recorded in 
the ediary/electronic flow meter.  Patients will also complete the EXACT once daily, 
each evening before bedtime within the ediary.  
At visit 6 and visit 8, patients will be contacted via telephone by investigational center 
personnel to monitor AEs and any issues regarding the inhaler function.  
The patients will return to the investigational center on visit 7 and visit 9 for an overall 
assessment of safety and tolerability, to verify inhaler technique, and to assess any inhaler 
issues/malfunctions.   
On visit 10, patients will return for a final treatment visit, in which vital signs will be 
assessed, inhaler issues/malfunctions assessed, and the ediary/electronic flow meter, 
albuterol/salbutamol MDI, and study medication collected and stored appropriately.  The 
patient should be contacted via phone 7 ±3 days after the final treatment visit (visit 10) 
for a final safety check and to be formally discharged from the study. 
If at any time patients experience a perceived issue with their inhaler, the ediary system 
will alert the investigational center who will arrange the necessary corrective action, if 
required.  The investigational center should endeavor to complete the electronic case 
report form (eCRF) within 24 hours of notification of an issue.  
Safety will be monitored throughout Part 1 and Part 2 of the study by vital signs 
measurements, albuterol/salbutamol MDI and concomitant medication usage, physical 
examinations, head, ears, eyes, nose, throat (HEENT)/chest examinations, spirometry 
(FEV1) measurements, electrocardiography (ECGs), ER-S: COPD scores (derived from 
the EXACT), COPD exacerbations, and AEs.  During the screening and run-in periods, 
safety will be assessed via FEV1 measurements, ER-S: COPD scores, and monitoring of 
AEs and COPD exacerbations. 
Refer to section 9.2.2.5 for details regarding COPD exacerbations. 
5.2 
DOSE RATIONALE 
The dose of the test product, Lupin Tiotropium Bromide Inhalation Powder, 18 mcg will 
be administered as 2 inhalations once daily via LUPINHALER, and is the maintenance 
dose of the marketed comparator product in this study (SPIRIVA HANDIHALER, 
18 mcg). 
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6 
SELECTION OF STUDY POPULATION 
For Part 1 of the study, patients will include male and female patients 40 years of age and 
older with COPD.  Part 2 of the study will enroll a subset of approximately 120 patients 
(from select investigational centers) who have successfully completed Part 1 of the study 
meeting and continue to meet the continuation criteria).  The duration of patient 
participation for Part 1 is approximately 14 weeks and for patients participating in both 
Part 1 and Part 2, the duration of patient participation is approximately 26 weeks. 
For Part 1, 240 patients will need to be randomized to allow for a 30% withdrawal rate 
with a goal of completing at least 180 per-protocol (PP) patients (40 per treatment 
sequence).  A blinded interim analysis will be performed in order to assess variability 
with the potential to increase the sample size to maintain 90% power.   
6.1 
INCLUSION CRITERIA 
A patient will be eligible for enrollment if all of the following inclusion criteria apply: 
1. Patient is able to give signed written informed consent prior to study entry.  
2. Male or female patients 40 years of age and older, inclusive, as of the screening 
visit (visit 1). 
3. Patient has a diagnosis of COPD according to the GOLD guidelines 2016. 
4. Ability to perform acceptable and repeatable spirometry according to the 
American Thoracic Society (ATS)/European Respiratory Society (ERS) 2005 
criteria and/or protocol defined criteria. 
Note: If the patient cannot meet the criterion, the visit may be rescheduled as per 
the retest criteria (section 9.3.6). 
5. Patient is able to achieve an inspiratory flow rate of ≥40 L/min using the In-Check 
DIAL by achieving ≥40 L/min inspiratory flow rate at the screening visit (visit 1). 
6. Patient is able to demonstrate proper inhalation technique using the DPI. 
7. Post-bronchodilator FEV1 of <80% of the predicted value at the screening visit 
(visit 1).  National Health and Nutrition Examination Survey (NHANES) III 
normative values will be used for all patients with adjustments to these values 
made for African American patients.  All spirometry tests should be carried out in 
accordance with the ATS/ERS 2005 criteria (Miller et al 2005). 
Note: If the patient cannot meet the criterion, the visit may be rescheduled as per 
the retest criteria (section 9.3.6). 
8. Post bronchodilator FEV1/FVC ratio of ≤0.70 at the screening visit (visit 1). 
Note: If the patient cannot meet the criterion, the visit may be rescheduled as per 
the retest criteria (section 9.3.6). 
9. Patient has demonstrated ≥15% reversibility of FEV1 within 30 or 60 minutes 
following 68 mcg of ipratropium bromide inhalation (pMDI) at the screening visit 
(visit 1).  If required, spacers are permitted for use during reversibility testing for 
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ipratropium administration.  Patients who do not demonstrate a positive 
improvement of at least 15% in FEV1 measured at 30 or 60 minutes post 
inhalation will not be eligible to participate in the study.  However, based on 
Investigator judgment, patients will be allowed to retest once no sooner than 24 
hours and no later than 2 weeks after the initial failure (see section 9.3.6).  
Reversibility values of 14.50-14.99 will be rounded to 15. 
10. Patient is a current smoker or non-smoker with a minimum 10 pack-years of 
historical use (the equivalent of one pack per day for 10 years). 
11. Patient is able to withhold all inhaled SABAs for at least 6 hours and SAMAs for 
at least 8 hours prior to lung function assessments on study visit days. 
12. Patient is medically able to tolerate permitted medications without a significant 
adjustment of dosage, formulation, dosing interval for the duration of the study, 
and judged able by the Investigator to withhold them for the specified minimum 
time intervals prior to each clinic visit. 
13. Patient is free of any concomitant conditions or treatments that could interfere 
with study conduct, influence the interpretation of study observations/results, or 
put the patient at increased risk during the study (eg, patient is not able to 
self-administer study medication or self-complete the ediary). 
14. Patient did not experience an AE that in the opinion of the Investigator would 
result in failure to meet the inclusion/exclusion criteria during the screening 
period. 
15. If female, is currently not pregnant, breast feeding, or attempting to become 
pregnant (for 4 weeks before the screening visit (visit 1) and throughout the 
duration of the study), and is of 
• nonchildbearing potential, defined as:  
- 
≥1 year post-menopausal 
- 
surgically sterile (tubal ligation, oophorectomy, or hysterectomy) 
- 
diagnosed as infertile and not undergoing treatment to reverse infertility 
or is of 
• childbearing potential, has a negative serum pregnancy test at the screening 
visit (visit 1), and willing to commit to using a consistent and acceptable 
method of birth control as defined below for the duration of the study or 
exclusively has same-sex partners:   
- 
systemic contraception used for ≥1 month prior to screening, including 
birth control pills, transdermal patch (EVRA® or equivalent), vaginal ring 
(NUVARING® or equivalent), levonorgestrel implant (NORPLANT® or 
equivalent), or injectable progesterone (DEPO-PROVERA® or equivalent)  
- 
double barrier methods (condoms, cervical cap, diaphragm, and vaginal 
contraceptive film with spermicide)  
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- 
intrauterine device (IUD) with a low failure rate <1% per year 
- 
monogamous with a vasectomized male partner or exclusively has same-
sex partners  
or is of 
• childbearing potential and not sexually active, has a negative serum pregnancy 
test at the screening visit (visit 1), and willing to commit to using a consistent 
and acceptable method of birth control as defined above for the duration of the 
study, in the event the patient becomes sexually active 
If male and sexually active, the patient is willing to commit to an acceptable 
method of birth control for the duration of the study or exclusively has same-sex 
partners. 
6.2 
EXCLUSION CRITERIA 
A patient who meets any of the following exclusion criteria must not be enrolled: 
1. Known respiratory disorder other than COPD, including but not limited to the 
following: alpha-1-antitrypsin deficiency, cystic fibrosis, significant asthma, 
active bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, 
pulmonary edema, or interstitial lung disease. 
2. Evidence or history of other clinically significant disease or abnormality (such as 
congestive heart failure, uncontrolled hypertension, uncontrolled coronary artery 
disease, myocardial infarction, stroke, glaucoma or cardiac dysrhythmia), sleep 
apnea, malignancy (excluding basal cell carcinoma).  In addition, historical or 
current evidence of significant hematologic, hepatic, neurologic, psychiatric, 
renal, pulmonary, or other diseases that in the opinion of the Investigator, would 
put the patient at risk through study participation, or would affect the study 
analyses if the disease exacerbated during the study. 
3. Known active tuberculosis. 
4. Hospitalization for a COPD exacerbation or pneumonia within 12 weeks prior to 
the screening visit (visit 1).   
5. History of frequent COPD exacerbations of moderate to severe severity averaging 
2 or more per year, or 2 or more exacerbations per year which resulted in 
hospitalization, averaged over the last 3 years. 
6. Treatment for a non-hospitalized COPD exacerbation or pneumonia requiring 
antibiotics and/or systemic corticosteroids within 12 weeks prior to the screening 
visit (visit 1).   
7. History of paradoxical bronchospasm, narrow angle glaucoma, prostatic 
hypertrophy or bladder neck obstruction, which, in the Investigator’s opinion, 
would contraindicate the use of an anticholinergic agent. 
8. The patient is pregnant or lactating, or plans to become pregnant or donate 
gametes (ova or sperm) during the study period or for 30 days after the patient’s 
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last study-related visit (for eligible patients only, if applicable).  Eligible female 
and male patients unwilling to employ appropriate contraceptive measures to 
ensure that pregnancy will not occur during the study will be excluded.  Any 
patient becoming pregnant during the study will be withdrawn from the study. 
9. Treatment with any protocol prohibited medications during the prescribed 
washout period before the screening visit (visit 1). 
10. Inability to discontinue COPD medications during the screening, run-in, and 
treatment periods. 
11. Documented or suspected viral or bacterial, upper respiratory infection (URI) or 
lower respiratory infection (LRI), sinusitis, sinus infection, rhinitis, pharyngitis, 
middle ear infection, urinary tract infection, or illness within 6 weeks prior to the 
screening visit (visit 1). 
12. History of allergy or hypersensitivity to anticholinergic/muscarinic receptor 
antagonist agent, beta-2 agonists, lactose/milk proteins, or specific intolerance to 
aerosolized tiotropium bromide containing products, or known hypersensitivity to 
any of the proposed ingredients or components of the delivery system. 
13. Factors (eg, infirmity, disability, or geographic location) that the Investigator feels 
would likely limit the patient's compliance with the study protocol or scheduled 
clinic visits. 
14. Current evidence or known history of alcohol or substance abuse within 2 years of 
the screening visit (visit 1). 
15. Positive urine drug screen at the screening visit (visit 1).  If a patient has a 
positive urine drug screen for a class of drug which is consistent with a 
medication that the patient is currently prescribed (excluding inhaled marijuana), 
the patient can be considered eligible for the study after the prescription is 
confirmed by the Investigator. 
16. Clinically significant abnormalities as judged by the Investigator on the 12-lead 
ECG at the screening visit (visit 1). 
17. History of a positive test for infection with human immunodeficiency virus (HIV), 
hepatitis B, or hepatitis C. 
18. Patient is either an employee of the investigational center or an immediate relative 
of an employee of the investigational center. 
19. History of lung volume reduction surgery, lung resection or on active phase of 
pulmonary rehabilitation within the previous 12 months prior to the screening 
visit (visit 1). 
20. Chronic oxygen use for >12 hours/day. 
21. Patient does not maintain regular day/night waking/sleeping cycles (eg, night shift 
workers). 
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6.3 
RANDOMIZATION CRITERIA 
1. Patient continues to be in general good health, and continues to meet all study 
entry criteria. 
2. Patient has not experienced an AE that would result in failure to continue to meet 
selection criteria. 
3. Patient has had no significant changes in COPD medications or taken any 
prohibited medication during the screening and run-in period. 
4. The patient has had no COPD exacerbation during the screening and run-in period 
as defined in section 6.5. 
5. Patient has withheld all inhaled SABAs for at least 6 hours and SAMAs for at 
least 8 hours prior to lung function assessments at visit 2.  
6. Patient has not had a viral/bacterial URI or LRI during the screening and run-in 
period.  A patient who develops symptoms of a URI or LRI during the screening 
and run-in period may rescreen no sooner than 6 weeks after resolution of 
symptoms, and at the discretion of the Investigator (see section 9.3.7). 
7. Patient has not had clinically significant abnormalities as judged by the 
Investigator on the 12-lead ECG at visit 2. 
8. Patient has no clinically significant laboratory abnormality as judged by the 
Investigator at the screening visit (visit 1). 
9. Patient has demonstrated ediary compliance to run-in medication within the 
margins of at least ≥75% and ≤125% of projected use. 
10. Patient has completed diary data on a minimum of 5 days out of the last 7 days 
prior to randomization (not including the day of randomization) and achieved a 
minimum of 75% compliance with the ediary during the single-blind run-in 
period. 
6.4 
CONTINUATION CRITERIA 
1. Patient continues to be in general good health, and continues to meet study 
eligibility criteria. 
2. Patient has not had a moderate to severe COPD exacerbation during the double-
blind period in Part 1 as defined in section 6.5. 
3. Patient has not had a viral/bacterial URI or LRI during the double-blind treatment 
in Part 1.  See section 6.5. 
4. Patient’s pre-bronchodilator FEV1 at visits 3 through 4 does not vary by more 
than ±10% of the value obtained at the randomization visit (visit 2).  Retests will 
be permitted at discretion of the Investigator and per the retest criteria is section 
9.3.6. 
Note: The pre-bronchodilator FEV1 value constitutes the average of the 2 values 
taken at 30 and 15 minutes before dosing with study medication. 
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5. Patient has not had clinically significant abnormalities as judged by the 
Investigator on the 12-lead ECG at visits 3-4.  
6. Patient has not experienced an AE that would result in failure to continue to meet 
the selection/continuation criteria. 
6.5 
WITHDRAWAL CRITERIA 
Patients may be discontinued from study treatment and assessments at any time.  Patients 
are also free to discontinue their participation in the study at any time, without prejudice 
to further treatment.  Wherever possible, patients should be seen and assessed by the 
Investigator(s).   
In the eCRF, study completion or discontinuation will be documented with the reason for 
any discontinuation.  
Study-specific (predefined COPD alert) criteria for withdrawal are listed below. 
The following criteria would require mandatory withdrawal from the study: 
• a moderate or severe COPD exacerbation occurring during the double-blind 
treatment period in Part 1:  
An exacerbation is defined as worsening of symptoms of COPD for at least 
2 consecutive days and classified as mild when patients do not require treatment 
with systemic corticosteroids and/or antibiotics; moderate when treatment with 
systemic corticosteroids and/or antibiotics are required; or severe when 
hospitalization or visit to the emergency care/acute care unit is required.  A 
separate exacerbation is considered when an interval of clinical improvement of at 
least 7 days is observed.  Note: A patient’s exacerbation should be deemed a 
moderate to severe exacerbation even if the symptoms have worsened in less than 
2 consecutive days, if the patient was treated with systemic corticosteroids and/or 
antibiotics, was hospitalized, or visited the emergency care/acute care unit. 
The following alert criteria should be evaluated by the Investigator for consideration of 
whether the patient should be withdrawn from the study. 
These criteria would include the following:  
• COPD exacerbation during Part 2 that prohibits the patient from administering 
their study medication (Lupin Tiotropium Bromide Inhalation Powder) once daily 
• use of medication for respiratory symptoms not allowed by the study protocol 
• viral or bacterial respiratory infection during Part 1 which results in an increase in 
the symptoms of COPD from the patient’s normal baseline level 
• prior to randomization (Part 1): a decrease in FEV1 of more than 20% from the 
predose FEV1 at the screening visit (visit 1) 
• post randomization (Part 1 and Part 2): more than 3 occurrences of a decrease in 
FEV1 of more than 20% from the predose FEV1 at the randomization visit (visit 2)  
• >20% decrease from the mean morning baseline FEV1 on more than 3 of the last 
7 (rolling) days during Part 1 (commencing once the predose pre-bronchodilator 
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study qualifying FEV1 (ie, pre-PFT) is performed at the screening visit [visit 1]) 
or Part 2  
•
viral or bacterial respiratory infection during Part 2 which results in an increase in
the symptoms of COPD from the patient’s normal baseline level
•
increase of ≥2 on the ER-S: COPD daily respiratory symptoms (RS) Total Score
during Part 1 (commencing at the start of the screening period) or Part 2
•
≥12 or more albuterol/salbutamol puffs per day on more than 2 of the last
7 (rolling) days during Part 1 (commencing at the start of the screening period) or
Part 2
Other possible reasons for a patient discontinuing participation in the study may include: 
•
patient withdrew consent
•
Sponsor requested patient to be withdrawn
•
protocol deviation/noncompliance
•
AE
•
lack of efficacy
•
lost to follow-up/failure to return
•
pregnancy
•
other (specify within eCRF)
6.6 
REPLACEMENT OF PATIENTS WHO WITHDRAW OR ARE 
DISCONTINUED 
Patients who withdraw, are discontinued, or are lost to follow-up will not be replaced.  
However, the final number of patients to be randomized will be determined following the 
blinded interim analysis.  The rate of patient early termination will be considered during 
the blinded interim analysis to help define the final number of patients to be randomized. 
The date the patient is withdrawn from the study and the reason for discontinuation will 
be recorded in the eCRF.  If there are multiple reasons for early discontinuation, the 
worst case scenario should be chosen. 
If a patient is withdrawn because of an AE, the event will be followed until the medical 
condition returns to baseline or is considered stable or chronic.  Discontinuation of 
patients due to AEs, including those due to abnormal laboratory results, should be 
promptly reported to Lupin Inc. 
If a patient is lost to follow-up (fails to return for study visits), a reasonable effort should 
be made to determine why the patient failed to return.  The occurrence of lost to follow-up 
will be documented in the eCRF. 
Every effort should be made for all randomly assigned patients prematurely 
discontinuing, regardless of cause, to undergo final evaluation procedures, in accordance 
with the early termination (ET) visit as described in section 9.3.5. 
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7 
TREATMENTS 
7.1 
TREATMENTS ADMINISTERED 
For Part 1, each patient will receive a single-dose of the following 3 treatments below in 
a double-blind, double-dummy crossover design. 
• Lupin Tiotropium Bromide Inhalation Powder, 18 mcg  
‒ 2 inhalations from one Lupin capsule via LUPINHALER  
(Lupin Tiotropium Bromide Inhalation Powder, 18 mcg)   
‒ 2 inhalations from one Lupin placebo capsule via HANDIHALER 
(Placebo SPIRIVA HANDIHALER)   
• 
SPIRIVA HANDIHALER, 18 mcg 
‒ 2 inhalations from one SPIRIVA capsule via HANDIHALER  
(SPIRIVA HANDIHALER 18 mcg)  
‒ 2 inhalations from one Lupin placebo capsule via LUPINHALER 
(Placebo LUPINHALER) 
• Placebo  
‒ 2 inhalations from one Lupin placebo capsule via LUPINHALER 
(Placebo LUPINHALER) 
‒ 2 inhalations from one Lupin placebo capsule via HANDIHALER 
(Placebo SPIRIVA HANDIHALER)   
Patients will be randomly assigned to these treatments via 1 of 6 treatment sequences as 
described in Table 7-1.  Each treatment period will be followed by a 21-day (+3 days) 
washout period. 
On each study day, the order of administration of the LUPINHALER and 
HANDIHALER will be randomly assigned via a randomization schedule separate from 
the main crossover randomization schedule. 
For Part 2, a subset of approximately 120 patients will administer Lupin Tiotropium 
Bromide Inhalation Powder, 18 mcg once daily (2 inhalations from 1 capsule) in the 
morning for 72 days. 
Patients will administer study medication as per the instructions in Appendix A. 
7.2 
IDENTITY OF INVESTIGATIONAL PRODUCT 
Lupin Tiotropium Bromide Inhalation Powder, designed to be substitutable for SPIRIVA 
HANDIHALER, consists of a capsule dosage form containing a dry powder formulation 
of tiotropium intended for oral inhalation with the LUPINHALER.  Each 
 
 Lupin capsule contains 18 mcg tiotropium (equivalent to 
22.5 mcg tiotropium bromide 
) blended with 
 (which 
may contain milk proteins) as the carrier.  The LUPINHALER is similar in size and 
shape to the HANDIHALER, and based on exactly the same operating principles. 
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7.3 
IDENTITY OF COMPARATORS 
SPIRIVA HANDIHALER (manufactured by Boehringer Ingleheim) consists of a capsule 
dosage form containing a dry powder formulation of tiotropium intended for oral 
inhalation only with the HANDIHALER device.  Each light green, hard gelatin SPIRIVA 
capsule contains 18 mcg tiotropium (equivalent to 22.5 mcg tiotropium bromide 
monohydrate) blended with lactose monohydrate (which may contain milk proteins) as 
the carrier.  The dry powder formulation within the SPIRIVA capsule is intended for oral 
inhalation only.  The active component of SPIRIVA HANDIHALER is tiotropium.  The 
drug substance, tiotropium bromide monohydrate, is an anticholinergic with specificity 
for muscarinic receptors.  It is chemically described as (1α, 2β, 4β, 5α, 7β)-7-
[(Hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane 
bromide monohydrate. 
Placebo products, similar to the Lupin Tiotropium Bromide Inhalation Powder and 
SPIRIVA HANDIHALER are comprised of a DPI and capsule (gelatin capsule for use in 
placebo SPIRIVA HANDIHALER and 
 capsule for use in placebo 
LUPINHALER) containing no active drug, just 
.  Placebo SPIRIVA 
HANDIHALER will be used in the double-blind portion of Part 1 and placebo 
LUPINHALER will also be used during the single-blind run-in period and double-blind 
portion of Part 1. 
7.4 
ANCILLARY SUPPLIES 
Albuterol/Salbutamol Medication 
Patients will be dispensed an albuterol/salbutamol pressurized metered dose inhaler 
(pMDI) for use during Part 1 and for patients participating in Part 2 of the study.   
Note: Dispensation of the albuterol/salbutamol MDI is not required during the screening 
period if the patient is taking this medication as part of their current COPD therapy.  
Once the patient is enrolled in the run-in period, dispensation/administration of the study 
albuterol/salbutamol MDI is required and the patient will discontinue the use of their own 
albuterol/salbutamol MDI. 
Placebo trainers 
Placebo product (LUPINHALER with placebo inhalation powder capsules) identical to 
the Lupin Tiotropium Bromide Inhalation Powder with no active drug contained in the 
capsules 
 will be provided for training purposes. 
ediary/electronic flow meter 
For the screening period, run-in period, Part 1 and Part 2 of the study, patients will be 
issued an ediary/electronic flow meter to record COPD symptom scores (EXACT); 
albuterol/salbutamol MDI usage; study medication usage (run-in and Part 2 only); and 
FEV1 measurements at home.  Diary collection begins at the time of signing the ICF.  
eDiaries/electronic flow meters will be dispensed on the 1st day of the screening period 
prior to patients beginning any medication washout, to assist with safety monitoring 
throughout the screening period. 
In addition device robustness data will be tracked via the ediary system. 
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In-Check DIAL device 
For Part 1 of the study, patients will be trained on inhaler technique using the In-Check 
DIAL, a hand held inspiratory flow measurement device.  Refer to section 9.2.3.5 and 
Appendix B for further details. 
7.5 
SUPPLY OF STUDY MEDICATION 
The Sponsor will provide an adequate amount of the study medication together with the 
appropriate release statement approving the study medication for human use in this 
clinical study.  All medications supplied by the Sponsor will be manufactured, tested, and 
released according to the current legal requirements and Good Manufacturing Practice 
(GMP). 
The study medication will be packed and shipped in appropriate storage boxes. Study 
medication should be examined immediately upon arrival at the study center.  If the study 
medication supplies appear to be damaged, quarantine the study medication, and contact 
the Sponsor  
Study medication must be kept in a secure, limited-access storage area, under the 
appropriate conditions.  Only authorized personnel will have access to the study 
medication at the investigational centers. 
Store Lupin Tiotropium Bromide Inhalation Powder, SPIRIVA HANDIHALER, placebo 
LUPINHALER, and placebo SPIRIVA HANDIHALER at 25°C (77°F); excursions 
permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].  The 
capsules (Lupin and SPIRIVA products) should not be exposed to extreme temperature or 
moisture.  Do not store the capsules in the DPIs. 
For storage of the albuterol/salbutamol pMDI, refer to the package insert. 
7.6 
METHOD OF ASSIGNING PATIENTS TO TREATMENT 
SEQUENCES 
Based on a Williams design Latin square, patients will be randomly allocated to treatment 
via 1 of the 6 treatment sequences shown in Table 7-1 below.  The randomization 
schedule will be generated within the Biometrics Department of the designated Contract 
Research Organization (CRO) by a statistician not involved in the study.   
Table 7-1. Randomization Scheme 
Treatment sequence 
Treatment period 1 
Treatment period 2 
Treatment period 3 
A (TRP) 
Lupin Tiotropium 
Bromide Inhalation 
Powder 18 mcg 
SPIRIVA 
HANDIHALER 
18 mcg 
Placebo  
B (RPT) 
SPIRIVA 
HANDIHALER 
18 mcg 
Placebo  
Lupin Tiotropium 
Bromide Inhalation 
Powder 18 mcg 
C (PTR) 
Placebo 
Lupin Tiotropium 
Bromide Inhalation 
Powder 18 mcg 
SPIRIVA 
HANDIHALER 
18 mcg 
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Treatment sequence 
Treatment period 1 
Treatment period 2 
Treatment period 3 
D (PRT) 
Placebo 
SPIRIVA 
HANDIHALER 
18 mcg 
Lupin Tiotropium 
Bromide Inhalation 
Powder 18 mcg 
E (TPR) 
Lupin Tiotropium 
Bromide Inhalation 
Powder 18 mcg 
Placebo 
SPIRIVA 
HANDIHALER 
18 mcg 
F (RTP) 
SPIRIVA 
HANDIHALER 
18 mcg 
Lupin Tiotropium 
Bromide Inhalation 
Powder 18 mcg 
Placebo 
Patients will be randomly assigned to the treatment sequences by means of a computer 
generated randomization list after confirmation of all eligibility criteria.  The 
randomization list and study medication will be assigned via interactive response 
technology (IRT). 
Additionally, on each study day, as this is a double-dummy study, the order of 
administration of the LUPINHALER and HANDIHALER will be assigned based on 
even/odd calendar days.  On odd calendar days (eg, 1, 3, 5, 29, 31), the LUPINHALER 
will be dosed first.  On even calendar days (eg, 2, 4, 6, 28, 30), the HANDIHALER will 
be dosed first. 
A subset of approximately 120 patients (at select investigational centers) will be enrolled 
into the open-label phase of the study (Part 2).  These patients will not be randomized and 
all patients in Part 2 will receive Lupin Tiotropium Bromide Inhalation Powder. 
7.7 
BLINDING 
7.7.1 Part 1 
This study will use commercially available SPIRIVA medication and inhalers which have 
attributes that make proper blinding of the assigned treatment a challenge; therefore there 
are some additional steps required to keep the patient and investigational center staff 
blinded to treatment allocation for Part 1 of the study.   
The SPIRIVA HANDIHALER and capsules are color-branded and labelled and would be 
recognizable to investigational center staff and patients who have previously used the 
medication.  To avoid the problem of bias, a double-blind, double-dummy approach will 
be adopted.  
The patients will administer study medication from 2 inhalers at each investigational 
center visit in Part 1 given by a specified unblinded administrator.  The inhalers will 
represent the commercially available HANDIHALER devices (from the USA) and the 
LUPINHALER.  
The unblinded administrator is not permitted to take part in any clinical or safety 
assessments and should not discuss the nature of the study medication administration 
with the other study team members. 
The unblinded administrator will collect the study medication from the pharmacy, 
remove the capsule from the relevant blister strips and prepare the inhalers out of sight of 
the patient.  The unblinded administrator will then obscure the observation windows in 
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the device with opaque tape and dispense to blinded study personnel, who will assist the 
patient to complete dosing as per the instructions for use (Appendix A). 
As indicated in the randomization scheme (Table 7-1), at each treatment visit the patient 
will receive either: 
• one active dose from 1 of the 2 inhalers; other inhaler contain placebo dose 
• 2 placebo doses  
Training of the patient on inhaler technique and dosing of the study medication will be 
undertaken by blinded study personnel.  The unblinded administrator will acknowledge 
all shipments, prepare blinded study medication, and dispense the blinded study 
medication to the blinded study personnel so that the core study team who are responsive 
for efficacy and safety assessments are unaware of the inhalers administered.  In addition, 
the unblinded administrator will witness dose administration in the double-blind portion 
of Part 1. 
The patient will self-administer the medication at the investigational center on each study 
day guided by this blinded study team member.  FEV1 testing will continue postdose by 
the blinded study team.   
Used inhalers, with the capsules contained in the inhaler, will be returned to the 
pharmacy (or designated study medication room) by the unblinded study team member 
for storage to aid drug accountability.   
7.7.2 Part 2 
Part 2 will be conducted via an open-label design; therefore, no blinding is required.  
Used inhalers and unused capsules will be returned to the investigational center. 
7.8 
TREATMENT COMPLIANCE 
For Part 1, compliance with administration of study medication during the double-blind 
treatment will be monitored by investigational center personnel through observation of 
dose administration at each treatment visit.  Compliance during the single-blind run-in 
period will be monitored via ediary by investigational center personnel.  Diary and FEV1 
data will be transferred to the study database at regular intervals.  If during the single-
blind run-in period, a patient is found to be less than 75% compliant with the completion 
of the ediary or <75% and >125% compliant with administration of placebo 
LUPINHALER, the patient will not be eligible to continue participation in the study. 
For Part 2, detailed compliance will be determined by reviewing the recorded dosing and 
study procedure data from the ediaries at each investigational center visit.  Diary and 
FEV1 data will be transferred to the study database at regular intervals.  If at any visit in 
Part 2, patients are found to noncompliant with study medication administration, the 
patient should be counseled on the importance of taking study medication as directed by 
the Investigator.  Patients are requested to administer treatment for 72 +3 days. 
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7.9 
DOSING PROCEDURES 
For Part 1, during the single-blind run-in period, patients will administer the placebo 
LUPINHALER once daily, in the morning for 14 (+2) days after completing FEV1 
measurements.  Patients will administer the 1st dose at the investigational center in the 
presence of investigational center personnel after completing spirometry procedures.  
Patients are to withhold their morning dose of placebo run-in medication on the morning 
of visit 2. 
For Part 1, prior to study visits 2 through 4, patients should refrain from using 
albuterol/salbutamol MDI and other prohibited medication; patients should not smoke at 
least 1 hour prior to lung function assessments during the visits; and patients should 
adhere to the dietary restrictions as per protocol (see section 8.2).  Patients will be trained 
on the correct use of the study medication.  Patients will administer 2 inhalations from 
each of 2 inhalers of the assigned study medication in the morning with the assistance of 
the blinded administrator.  Patients may stay overnight at the investigational center or at 
nearby housing facility (eg, hotel) to complete the FEV1 serial measurements over a 24-
hour period.  In certain cases, the patient may return home after the 12 hour FEV1 
measurement and return for the 23 and 24 FEV1 measurements, at the discretion of the 
Investigator.   
After administration of study medication, the patient will enter a washout period of 
21 days + 3 days between treatment periods, where the patient may continue to use 
albuterol/salbutamol MDI and other medications permitted per protocol (see section 8).  
For visits 2 through 4, patients should present at the investigational center so that the start 
of lung function testing will be within ±1 hour from the lung function testing at visit 1. 
For Part 2 of the study, patients will be trained on the correct use of the DPI by the 
blinded study personnel.  The dose should be taken at home in the morning.  Predose 
FEV1 measurements should be performed upon awakening in the morning immediately 
prior to dosing with the study medication; postdose FEV1 measurements are to be 
performed 2 (+2) hours after study medication administration.  
7.10 STUDY MEDICATION ACCOUNTABILITY 
The Investigator is responsible for study medication accountability (including test, 
reference, placebo, and albuterol/salbutamol MDI), reconciliation, and record 
maintenance.  In accordance with applicable regulatory requirements, the Investigator or 
designated investigational center staff must maintain study medication accountability 
records. 
Study medication accountability records must be maintained at the investigational center 
at all times.  The identification number of the patient, the date, expiry date and quantity 
of study medication dispensed will be recorded.  The returned medication should be 
noted on the appropriate inventory forms. 
At study conclusion, all used and unused study medication (with the exception of used 
capsules during the run-in period and open-label extension), albuterol/salbutamol 
medication, and placebo trainers must be returned to the Sponsor or Sponsor’s designee.  
Documented evidence of destruction should be made available to the Sponsor.  
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See section 7.11 for retention samples. 
Instructions on how to manage device problems (eg, malfunction and damage) will be 
described in the study procedures manual.  
7.11 RETENTION 
Drug retains will be handled as described in the study procedures manual and maintained 
by the study site for at least 5 years, as determined by Lupin Inc., to demonstrate the 
packaging of these medications if requested and required by regulatory authorities. 
7.12 EMERGENCY CODE BREAKING 
In case of a serious adverse event (SAE) or pregnancy, the Investigator may unblind the 
patient’s study medication assignment via IRT when the code is needed to make 
treatment decisions for the patient.  The Sponsor should be notified of the event prior to 
breaking the code, if possible.  If this is not possible, the Sponsor should be notified 
immediately afterwards, and the patient’s treatment code should not be revealed to the 
Sponsor.  The circumstances leading to the breaking of the code should be fully 
documented in the Investigator’s study files and in the patient’s source documentation.  
The patient’s treatment assignment should not be recorded in any study documents. 
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8 
PROHIBITED AND RESTRICTED MEDICATIONS AND 
PROCEDURES 
Medications (including vitamins and over-the-counter [OTC] medications and therapies) 
used within 90 days before the screening visit (visit 1) will be recorded in the eCRF.  The 
administration of any additional medication during the study (including OTC medications 
and vitamins) beyond those specified in the protocol will be clearly documented both in 
the source document and the eCRF.   
No medication, other than the study medication and allowed medications, should be taken 
during the study.  Exceptions to this rule apply to medication that may be needed to treat 
AEs.  Such administration will be clearly documented and cross-referenced with the AE 
on the eCRF.  If administration of any prohibited medication becomes necessary during 
the study for medical reasons, the Investigator should consult with the Sponsor to 
determine whether to continue or withdraw the patient from further participation in the 
study. 
All other therapies prohibited as per protocol must have been discontinued prior to the 
protocol specified periods.  Patients are not allowed to enter the study if they receive any 
prohibited concomitant medication or medication in a dosage not allowed and which 
cannot be discontinued or reduced.  These medications should only be discontinued if the 
Investigator decides that discontinuing patients from therapy is the best course of action 
for the patient.  These prohibited medications and therapies should not be discontinued 
for the sole purpose of making a patient eligible for enrollment into the study. 
8.1 
PROHIBITED CONCOMITANT MEDICATIONS 
The medications listed in Table 8-1 are not allowed or are restricted during this study 
(Part 1 and Part 2).   
Table 8-1. Prohibited Medications (Part 1 and Part 2)  
Type of medication 
Washout period before the screening visit 
(visit 1) and throughout the study (unless 
otherwise specified) 
Prohibited 
Depot steroids 
90 days 
Immunologically active biologic medications (eg, 
anti-tumor necrosis factor alpha, abatacept) 
90 days 
Any other investigational drugs 
30 days or 5 half-lives, whichever comes first 
Strong CYP3A4 inhibitors (eg, azole antifungals, 
ritonavir, clarithromycin) 
30 days  
Immunosuppressive therapy (eg, methotrexate, gold, 
azathioprine) 
30 days 
Marijuana (via smoking) 
30 days 
Oral or systemic corticosteroids 
30 days 
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Type of medication 
Washout period before the screening visit 
(visit 1) and throughout the study (unless 
otherwise specified) 
ICS (monotherapy) or ICS/LABA combination 
therapy 
30 days 
LAMA or LAMA/LABA combination therapy 
21 days  
Beta-adrenergic receptor blocking agentsa 
14 days 
Cromones 
14 days 
Leukotriene modifiers 
14 days 
Monoamine oxidase inhibitors 
14 days 
Polycyclic antidepressants 
14 days 
Once or twice daily LABA monotherapy  
(eg, indacaterol) 
7 days 
Oral β2-agonists (tablets, syrup) 
48 hours for long and 12 hours for short 
H2 antagonists (eg, cimetidine) 
24 hours 
Drugs of abuse (cannabinoids, amphetamines, 
barbiturates, cocaine, benzodiazepines, methadone, 
and opiates)b 
A negative test is required at the screening visit 
and use is prohibited throughout the study. 
a. 
Cardioselective beta blockers are permitted as long as therapy was initiated at least 7 days before the 
screening visit (visit 1) and is expected to remain at a stable dose throughout the study. 
b. If a patient has a positive urine drug screen for a class of drug which is consistent with a medication 
that the patient is currently prescribed (excluding inhaled marijuana), the patient can be considered 
eligible for the study after the prescription is confirmed by the Investigator.  Inhaled marijuana is not 
permitted even if prescribed. 
CYP=cytochrome P450; ICS=inhaled corticosteroid; LAMA=long-acting anti-muscarinic agent; 
LABA=long-acting β2 agonist.  
8.1.1 Washout Restrictions during Part 1 of the Study Only 
The washout period for LAMA or LABA is as follows: 
• LAMA medications (including mono products and combination products 
containing LAMAs [eg, LAMA/LABA]) will not be permitted within 21 days of 
the screening visit (visit 1) and throughout the study (except for the study 
medication provided at each treatment period).  Any patients taking LAMA 
medications will need to discontinue these medications, and at the Investigator’s 
discretion, the LAMA may be replaced with ipratropium bromide (SAMA), 
adhering to the washout restrictions below.   
• LABA mono products will need to be discontinued 7 days before the screening 
visit (visit 1) and throughout the study.  Any patients taking LABAs will need to 
discontinue these medications, and at the discretion of the Investigator, the LABA 
may be replaced with ipratropium bromide (SAMA), adhering to the washout 
restrictions below. 
• ICS/LABA combination products will need to be discontinued 30 days before the 
screening visit (visit 1) and throughout the study.  Any patients taking 
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ICS/LABAs will need to discontinue these medications, and at the discretion of 
the Investigator, the ICS/LABA may be replaced with ipratropium bromide 
(SAMA), adhering to the washout restrictions below 
Patients should refrain from taking the following medications from the specified time 
points below prior to spirometry assessments at each clinic visit (both days of each 
inpatient visit) during Part 1 of the study: 
• SABAs 
 
 
 
 
 
 
   
  6 hours 
• SAMAs: 
 
 
 
 
 
 
   
  8 hours  
• short-acting forms of theophylline:   
 
 
 
12 hours  
• twice-a-day controlled-release forms of theophylline:  
 
24 hours 
• once-a-day controlled-release forms of theophylline: 
 
36 hours 
• caffeine-containing medications (eg, MIDOL®, EXCEDRIN®) 
  6 hours 
If a patient requires the use of a SABA for rescue during the serial spirometry, the 
administration of the rescue medication should be recorded as a protocol deviation and the 
patient should continue with the pulmonary function testing as scheduled for that day.   
8.1.2 Permitted Medication with Restrictions during Part 1 of the Study Only 
The following medications (Table 8-2) are also permitted during the study if the noted 
conditions are met.  Note: If patients are taking these restricted medications on an as 
needed (PRN) basis, then a start/stop date must be entered in the eCRF prior to the 
screening visit (visit 1) and for each instance thereafter, as applicable. 
Table 8-2. Permitted Medications with Restrictions 
Type of medication 
Washout period before the screening visit (visit 1), unless 
otherwise specified 
Nasal corticosteroids 
Chronic stable doses at least 14 days duration before the 
screening visit (visit 1) and stable throughout the study duration 
allowed throughout the study 
Theophyllines 
Permitted if without a significant adjustment of dosage, 
formulation, dosing interval for the duration of the study, and 
judged able by the Investigator to withhold them for the time 
intervals prior to each clinic visit 
-short-acting forms: 12 hrs 
-twice a day controlled-release forms: 24 hrs 
-once a day controlled-release forms: 36 hrs. 
PDE4 inhibitors 
Permitted if without a significant adjustment of dosage, 
formulation, and dosing interval for the duration of the study 
Oral or nasal antihistamines (eg, 
loratadine, diphenhydramine, 
cetirizine) 
Discontinue 24 hours before each visit and may resume after the 
visit 
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8.1.3 Permitted Concomitant Medication/Therapy during Part 2 of the Study Only 
In Part 2 of the study, patients will be supplied with Lupin Tiotropium Bromide 
Inhalation Powder for once daily administration over 72 days. 
Patients will also be permitted to resume other non-study medications and 
albuterol/salbutamol MDI as long as the medications do not contravene the prohibited 
medications in Table 8-1, excluding the use of the LAMA study medication. 
8.2 
GENERAL AND DIETARY RESTRICTIONS 
For Part 1, patients will be required to comply with the following restricted activities: 
• 
Patients are not to engage in strenuous exercise on the mornings of any scheduled 
visit (visit 1 through visit 4).  
• 
If possible, patients should avoid cold air exposure on the mornings prior to 
spirometry testing at any scheduled visit (visit 1 through visit 4).  Patients who 
experience bronchial symptoms related to exposure to cold air should be 
adequately stabilized at room temperature before any study-related pulmonary 
function tests (PFTs) are conducted. 
• 
Patients should not smoke or be in a smoky atmosphere for at least 1 hour prior to 
spirometry assessments at any scheduled visit (visit 1 through visit 4). 
• 
Patients should avoid intake of caffeinated beverages for at least 6 hours prior to 
spirometry testing on the mornings of any scheduled visit (visit 1 through visit 4). 
Note: If the patient has failed to comply with any of the general and dietary 
restrictions above, the visit/spirometry should be postponed until the condition is met 
(see section 9.3.6).   
For Part 2, there are no activity or dietary restrictions. 
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9 
STUDY PROCEDURES 
9.1 
SCHEDULE OF EVENTS 
The schedule of events is provided in Table 9-1. 
Table 9-1. Schedule of Events 
 
Screening 
period 
Single-
blind 
run-in 
period 
Part 1 
Double-blind treatment period 
Part 2 
Open-label extension 
 
Study visit  
Visit 1 
NA 
TP1 
(Visit 2) 
TP2 
(Visit 3) 
TP3 
(Visit 4) 
F/U1 
Visit 
5 
Visit  
6 
Visit  
7 
Visit  
8 
Visit  
9 
Visit  
10 
F/U2 
ET3 
Study days4 
-44 to -145 
 
14-16 
day 
period 
before 
day 0 
0 
1 
21 
(+3) 
22 
42 
(+3) 
43 
50 
(±3) 
436 
57 
(±2) 
71 
(±2) 
85 
(±2) 
99 
(±2) 
115 
(+3) 
122 
(±3) 
NA 
Clinic visit7 
X 
 
X 
X 
X 
X 
X 
X 
Tele-
phone 
only 
X 
Tele-
phone 
only 
X 
Tele-
phone 
only 
X 
X 
Tele-
phone 
only 
X 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assign patient via IRT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess inclusion/ 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X8 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
Height and weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HEENT and chest 
examination 
 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
 
 
 
Medical history 
including prior 
concomitant 
medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG  
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
X 
X 
 
 
Clinical laboratory 
tests (hematology, 
biochemistry, and 
urinalysis) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
(female patients of 
X 
 
 
 
 
 
 
X9 
 
 
 
 
 
 
X9 
 
X 
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Screening 
period 
Single-
blind 
run-in 
period 
Part 1 
Double-blind treatment period 
Part 2 
Open-label extension 
 
Study visit  
Visit 1 
NA 
TP1 
(Visit 2) 
TP2 
(Visit 3) 
TP3 
(Visit 4) 
F/U1 
Visit 
5 
Visit  
6 
Visit  
7 
Visit  
8 
Visit  
9 
Visit  
10 
F/U2 
ET3 
Study days4 
-44 to -145 
 
14-16 
day 
period 
before 
day 0 
0 
1 
21 
(+3) 
22 
42 
(+3) 
43 
50 
(±3) 
436 
57 
(±2) 
71 
(±2) 
85 
(±2) 
99 
(±2) 
115 
(+3) 
122 
(±3) 
NA 
Clinic visit7 
X 
 
X 
X 
X 
X 
X 
X 
Tele-
phone 
only 
X 
Tele-
phone 
only 
X 
Tele-
phone 
only 
X 
X 
Tele-
phone 
only 
X 
childbearing potential 
only) 
Urine pregnancy test 
(female patients of 
childbearing potential 
only) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs  
measurements10 
X 
 
X11 
X 
X11 
X 
X11 
X 
 
 
 
X 
 
X 
X 
 
X 
Demonstrate study 
medication inhalation 
technique 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
Demonstrate 
albuterol/salbutamol 
MDI inhalation 
technique 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
Dispense single-blind 
run-in medication 
 
X12 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess inspiratory flow 
rate via In-Check 
DIAL device  
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Ipratropium 
reversibility13 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study qualifying FEV1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Determine FEV1 
baseline/stability limits 
X14 
 
X15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer 
single-blind run-in 
medication 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Screening 
period 
Single-
blind 
run-in 
period 
Part 1 
Double-blind treatment period 
Part 2 
Open-label extension 
 
Study visit  
Visit 1 
NA 
TP1 
(Visit 2) 
TP2 
(Visit 3) 
TP3 
(Visit 4) 
F/U1 
Visit 
5 
Visit  
6 
Visit  
7 
Visit  
8 
Visit  
9 
Visit  
10 
F/U2 
ET3 
Study days4 
-44 to -145 
 
14-16 
day 
period 
before 
day 0 
0 
1 
21 
(+3) 
22 
42 
(+3) 
43 
50 
(±3) 
436 
57 
(±2) 
71 
(±2) 
85 
(±2) 
99 
(±2) 
115 
(+3) 
122 
(±3) 
NA 
Clinic visit7 
X 
 
X 
X 
X 
X 
X 
X 
Tele-
phone 
only 
X 
Tele-
phone 
only 
X 
Tele-
phone 
only 
X 
X 
Tele-
phone 
only 
X 
Collect single-blind 
run-in medication 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Review randomization 
criteria 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization via 
IRT 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review continuation 
criteria 
 
 
 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
Administer study 
medication at clinic 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
Enroll in open-label 
extension via IRT16 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Predose and serial 
FEV1
 measurements17 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Dispense ediary/ 
electronic flow meter 
X18 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Review ediary/ 
electronic flow meter 
instructions 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
Dispense 
albuterol/salbutamol 
MDI, as applicable 
X19 
X 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
Dispense/collect 
placebo trainer 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Dispense study 
medication20 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
Assess ediary data 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
 
X 
Collect ediary/ 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
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Screening 
period 
Single-
blind 
run-in 
period 
Part 1 
Double-blind treatment period 
Part 2 
Open-label extension 
 
Study visit  
Visit 1 
NA 
TP1 
(Visit 2) 
TP2 
(Visit 3) 
TP3 
(Visit 4) 
F/U1 
Visit 
5 
Visit  
6 
Visit  
7 
Visit  
8 
Visit  
9 
Visit  
10 
F/U2 
ET3 
Study days4 
-44 to -145 
 
14-16 
day 
period 
before 
day 0 
0 
1 
21 
(+3) 
22 
42 
(+3) 
43 
50 
(±3) 
436 
57 
(±2) 
71 
(±2) 
85 
(±2) 
99 
(±2) 
115 
(+3) 
122 
(±3) 
NA 
Clinic visit7 
X 
 
X 
X 
X 
X 
X 
X 
Tele-
phone 
only 
X 
Tele-
phone 
only 
X 
Tele-
phone 
only 
X 
X 
Tele-
phone 
only 
X 
electronic flow meter, 
as applicable 
Check for issues with 
study inhalers   
 
X 
X 
 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
X21 
Collect COPD 
exacerbation data 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record concomitant 
medication/therapies 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collect study 
medication 
 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
X 
Collect 
albuterol/salbutamol 
MDI, as applicable 
X 
 
X 
 
X 
 
X 
X 
 
 
 
X 
 
X 
X 
 
X 
Schedule next visit 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
Discuss COPD 
treatment options 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
X 
X 
X 
Discharge patient via 
IRT 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Home-based FEV1 
measurements 
Record morning predose in ediary/electronic flow meter22 
 
Record morning predose and 2 hours postdose in 
ediary/electronic flow meter  
 
 
Assess EXACT 
symptom scores 
Record once daily in the evening before bedtime via ediary 
 
Record once daily in evening before bedtime via 
ediary  
 
 
Albuterol/salbutamol 
MDI medication use 
Record daily in ediary 
 
Record daily in ediary 
 
 
1) For patients participating in Part 1 only, a follow-up visit will occur via phone contact by investigational center personnel 7 days (±3 days) after 
completing visit 4. 
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2) This follow-up visit will only be required for patients participating in Part 2 of the study, and will occur via phone contact by investigational center 
personnel 7 ±3days after the final treatment visit (visit 10). 
3) Regardless if patient is participating in Part 1 or Part 2, the assessments listed for ET will be performed for any patient who is withdrawn prematurely 
from the study. 
4) As there is only the potential to extend visit intervals with permitted visit windows, the terminology of study days will not necessarily represent the 
exact day of the visit.  
5) The screening visit (visit 1) may take place over several days beginning on day -44 to -14 dependent on the patient’s washout.  If a patient is washing 
out of ICS (monotherapy) or ICS/LABA combination therapy, an additional 3 days is permitted to complete the assessments for the screening visit 
(visit 1).  All results, with the exception of the clinical laboratory assessments, must be available and evaluated prior to commencing the run-in period.  
The clinical laboratory results must be available and evaluated prior to randomization.  The procedures for the screening visit (visit 1), with the 
exception of signing of the ICF, performing a pre-washout physical examination, and dispensing/completing the ediary, cannot occur until appropriate 
medication washouts have been completed in accordance with the protocol.  Once the washout requirements have been met, the screening visit (visit 1) 
should immediately precede the start of the run-in period.  If a patient does not require washout, and the patient passes all entry criteria at the screening 
visit (visit 1), the patient will be eligible to enter the run-in period on the same day as the screening visit (visit 1).  The patient must successfully 
complete the visit 1 procedures/assessments prior to entering the run-in period. 
6) After completion of visit 4 (days 42 and 43), patients will either be discharged from the study after completing all double-blind study assessments at 
visit 4 or a subset of patients (approximately 120 patients) will be eligible for enrollment into a 12-week open-label extension, which will begin on the 
same day as the final visit in the double blind treatment period. 
7) All visits for Part 1 should be scheduled in the mornings between 0600 and 1000 and spirometry testing should begin at ±1 hour of the start of visit 1 
testing time. 
8) If washout of baseline therapy is needed, then 2 physical examinations are required: one before a patient commences the washout period and one after 
the washout period ends, prior to enrolling into the run-in period. 
9) The visit 4 end of study serum pregnancy test will be performed for women of childbearing potential who are only participating in Part 1 of the study.  
For women of childbearing potential who are participating in both Part 1 and Part 2, the end of study serum pregnancy test will be performed at visit 10. 
10) Vital signs measurements include blood pressure, heart rate, respiration rate, and temperature. 
11) Vital signs will be collected within 60 minutes of measuring the predose FEV1 on days 0, 21, and 42. 
12) Single blind run-in must be dispensed 14 to 16 days prior to randomization.  Patients will administer the single-blind placebo LUPINHALER one daily 
in the morning for 14 (+2) days after completing the FEV1 measurements. 
13) Patient has demonstrated ≥15% reversibility of FEV1 within 30 or 60 minutes following 68 mcg of ipratropium bromide inhalation (pMDI).  If required, 
spacers are permitted for use during reversibility testing for ipratropium bromide administration. Patients who do not demonstrate a positive 
improvement of at least 15% in FEV1 measured at 30 or 60 minutes (±5 minutes) post inhalation will not be eligible to participate in the study.  
However, based on Investigator judgment, patients will be allowed to retest once no sooner than 24 hours and no later than 2 weeks after initial failure 
to meet the reversibility criteria.  Reversibility values of 14.50-14.99 will be rounded to 15.   
14) A stability limit will be established at the screening visit (visit 1) to determine alert criteria for worsening COPD during the screening and run-in 
periods, and will be calculated by selecting the best pre-bronchodilator qualifying FEV1 measurement at the screening visit using the onsite spirometer x 
80%. 
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15) Two stability limits (at home and investigational center) will be re-established at the randomization visit (visit 2) for use during the double-blind and 
open-label treatment periods.  The at home limit will be calculated by taking the mean of the best predose FEV1 measurements on the last 3 days before 
randomization on the electronic flow meter (home device) x 80%, and the investigational center limit will be the mean FEV1 of the predose 
pre-bronchodilator qualifying FEV1 measurements (-30 and -15 minutes) using the onsite spirometer × 80%. 
16) A subset of patients (approximately 120 patients) at select investigational centers who successfully completed Part 1 will be eligible for enrollment into 
the open-label extension (Part 2). 
17) Predose FEV1 will be measured at 30 and 15 minutes before administration of study medication.  Serial FEV1 spirometry measured at 0 hours (within 
30 and 15 minutes prior to study medication administration [equivalent to the predose FEV1]), and at 5 and 30 minutes postdose, and at 1, 2, 4, 6, 8, 10, 
12, 23, and 24 hours postdose.  The following windows are permitted: +5 minutes for predose measurements (-30 and -5 minutes) and 5 minute postdose 
measurement; ±5 minutes for 0.5-6 hours, and ±15 minutes for 8-24 hours. 
18) Diary collection begins at the time of signing the ICF, and then continues throughout Part 1 and Part 2, per the randomization scheme. 
19) Dispensation of the albuterol/salbutamol MDI is not required during the screening period if the patient is taking this medication as part of their current 
COPD therapy.  Once the patient is enrolled in the run-in period, dispensation/administration of the study albuterol/salbutamol MDI is required and the 
patient will discontinue the use of their own albuterol/salbutamol MDI. 
20) Administration of study medication at the investigational center will occur in the presence of the unblinded and blinded staff members. 
21) For patients participating in Part 2. 
22) Home based FEV1 measurements will not be performed on the mornings of visit 2 (both day 0 and day 1), visit 3 (both day 21 and day 22), and visit 4 
(both day 42 and day 43). 
 
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9.2 
STUDY PROCEDURES 
9.2.1 Efficacy Procedures 
9.2.1.1 Spirometry (Part 1 Only) 
FEV1 
The spirometry endpoint data will be captured using standardized equipment supplied by 
a central spirometry vendor.  This equipment will meet or exceed the ATS/ERS 
recommendations for forced spirometry testing equipment, and spirometry measurements 
will be performed according to ATS guidance document recommendations to ensure both 
technical acceptability and repeatability of test data (Miller 2005).  The test data will be 
overread by the central spirometry provider and any discrepancies in relation to the best 
test effort will be communicated back to the investigational center. 
Spirometry testing will be performed by experienced research staff who have passed a 
proficiency process to ensure understanding of the equipment used and forced spirometry 
technique.  To collect data in a consistent manner, the same staff member will conduct all 
spirometry assessments for the same patient whenever possible.  The same spirometer 
should be used on a patient throughout the study.  Onsite spirometry assessments 
(baseline/study qualifying/reversibility) must occur after washout of the protocol 
prohibited and restricted medications.   
Patients should be at rest for approximately 15 minutes prior to testing and should be 
comfortable.  Tight clothes should be loosened to allow the thorax to move freely; the 
patient should be seated in an upright posture and with a nose clip in place.  The patient 
should not smoke or have been in a smoky atmosphere for at least 1 hour prior to each 
FEV1 assessment, should have avoided highly caffeinated drinks for at least 6 hours, and 
should have adhered to the restricted medication criteria for the appropriate time as 
outlined in section 8.  If these criteria have not been met, the patient should have the visit 
rescheduled. 
All visits to the investigational center for Part 1 must be scheduled in the mornings 
between 0600 and 1000 and spirometry testing should begin at ±1 hour of the start of 
visit 1 study qualifying spirometry testing time.  Predose FEV1 measurements will be 
recorded at 0 hours (-30 and -15 minutes before administration of study medication) at 
the investigational center at visits 1 through 4; serial FEV1 measurements will be 
recorded postdose at 5 and 30 minutes, and at 1, 2, 4, 6, 8, 10, 12, 23, and 24 hours.   
The following windows are permitted: +5 minutes for predose measurements 
(-30 and -15 minutes) and 5 minute postdose measurement, ±5 minutes for 0.5-6 hours, 
and ±15 minutes for 8-24 hours. 
Spirometry procedures are described in the spirometry manual. 
Reversibility Testing 
For reversibility testing, patients will receive 68 mcg of ipratropium bromide inhalation 
pMDI as 4 actuations of 17 mcg/actuation (ex-mouthpiece); given at approximately 
30 second intervals.  If required, spacers are permitted for use during reversibility testing 
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for ipratropium bromide administration.  All actuations are to be completed within 3 
minutes of the 1st actuation.  The ATS/ERS criteria will be followed for spirometry 
measures.  Patients who do not demonstrate a positive improvement of at least 15% in 
FEV1 measured at 30 or 60 minutes (±5 minutes) post inhalation will not be eligible to 
participate in the study (except as permitted per the retest specified below).  Reversibility 
values of 14.50-14.99 will be rounded to 15.  
Refer to the spirometry manual for additional information related to reversibility testing. 
Patients failing to meet the reversibility requirement will be permitted to retest once, 
based on Investigator judgment (for only those patients who would normally achieve this 
level of reversibility) no sooner than 24 hours and no later than 2 weeks after the initial 
failure, as per the retest criteria in section 9.3.6. 
FEV1 Stability Limits  
FEV1 stability limits will be calculated for each patient at the screening visit (visit 1) 
using the onsite spirometer and the randomization visit (visit 2), using both the home 
device and onsite spirometer. 
Screening Visit: 
The stability limit established at the screening visit will be used to determine alert criteria 
for worsening COPD during the screening and run-in periods.  The FEV1 stability limit at 
the screening visit will be calculated as follows: 
Best pre-bronchodilator qualifying FEV1 measurement at the screening visit (visit 1) 
using the onsite spirometer × 80%. 
Randomization Visit 
Two stability limits will be re-established at the randomization visit (visit 2) for use 
during the double-blind and open-label treatment periods using the following equations: 
• Investigational Center Stability Limits (for use with onsite spirometer at the 
double-blind visits only): 
mean FEV1 of the predose pre-bronchodilator qualifying FEV1 measurements 
(-30 and -15 min) using the onsite spirometer × 80% 
• At Home Stability Limits (for use with the electronic flow meter [home device]): 
mean of the best predose FEV1 measurements on the last 3 days before 
randomization on the home device × 80% 
If a patient falls below any of the above FEV1 stability limits, an alert will be triggered to 
the patient and investigational center personnel.  
Note: If the reschedule icon on the site spirometer is chosen for the screening visit 
(visit 1) or visit 2, and therefore, visit 1 or visit 2 is performed again, the FEV1 stability 
limit will be updated accordingly.  If V1_RETEST on the site spirometer is performed, 
the stability limit will not be updated. 
 
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Refer to the spirometry manual for these instructions and further details regarding general 
spirometry procedures. 
9.2.2 Safety Procedures  
9.2.2.1 Physical and HEENT/Chest Examinations (Part 1 and Part 2) 
Physical and HEENT/Chest examinations will be performed as indicated in Schedule of 
Events, Table 9-1 by a qualified healthcare provider, Investigator, or sub-Investigator.  
Height and weight measurements will also be performed at the screening visit (visit 1). 
An assessment of normal, abnormal but not clinically significant, or abnormal and 
clinically significant will be recorded in the eCRF for each required body system.  The 
Investigator or designee will be required to provide a comment regarding any finding of 
abnormal but not clinically significant and abnormal and clinically significant. 
9.2.2.2 Vital Signs (Part 1 and Part 2) 
Vital signs measurements (blood pressure, heart rate, respiration rate, and body 
temperature) will be performed as indicated in Schedule of Events, Table 9-1 by a 
qualified healthcare provider, Investigator, or sub-Investigator.  A window of within 
60 minutes of measuring the predose FEV1 is permitted on days 0, 21, and 42.  The 
patient must be in a seated position and resting for at least 5 minutes.  The same position 
and arm should be used each time vital signs are measured for a given patient.  For any 
abnormal vital sign finding, the measurement should be repeated as soon as possible.  
Any vital sign value that is judged by the Investigator as a clinically significant change 
(worsening) from a baseline value will be considered an AE. 
9.2.2.3 Spirometry (Part 1 and 2) 
Patients enrolled in Part 1 and Part 2 of the study will be issued with an ediary/electronic 
flow meter to assess their lung function (FEV1).  FEV1 collection begins at the time of 
signing the ICF, and then continues throughout Part 1 and Part 2, per the randomization 
scheme. 
For Part 1, FEV1 will be measured once daily: prior to dosing in the morning (if 
applicable) at approximately the same time each day.  On days of the investigational 
center visits, spirometry will be performed using the equipment at the investigational 
center. 
For Part 2, FEV1 will be measured twice daily at home: upon awakening in the morning 
immediately prior to dosing with study medication and at 2 (+2) hours after study 
medication administration.  Three (3) FEV1 measures should be taken at each time point; 
the highest effort will be used. 
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9.2.2.4 Adverse Events (Part 1 and Part 2) 
All AE/SAEs (including treatment-emergent AEs) will be assessed throughout the study 
visits and followed to resolution/satisfaction.  Adverse events (AEs) will be recorded 
after the patient has signed the informed consent form (ICF) and captured via patient 
interview during the onsite or telephone visits. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
the most current version (19.0 or later), for system organ class (SOC), preferred term 
(PT), and lowest level term (LLT), respectively. 
9.2.2.5 Monitoring of COPD Exacerbations (Part 1 and Part 2) 
A COPD exacerbation is defined as worsening of symptoms of COPD for at least 
2 consecutive days and classified as mild when patients do not require treatment with 
systemic corticosteroids and/or antibiotics; moderate when treatment with systemic 
corticosteroids and/or antibiotics are required; or severe when hospitalization or visit to 
the emergency care/acute care unit is required.  A separate exacerbation is considered 
when an interval of clinical improvement of at least 7 days is observed. 
Any moderate or severe COPD exacerbation occurring during Part 1 will result in 
withdrawal (see section 6.5). 
COPD exacerbations are not considered AEs unless they meet the definition of an SAE. 
COPD exacerbations will be documented separately from AEs on a COPD exacerbation 
log in the eCRF, unless the exacerbation meets the definition of an SAE as described 
above.  In this instance, the exacerbation will be recorded on both the AE and COPD 
exacerbation pages of the eCRF.   
Collection of COPD exacerbations will begin at the time of consent and will continue 
through the final visits in Part 1 and Part 2 of the study.  COPD exacerbations will be 
captured via patient interview during the onsite or telephone visits. 
9.2.2.6 COPD Symptom Scores (Part 1 and Part 2) 
During Part 1 (commencing at the time of consent) and Part 2 of the study, as indicated 
in, Schedule of Events, Table 9-1, patients will assess and record their COPD symptoms 
scores once daily in the evening before bedtime using the EXACT.   
The EXACT is a 14-item daily diary designed to provide a direct measure of 
patient-reported symptoms of COPD exacerbation.  The EXACT Total score is computed 
across the 14 items and has a theoretical range of 0 to 100, with higher values indicating a 
more severe condition.  The total score is used in the determination of exacerbation 
frequency, severity, and duration of exacerbation. 
All 14 items of the EXACT are to be completed by the patient each evening prior to 
bedtime, reflecting back on their experiences “today.” 
The ER-S: COPD is a derivative instrument of the EXACT designed to address the need 
for standardized daily diary to assess respiratory symptoms in patients with COPD.   
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The ER-S: COPD is comprised of 11 respiratory symptom items contained in the 14-item 
EXACT.  A daily Total score (RS-Total score) representing respiratory symptom 
severity, overall and 3 subscale scores (RS-Breathlessness, RS-Cough and Sputum, and 
RS-Chest Symptoms) can be computed from the E-RS.  The daily RS-Total score is 
computed by summing the raw score assigned to each of the 11 items and has a 
theoretical range of 0 to 40, with higher values indicating more severe respiratory 
symptoms.  The same simple summation procedure is used for obtaining the 3 daily 
domain scores of the E-RS: RS-Breathlessness is the sum of items 7, 8, 9, 10, and 11 
(score range 0-17); RS-Cough and Sputum is the sum of items 2, 3, 4 (score range 0-11); 
and RS-Chest Symptoms is the sum of items 1, 5, 6 (score range 0-12). 
The ER-S: COPD (derived from the EXACT score) will be used to assess disease 
stability throughout the study.  A baseline score will be obtained from the first available 
evening session after signing the ICF for use during the screening and run-in periods and 
from the latest available evening session before the randomization visit (visit 2) for use 
during the double-blind and open-label treatment periods.  If at any time, there is increase 
in the ERS-COPD daily RS-Total score of ≥2 from baseline, the ediary will alert the 
patient to notify the investigational center personnel to discuss the patient’s current health 
status.  The Investigator will need to determine if the patient is able to continue 
participating in the study as per the withdrawal criteria in section 6.5.   
Refer to Appendix C for additional details. 
9.2.2.7 Electrocardiography 
A 12-lead ECG will be performed for Part 1 and Part 2 as indicated in Schedule of 
Events, Table 9-1.  For Part 1, the ECGs will be collected prior to lung function 
assessments.  Procedures for conducting ECGs are described in the ECG manual.  The 
patient should be in a supine position and resting for at least 5 minutes.  A qualified 
physician at a central diagnostic center will be responsible for interpreting the ECG.  
However, at the screening visit (visit 1), the Investigator will preliminarily interpret the 
ECG to determine if the patient is eligible to proceed with screening assessments; final 
interpretation of the ECG will the responsibility of the central ECG reader.  The 
Investigator is responsible for determining whether an abnormality is clinically relevant. 
Patients should have an ECG that is normal or free of clinically significant findings at the 
screening visit (visit 1) and visit 2. 
9.2.3 Other Procedures 
9.2.3.1 Medical History 
A complete medical history will be recorded and evaluated as indicated in Schedule of 
Events, Table 9-1. 
9.2.3.2 Clinical Laboratory Assessments 
Standard clinical laboratory tests will be performed as indicated in Schedule of Events, 
Table 9-1 using a central laboratory as indicated in the study procedures manual. 
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9.2.3.3 Pregnancy Testing 
Serum and urine pregnancy testing will be performed as indicated in Schedule of Events, 
Table 9-1 or as indicated by the patient’s condition.  The urine pregnancy test will be 
completed by dipstick evaluation at the investigational center on all female patients of 
childbearing potential.  The dipstick testing is based on the detection of beta-HCG and 
will be carried out as per manufacturer’s instructions.   
A positive finding during the screening visit (visit 1) will prevent the patient from 
participating in the study and a positive finding at or after visit 2 will require immediate 
Sponsor notification, discontinuation of study medication, and withdrawal from the 
study. 
9.2.3.4 Urine Drug Screening  
Urine drug screening will be performed via a urine dipstick at the investigational center 
as indicated in Schedule of Events, Table 9-1 or at any time during the study should the 
Investigator deem it is warranted.  A positive finding during the screening visit (visit 1) 
will prevent the patient from participating in the study, and a positive finding after the 
screening visit will require immediate Sponsor notification, and may result in 
discontinuation of study medication and termination from the study (if not related to a 
currently prescribed medication as described below).   
If a patient has a positive urine drug screen for a class of drug which is consistent with a 
medication that the patient is currently prescribed (excluding inhaled marijuana), the 
patient can be considered eligible for the study after the prescription is confirmed by the 
Investigator.  Inhaled marijuana is not permitted even if prescribed. 
Additional details are provided in the laboratory instruction manual. 
9.2.3.5 In-Check DIAL Training 
For Part 1 of the study, patients will be trained on inspiratory flow rate using the 
In-Check DIAL, a hand held inspiratory flow measurement device (see Appendix B).  
Training will be performed as indicated in Schedule of Events, Table 9-1.  Patients must 
achieve an inspiratory flow rate of ≥40 L/min at the screening visit.  Although this 
criterion is not required for visits 2-4, it is expected that each patient will achieve an 
inspiratory flow rate of ≥40 L/min for these visits, as this was a requirement for study 
entry. 
9.3 
STUDY VISITS 
The study consists of 2 parts.  Part 1 (double-blind treatment period) consists of a 
screening period, 3 double-blind treatment periods at the investigational center, and a 
follow-up telephone call at the end of the double-blind treatment period for only those 
patients participating in Part 1.  All visits for Part 1 must be scheduled in the mornings 
between 0600 and 1000 and spirometry testing should begin at ±1 hour of the start of 
visit 1 testing time.  Part 2 (open-label extension) consists of 7 visits (visit 5 through visit 
10, and follow-up), which will begin on the last day of visit 4 (Part 1).  Visit 6 and visit 8 
will be conducted via telephone contact.  The final safety follow-up for those patients 
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participating in Part 2 will be conducted via telephone 7 days (±3 days) after the last 
active treatment of the open-label extension (ie, visit 10). 
A screening failure is defined as any patient that signed an ICF and was either not 
enrolled in the study or failed to meet the inclusion/exclusion criteria during the 
screening period.   
A randomization failure is defined as any patient that signed an ICF, underwent all 
screening assessments, was dispensed single-blind run-in medication, but failed to meet 
the randomization criteria listed in section 6.3, Randomization Criteria, at visit 2. 
The patient number and information regarding screening/randomization failures will be 
documented in the study database. 
Note: As there is only the potential to extend visit intervals with permitted visit windows, 
the terminology of study day will not necessarily represent the exact day of the visit.  
Study day 0 of treatment period 1 will be used as baseline when scheduling study 
days/visits. 
See section 9.3.6 and 9.3.7 for retesting and rescreening parameters, respectively. 
9.3.1 Screening Period 
During the screening period, a signed and dated ICF will be obtained first before 
screening procedures commence.  The screening period may be conducted up to 30 days 
(day -44 to day -14) before the start of the run-in period.  The screening period begins 
once the ICF is signed, and ends at the start of the run-in period.  The screening period 
may take place over several days beginning on day –44 to day –14 dependent on the 
patient’s washout.  If a patient is washing out of ICS (monotherapy) or ICS/LABA 
combination therapy, an additional 3 days is permitted to complete the assessments for 
the screening visit (visit 1).  The screening visit (visit 1) should immediately precede the 
start of the run-in period.  If a patient does not require washout, and the patient passes all 
entry criteria at the screening visit (visit 1), the patient will be eligible to enter the run-in 
period on the same day as the screening visit (visit 1).  The patient must successfully 
complete the visit 1 procedures/assessments prior to entering the run-in period. 
The procedures for the screening visit (visit 1), with the exception of signing of the ICF, 
assigning a patient number, performing a pre-washout physical examination, and 
dispensing/completing the ediary, cannot occur until appropriate medication washouts 
have been completed in accordance with the protocol.  Once the washout requirements 
have been met, the screening visit (visit 1) should immediately precede the start of the 
run-in period. 
The following procedures and assessments will be conducted at the screening visit 
(visit 1) with the exception of the procedures listed above if medication washout is 
required: 
• obtain informed consent 
• assign patient identification number via IRT 
• review inclusion/exclusion criteria 
• collect demographic information 
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• perform physical examination 
Note: If washout of baseline therapy is needed, then 2 physical examinations are 
required: one before a patient commences the washout period and one after the 
washout period ends, prior to enrolling into the run-in period. 
• perform height and weight measurements 
• collect medical history, including COPD history and prior and concomitant 
medications 
• discuss COPD treatment options for patient 
• perform 12-lead ECG, prior to measuring study qualifying spirometry 
• perform clinical laboratory tests (serum chemistry, hematology, urinalysis) 
• perform serum pregnancy test for all female patients of childbearing potential 
• perform urine drug screen 
• perform vital signs measurements (blood pressure, heart rate, respiration rate, and 
body temperature) prior to measuring study qualifying spirometry 
• demonstration of albuterol/salbutamol MDI and study medication inhaler 
technique 
• assess inspiratory flow rate via In-Check DIAL device 
• perform study qualifying spirometry measurements 
• perform reversibility to ipratropium bromide 
• determine screening/run-in FEV1 stability limits using the onsite spirometer 
• dispense albuterol/salbutamol MDI, as applicable 
Note: Dispensation of the albuterol/salbutamol MDI is not required during the 
screening period if the patient is taking this medication as part of their current 
COPD therapy.  Once the patient qualifies for the run-in period, 
dispensation/administration of the study albuterol/salbutamol MDI is required and 
the patient will discontinue the use of their own albuterol/salbutamol MDI. 
• dispense/collect placebo trainer 
• dispense ediary/electronic flow meter 
Note: Diary collection begins at the time of signing the ICF until the conclusion 
of the run-in period, and then continues throughout Part 1 and Part 2, per the 
randomization scheme. 
• review ediary/electronic flow meter instructions 
• assess ediary data 
• collect ediary/electronic flow meter, as applicable 
• collect albuterol/salbutamol MDI (as needed) 
• record AEs 
• record COPD exacerbations 
• schedule next visit 
The patient will begin using an ediary/electronic flow meter for use throughout the 
screening period, if applicable and asked to measure their lung function (FEV1) in the 
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morning prior to dosing with COPD medication (as applicable) at approximately the 
same time each day.  Patients will be asked to record EXACT symptom scores (see 
Appendix C) and albuterol/salbutamol MDI use in their ediary during the screening 
period, if applicable. 
9.3.2 Run-in Period 
The run-in period will occur over a period of 14 to 16 days before randomization (day 0).  
The following activities will occur at the investigational center at the start of the run-in 
period. 
• dispense/administer single-blind run-in medication 14 to 16 days before 
randomization to patients who meet all selection criteria (perform after 
spirometry/reversibility are conducted) 
• dispense albuterol/salbutamol MDI, as applicable 
• record AEs 
• record concomitant medications/therapies 
• record COPD exacerbations 
• check for issues with study inhaler 
The patient will continue using an ediary/electronic flow meter for use throughout the 
run-in period and asked to measure their lung function (FEV1) in the morning prior to 
dosing with placebo LUPINHALER at approximately the same time each day.  Patients 
will be asked to record EXACT symptom scores (see Appendix C) once daily in the 
evening before bedtime, and albuterol/salbutamol MDI/study medication use in their 
ediary. 
Patients are to withhold their morning dose of placebo run-in medication on the morning 
of visit 2.  Patients will be reminded to follow restrictions on diet and medication use 
prior to visit 2.  Patients should not perform FEV1 measurements on the home device 
prior to visit 2 (both day 0 and day 1). 
9.3.3 Double-blind Treatment Period (Part 1) 
9.3.3.1 Visit 2 
Visit 2 is the beginning of the double-blind treatment period and will be conducted as 
day 0 and day 1.   
The following procedures and assessments will be conducted at visit 2: 
Day 0 
• perform HEENT and chest examination  
• perform 12-lead ECG, prior to measuring predose FEV1 
• perform urine pregnancy test for all female patients of childbearing potential  
• perform vital signs measurements (blood pressure, heart rate, respiration rate, and 
body temperature) prior to measuring predose FEV1 
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• perform predose FEV1 measurements at 0 hours (30 and 15 minutes before 
administration of study medication); see permitted spirometry windows in 
section 9.2.1.1 
• Re-establish stability limits 
o Two stability limits (at home and investigational center) will be re-established 
(see section 9.2.1.1). 
• demonstration of albuterol/salbutamol MDI and study medication inhaler 
technique 
• assess inspiratory flow rate via In-Check DIAL device 
• dispense/collect study medication 
• review randomization criteria 
• randomization via IRT 
• administration of study medication at the investigational center 
• check for issues with study inhaler 
• perform serial FEV1 measurements at the following time points: 5 and 30 minutes 
postdose, and at 1, 2, 4, 6, 8, 10, and 12 hours postdose; see permitted spirometry 
windows in section 9.2.1.1 
• dispense/collect albuterol/salbutamol MDI (as needed) 
• dispense/collect placebo trainer 
• review ediary/electronic flow meter instructions 
• assess ediary data 
• collect ediary/electronic flow meter, as applicable 
• record AEs 
• record COPD exacerbations 
• record concomitant medications/therapies 
The patient will continue using the ediary/electronic flow meter throughout the remainder 
of Part 1 and asked to measure their lung function (FEV1) in the morning prior to 
administering COPD medication at approximately the same time each day.  Patients 
should not perform FEV1 measurements on the home device prior to day 1, visit 3 (both 
day 21 and day 22) and visit 4 (both day 42 and 43).  Patients will be asked to record 
EXACT symptom scores (see Appendix C) and albuterol/salbutamol MDI in their 
ediary. 
Patient will be instructed to return for day 1 of visit 2 with adequate time to complete the 
serial spirometry measurements at the time points listed below.  Patients will be reminded 
to conform to the smoking, dietary, and medication restrictions prior to day 1 visit.   
Day 1 
• perform vital signs measurements (blood pressure, heart rate, respiration rate, and 
body temperature) 
• perform serial FEV1 measurements at 23 and 24 hours after study medication 
administration on day 0; see permitted spirometry windows in section 9.2.1.1 
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• record AEs 
• record COPD exacerbations 
• record concomitant medications/therapies 
• schedule next visit  
9.3.3.2 Visit 3 
Day 21 (+3 days) 
The following procedures and assessments will be conducted on day 21: 
• perform HEENT and chest examination   
• perform 12-lead ECG, prior to measuring predose FEV1 
• perform vital signs measurements (blood pressure, heart rate, respiration rate, and 
body temperature) prior to measuring predose FEV1 
• demonstration of albuterol/salbutamol MDI and study medication inhaler 
technique  
• assess inspiratory flow rate via In-Check DIAL device 
• perform predose FEV1 measurements at 0 hours (30 and 15 minutes before 
administration of study medication); see permitted spirometry windows in 
section 9.2.1.1 
• perform serial FEV1 measurements at the following time points: 5 and 30 minutes 
postdose, and at 1, 2, 4, 6, 8, 10, and 12 hours postdose; see permitted spirometry 
windows in section 9.2.1.1 
• dispense/collect study medication 
• dispense/collect albuterol/salbutamol MDI (as needed) 
• review continuation criteria 
• dispense/collect placebo trainer 
• administration of study medication at the investigational center 
• check for issues with study inhaler 
• assess ediary data 
• review ediary/electronic flow meter instructions 
• record AEs 
• record COPD exacerbations 
• record concomitant medications/therapies 
Day 22 
The patient will be instructed to return for the second day of the study visit (day 22) and 
the following procedures and assessments will be conducted: 
• perform vital signs measurements (blood pressure, heart rate, respiration rate, and 
body temperature) 
• perform serial FEV1 measurements at 23 and 24 hours after study medication 
administration; see permitted spirometry windows in section 9.2.1.1 
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• record AEs 
• record COPD exacerbations 
• record concomitant medications/therapies 
• schedule next visit  
9.3.3.3 Visit 4 
Day 42 (+3 days) 
The following procedures and assessments will be conducted on day 42: 
• perform HEENT and chest examination   
• perform 12-lead ECG, prior to measuring predose FEV1 
• perform vital signs measurements (blood pressure, heart rate, respiration rate, and 
body temperature) prior to measuring predose FEV1 
• demonstration of albuterol/salbutamol MDI and study medication inhaler 
technique  
• assess inspiratory flow rate via In-Check DIAL device 
• perform predose FEV1 measurements at 0 hours (30 and 15 minutes before 
administration of study medication); see permitted spirometry windows in 
section 9.2.1.1 
• perform serial FEV1 measurements at the following time points: 5 and 30 minutes 
postdose, and at 1, 2, 4, 6, 8, 10, and 12 postdose; see permitted spirometry 
windows in section 9.2.1.1 
• dispense/collect study medication 
• dispense/collect albuterol/salbutamol MDI (as needed) 
• review continuation criteria 
• dispense/collect placebo trainer 
• administration of study medication at the investigational center 
• check for issues with study inhaler 
• assess ediary data 
• review ediary/electronic flow meter instructions 
• record AEs 
• record COPD exacerbations 
• record concomitant medications/therapies 
Day 43 for Visit 4 
The patient will be instructed to return for the second day of the study visit (day 43) and 
the following procedures and assessments will be conducted: 
• perform physical examination 
• perform serum pregnancy test for all female patients of childbearing potential (for 
those patients only participating in Part 1) 
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• perform vital signs measurements (blood pressure, heart rate, respiration rate, and 
body temperature) 
• perform serial FEV1 measurements at 23 and 24 hours after study medication 
administration; see permitted spirometry windows in section 9.2.1.1 
• assess diary data 
• collect ediary/electronic flow meter 
• collect albuterol/salbutamol MDI (as needed) 
• record AEs 
• record COPD exacerbations 
• record concomitant medications/therapies 
• discuss COPD treatment options for patient (for those patients only participating 
in Part 1) 
• schedule next visit 
See section 9.3.3.4 for patients only participating in Part 1 of the study and section 9.3.4 
for patients enrolling into Part 2, the open-label extension. 
9.3.3.4 Follow-up Part 1 (Telephone Follow-up) 
Patients who are not continuing into Part 2 will be contacted via telephone by 
investigational center personnel on day 50 ±3 days to ensure that there are no lasting 
issues related to study participation. 
The following assessments will be performed: 
• record AEs 
• record COPD exacerbations 
• record concomitant medications/therapies 
• discuss COPD treatment options for patient  
• end patient participation via IRT 
The patient will be deemed to have completed Part 1 if they have completed the 
screening visit, single-blind run-in period, and all double-blind treatment visits. 
9.3.4 Open-Label Treatment Period (Part 2) 
9.3.4.1 Visit 5 (Day 43)  
Patients participating in the open-label extension will begin study activities on the same 
day as the final clinic visit in the double-blind treatment period (visit 4, day 43) and will 
be considered the first day of the open-label extension (visit 5). 
The following procedures and assessments will be conducted:  
• register/enroll patient in IRT 
• demonstration of albuterol/salbutamol MDI and study medication inhaler 
technique 
• dispense ediary/electronic flow meter 
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• dispense albuterol/salbutamol MDI, as applicable 
• review continuation criteria 
• dispense study medication and patient to administer 1st dose in the investigational 
center under supervision of site personnel (after all visit 4 procedures are 
completed in Part 1, and patient is enrolled in Part 2) 
• check for issues with study inhaler 
• review ediary/electronic flow meter instructions 
• record AEs  
• record COPD exacerbations 
• record concomitant medications/therapies 
• schedule next visit 
The patient will be issued with a 90-day supply of Lupin Tiotropium Bromide Inhalation 
Powder.  The daily administration of study medication should be taken at approximately 
the same time each morning for 72 days. 
The patient will also continue using the ediary/electronic flow meter throughout Part 2 
and asked to measure their lung function (FEV1) twice daily: upon awakening in the 
morning immediately prior to dosing with the study medication and at 2 (+2) hours after 
study medication administration.  Patients will be asked to record EXACT symptom 
scores (see Appendix C) and albuterol/salbutamol MDI/study medication use in their 
edairy. 
If at any time patients experience an actual or perceived issue with their inhaler, the 
ediary/IRT system will alert the investigational center who will arrange the necessary 
corrective action, if required.  The investigational center should endeavor to complete the 
eCRF within 24 hours of notification of an issue.  
9.3.4.2 Visit 6 and 8 Telephone Contact 
Visit 6 (day 57 [±2 days]) and visit 8 (day 85 [±2 days]) will be conducted via telephone 
by investigational center personnel. 
The following assessments will be conducted: 
• assess diary data 
• review continuation criteria 
• check for issues with study inhaler  
• record AEs  
• record COPD exacerbations 
• record concomitant medications/therapies 
The patient will be reminded about the date of their next clinic visit.  Patients will 
continue to administer study medication once daily and record FEV1 twice daily, EXACT 
symptom scores, and albuterol/salbutamol MDI/study medication usage in the 
ediary/electronic flow meter. 
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9.3.4.3 Visit 7 and 9 Clinic Visits  
Visit 7 (day 71 [±2 days]) and visit 9 (day 99 [±2 days]) will occur at the investigational 
center.  The following procedures and assessments will be conducted: 
• perform HEENT and chest examination   
• perform vital signs measurements (blood pressure, heart rate, respiration rate, and 
body temperature) 
• perform 12-lead ECG 
• demonstration of albuterol/salbutamol MDI and study medication inhaler 
technique 
• review continuation criteria 
• dispense/collect albuterol/salbutamol MDI, as needed 
• assess diary data 
• check for issues with study inhaler 
• record AEs  
• record COPD exacerbations 
• record concomitant medications/therapies 
The patient will be reminded about the date of their next clinic visit.  Patients will 
continue administering study medication once daily and to record FEV1 twice daily, 
EXACT scores and albuterol/salbutamol MDI/study/rescue medication usage, in the 
ediary/electronic flow meter.  
9.3.4.4 Visit 10  
Visit 10 will occur on day 115 (+3 days) at the investigational center.  The following 
procedures and assessments will be conducted: 
• perform physical examination 
• perform serum pregnancy test for all female patients of childbearing potential 
• perform vital signs measurements (blood pressure, heart rate, respiration rate, and 
body temperature) 
• perform 12-lead ECG 
• assess diary data 
• collect ediary/electronic flow meter (patient will discontinue recording in diary 
and taking FEV1 measurements) 
• check for issues with study inhaler 
• collect albuterol/salbutamol MDI and study medication 
• record AEs  
• record COPD exacerbations 
• record concomitant medications/therapies 
• discuss COPD treatment options for patient 
• schedule next visit 
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9.3.4.5 Part 2 (Telephone Follow-up call) 
Patients who have completed therapy up to visit 10 (72 days of dosing) will be contacted 
via telephone by investigational center personnel on day 122 (±3 days) to ensure there are 
no lasting issues related to study participation. 
The following assessments will be performed: 
• record AEs  
• record COPD exacerbations 
• record concomitant medications/therapies 
• discuss COPD treatment options for patient  
• end patient study participation via IRT 
The patient will be deemed to have completed Part 2 if they have completed open-label 
therapy up to visit 10 (72 days of dosing) and have returned the open-label study 
medication. 
9.3.5 Early Termination (ET) Visit  
Regardless of participation in Part 1 or Part 2 of the study, patients who prematurely 
withdraw or who are withdrawn from the study will have the following procedures and 
assessments performed: 
• perform physical examination   
• perform serum pregnancy test for all female patients of childbearing potential 
• perform vital signs measurement (blood pressure, heart rate, respiration rate, and 
body temperature) 
• assess diary data 
• collect diary/electronic flow meter 
• check for issues with study inhaler (Part 2 study only) 
• collect albuterol/salbutamol MDI or study medication 
• record AEs  
• record COPD exacerbations 
• record concomitant medications/therapies 
• discuss COPD treatment options for patient  
• end patient/study participation via IRT 
9.3.6 Retest Visits 
Pre-randomization (includes the assessments conducted at the screening visit (visit 1) and 
visit 2 prior to the patient being randomized): 
Only 1 retest for spirometry quality/baseline spirometry/stability or reversibility will be 
permitted for each patient. 
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Patients who have failed screening for FEV1 or reversibility may retest once no sooner 
than 24 hours and no later than 2 weeks later provided that they have met all selection 
criteria.  
Post-randomization: 
During Part 1, patients may retest for FEV1 if the value varies by more than ±10% from 
the predose FEV1 at visit 2 up to 3 times.  If 3 retests have been conducted, the patient 
may need to be withdrawn at the discretion of the Investigator.  
Note: Postponing/rescheduling for failure to meet the general and dietary restrictions 
(section 8.2) is permitted and is not considered a retest per the criteria above. 
9.3.7 Rescreening 
Only 1 rescreen will be permitted. 
Patients may rescreen for the following reason: 
• Patients who develop symptoms of a URI/LRI during the screening/single-blind 
run-in period may rescreen once no sooner than 6 weeks after resolution of 
symptoms, and within the discretion of the Investigator. 
The decision to rescreen patients will be based on the Investigator’s judgment.  In the 
case of rescreening, the Sponsor or designee should be notified of the pending 
rescreening. 
Patients who undergo rescreening will need to repeat all screening procedures and 
evaluations, and be assigned a new patient number via IRT. 
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10 
SAFETY AND PHARMACOVIGILANCE 
10.1 DEFINITION OF AN ADVERSE EVENT 
An AE is defined as any untoward medical occurrence in a clinical trial patient 
administered a medicinal product and which 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 temporally associated with the use of an 
investigational medicinal product, whether or not considered related to the investigational 
medicinal product. 
A new medical condition or the worsening of a pre-existing condition will be considered 
an AE.  Stable chronic medical conditions such as arthritis that are present prior to study 
entry and do not worsen during the study will not be considered AEs.  Worsening of the 
disease under study should only be recorded as an AE if the outcome is more serious than 
would normally be expected from the normal course of the disease in a particular patient. 
10.2 INTENSITY OF ADVERSE EVENTS 
The intensity or severity of the AE will be characterized as: 
• Mild:  AE which is easily tolerated 
• Moderate:  AE sufficiently discomforting to interfere with daily activity 
• Severe:  AE which prevents normal daily activities 
The maximum severity for the event should be listed when the intensity changes during 
the course of an AE.  If the change in severity represents distinct events rather than a 
single event, this should be recorded as separate AEs. 
10.3 RELATIONSHIP OF ADVERSE EVENTS TO STUDY 
MEDICATION 
The causal relationship of the investigational product to the AE(s) should be 
characterized as: 
Not Related: There is no reasonable possibility that the AE was caused by or attributed to 
the investigational product. 
Related: 
There is a reasonable possibility that the AE was caused by or attributed to 
the investigational product.  A causal relationship cannot be ruled out. 
10.3.1 Definition of “No Reasonable Possibility” 
The assessment term, “no reasonable possibility”, can only be applied to those AEs 
which, after careful consideration, are clearly due to extraneous causes (disease, 
environment, etc.) or to those AEs which, after careful medical consideration at the time 
they are evaluated, are judged to be unrelated to the study drug. 
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An AE may be considered as being meeting the definition of “no reasonable possibility” 
if data are available to identify a clear alternative cause for the AE other than study drug; 
such as the patient’s clinical state, concomitant therapy, and/or other interventions or the 
AE/SAE has no plausible temporal relationship to administration of study drug. 
10.3.2 Definition of “Reasonable Possibility” 
The assessment term, “reasonable possibility”, can only be applied to those AEs which, 
after careful medical consideration at the time they are evaluated, a connection with the 
study drug administration cannot be ruled out with certainty or is felt with a high degree 
of certainty to be related to the study drug. 
An AE may be considered as meeting the definition of “reasonable possibility” if there is 
a plausible temporal relationship between the onset of the AE/SAE and study drug 
administration and the AE/SAE cannot be readily explained by the patient’s clinical state, 
intercurrent illness, or concomitant therapies; and/or the AE/SAE follows a known 
pattern of response to study drug; and/or the AE/SAE abates or resolves upon 
discontinuation of study drug or dose reduction and, if applicable, reappears upon 
re-challenge. 
10.4 RECORDING OF ADVERSE EVENTS 
AEs are illnesses or signs/symptoms that appear or worsen during the testing of a drug 
whether or not considered related to the investigational product (synonyms = medicinal 
or pharmaceutical product, study medication, clinical trial materials, etc.), including side 
effects, injury, toxicity, or hypersensitivity reactions. 
All AEs, including observed, elicited, or volunteered problems, complaints or symptoms, 
are to be recorded on the AE page in the patient’s eCRF. 
The need to capture this information is not dependent upon whether adverse events are 
associated with use of the investigational product. 
AEs resulting from concurrent illnesses, reactions to concurrent illnesses, reactions to 
concurrent medications progression of disease states should also be recorded.  In order to 
avoid vague, ambiguous or colloquial expressions, AEs should be recorded in standard 
medical terminology rather than the patient's own words.  Signs and symptoms should be 
reported individually unless, in the judgment of the Investigator, they can be grouped 
under an inclusive term (e.g., gastroenteritis in lieu of abdominal pain, nausea, vomiting, 
and diarrhea). 
Each AE is to be evaluated for date/time of onset, duration, intensity, and causal 
relationship with the investigational product or other factors. 
At every study visit, including the prescreening/screening visit (visit 1), the Investigator 
must document new AEs and the outcome of ongoing AEs.  Any patient with an AE 
(including SAEs) or any clinically significant abnormal laboratory result or physical 
finding reported as an AE will be followed by the Investigator until the AE resolves, 
resolves with sequalae, is otherwise explained by a medical condition, follow-up is not 
possible (document), or the patient dies.  All attempts to follow-up will be documented. 
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10.4.1 Clinical Laboratory Abnormalities and Other Abnormal Assessments as AE: 
Clinically significant abnormal laboratory findings or clinically significant abnormal 
findings from other assessments that are detected during the study or are present at 
baseline and significantly worsen following the start of the study will be reported as AEs.  
Abnormal laboratory findings or other assessments deemed as abnormal will not be 
reported as AEs if they are determined to be clinically insignificant. 
If an abnormal laboratory value or other assessment is clearly related to a 
medically-defined diagnosis or syndrome, the diagnosis or syndrome will be recorded on 
the AE form, not the individual laboratory values or assessment.  
Clinically significant abnormal laboratory results or other clinically significant 
assessments will be followed until they resolve (return to normal or baseline values) or 
stabilize, or until they are judged by the Investigator to be no longer clinically significant.  
Clinically significant abnormal laboratory findings or abnormal findings from other 
assessments that are present at baseline will be recorded as medical history.  
10.4.1.1 Clinical Laboratory Abnormalities 
It is the responsibility of the Investigator to assess the clinical significance of all 
abnormal laboratory values as defined by the appropriate reference range(s).   
An abnormal laboratory value is considered to be an AE if the abnormality meets any of 
the following conditions below: 
• 
results in discontinuation from the study 
• 
requires treatment, modification/interruption of study drug dose, or any other 
therapeutic intervention 
• 
is judged to be of significant clinical importance 
Laboratory abnormalities that fulfill a seriousness criterion need to be documented as a 
SAE. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does 
not constitute an AE.  Any abnormal test result that is determined to be an error, either by 
laboratory or by Investigator does not require reporting as an AE. 
10.4.1.2 Other Safety Assessments: 
Any abnormal finding determined from physical examinations or from other safety 
assessments (eg, vital signs, ECGs, diagnostic imaging, or any other potential safety 
assessment required or not required by protocol) should be assessed for clinical 
significance by the Investigator.  Only clinically significant abnormal findings should be 
recorded as an AE. 
10.5 DEFINITION OF A SERIOUS ADVERSE EVENT 
An SAE is defined as an AE that results in any of the following: 
• death 
• life-threatening 
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• requires hospitalization or prolongs existing hospitalization 
• results in persistent or significant disability or incapacity 
• results in a congenital abnormality or birth defect 
• an important medical event which requires medical intervention to prevent 
any of the above outcomes 
Important medical events are those which may not be immediately life-threatening, but 
may jeopardize the patient and may require intervention to prevent one of the other 
serious outcomes listed above.  Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm or paradoxical bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; resulting in an 
adverse event will normally be considered serious by this criterion. 
Inpatient hospitalization or prolongation of existing hospitalization means that hospital 
inpatient admission and/or prolongation of hospital stay were required for treatment of 
AE, or that they occurred as a consequence of the event.  It does not refer to pre-planned 
elective hospital admission for treatment of a pre-existing condition that has not 
significantly worsened, or to diagnostic procedures. 
The term "life-threatening" in the definition of "serious" refers to an event in which the 
patient 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. 
The term “disability” in the definition of “serious” refers to an event in which the 
patient’s ability to conduct normal life functions was substantially disrupted. 
Severe vs. Serious AEs: The term “severe” is often used to describe the intensity 
(severity) of a specific event (as in mild, moderate, or severe headache).  This is not the 
same as “serious”, which is based on patient/event outcome or reaction criteria usually 
associated with events that pose a threat to a patient’s life or functioning.  Seriousness 
(not severity) serves as a guide for defining regulatory reporting obligations. 
Any new SAE that occurs after the study period and is considered to be related 
(possibly/probably) to the study drug or study participation should be recorded and 
reported immediately (Section 10.6).  The study period for the purpose of SAE reporting 
is defined as the period from the patient's signature on the informed consent form until 
the end of the protocol-defined follow-up visit/period. 
10.6 SERIOUS ADVERSE EVENT REPORTING 
In order to satisfy regulatory requirements, any SAE, whether deemed study drug-related 
or not, must be reported to the Sponsor’s Local Clinical Management (LCM) or designee 
as soon as possible after the Investigator or site coordinator has become aware of its 
occurrence.  The SAE form completion and reporting must not be delayed even if all of 
the information is not available at the time of the initial contact. 
The LCM contact for this study is the CRO, 
. 
 
 
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The SAE should be submitted within 24 hours of becoming aware of the event to the 
Sponsor's LCM or designee.  LCM or designee will forward the SAE report to the 
following Sponsor pharmacovigilance unit. 
Additional information (follow-up) about any SAE unavailable at the initial reporting 
should be forwarded by the site within 24 hours of the information becoming available to 
the LCM or designee. 
For both initial and follow-up SAE reports, the LCM or designee will forward this 
information to the appropriate pharmacovigilance unit at the Sponsor within 24 hours.  
The Sponsor pharmacovigilance units will submit a summary of the clinical course of the 
SAEs back to the LCM or designee for local submission to the institutional review 
board/independent ethics committee (IRB/IEC) and Investigators according to 
regulations.  All other investigators will be notified as per Safety Monitoring Plan. 
The Lupin Medical Monitor for this study is: 
 
 
The following information should be provided by the Investigator or designee to 
accurately and completely record the event: 
• Investigator name and center number 
• patient number 
• patient initials 
• patient demographics 
• clinical event 
o description 
o date of onset 
o severity 
o treatment (if blind needs to be broken) 
o relationship to study drug (causality) 
o action taken regarding study drug 
o outcome 
o date of resolution 
• if the AE results in death 
o cause of death (whether or not the death was related to study medication) 
o autopsy findings (if available) 
• medical history CRF (copy) 
• concomitant medication CRF (copy) 
• any relevant reports (laboratory, discharge, x-ray, etc) 
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Patients who have had an SAE during the treatment period must be followed clinically 
until all parameters (including laboratory) have either returned to normal or have 
stabilized or are otherwise explained. 
Any newly emergent SAEs after treatment is discontinued or the patient has completed 
the study and is considered to be related to the study drug or study participation should be 
recorded and reported immediately.  The poststudy period for the purpose of SAE 
reporting is up to the follow-up visit of the study. 
Pregnancy reports: Pregnancy reports should be forwarded to the LCM/CRO within 24 
hours of the Investigator’s knowledge using the Pregnancy Report form who will then 
submit to Lupin pharmacovigilance unit for data-entry to the global safety database.  This 
includes also normal pregnancies without AE. 
The pregnancy should be followed up to determine outcome, including spontaneous or 
voluntary termination, details of birth, and presence or absence of any birth defect, 
congenital abnormalities or maternal and newborn complications.  Pregnancy follow-up 
should be recorded on the study specific pregnancy reporting form. 
10.7 REPORTING TO THE UNITED STATES FOOD AND DRUG 
ADMINISTRATION (US FDA)  
All SAEs observed during the conduct of the study, regardless of whether the event is 
considered drug related will be reported to US FDA.  If the AE is fatal or life-threatening, 
the Clinical Safety Coordinator in the Center for Drug Evaluation and Research 
(CDER)’s Office of Generic Drugs will be notified within 7 calendar days after Lupin 
Inc. or the CRO becoming aware of its occurrence.  All other SAEs will be reported 
within 15 calendar days after Lupin Inc. or the CRO becoming aware of its occurrence.  
All follow-up reports will be submitted within 15 calendar days of Lupin Inc. or the CRO 
receiving the information. 
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11 
DATA COLLECTION AND ANALYSIS 
This section describes the biostatistical analysis as foreseen at the time of planning the 
study.  Changes, additions, and further details about the analyses will be described in the 
Statistical Analysis Plan (SAP).  The SAP will take precedence over the protocol in the 
case of discrepancy.  After finalization of the SAP and unblinding, any additional 
analyses or changes to analyses that may be required will be fully disclosed in the clinical 
trial report. 
11.1 DATA COLLECTION METHODS 
Data will be collected using eCRFs that are specifically designed for this study. The 
eCRF data will be captured within a clinical data management system (CDMS) that is 
21 CFR part 11 compliant. The CDMS will be fully validated prior to use on the study to 
ensure that it meets the scientific, regulatory, and logistical requirements of the study. All 
CDMS users will be provided system and study specific training prior to use, then trained 
users will be provided with individual system access rights. 
Data corrections to the CDMS will be performed using the CDMS update function. For 
each instance of data modification, the system requires a reason for change. The system 
keeps a full audit trail of the data values, date and time of modification, and an authorized 
electronic signature approving the change 
Data will be extracted from the CDMS to SAS.®  The data may be extracted on a 
scheduled or ad hoc basis to be used for data cleaning, study management, safety 
monitoring, data analysis, or other study related purposes. 
At the conclusion of the study, an electronic copy of each patient’s eCRF in PDF format 
will be supplied to the Investigator, who will maintain these records as described in 
section 12.8. 
11.2 SAMPLE SIZE CALCULATIONS 
The sample size estimation was determined based on demonstrating equivalence between 
the Test (T) product (Lupin Tiotropium Bromide Inhalation Powder) and the Reference 
(R) product (SPIRIVA HANDIHALER) for the primary endpoint change from baseline 
in FEV1 AUC0-24 on the treatment day, and to demonstrate that both the Test (T) and 
Reference (R) products are superior to the placebo.  Bioequivalence (BE) will be 
demonstrated if the 90% confidence interval (CI) on the T to R ratio for the endpoint is 
contained within the interval (0.80, 1.25).  Superiority will be demonstrated by showing 
that each active treatment’s response for the endpoint is greater than, and statistically 
different from (p<0.05, two-sided), that of the Placebo (P).  For the equivalence 
evaluation, the results in the PP analysis set will be considered definitive and for the 
superiority evaluations, those in the Intent-to-Treat (ITT) population will be considered 
definitive. 
A review of the literature did not yield any estimates of within-patient variability of 
baseline-adjusted FEV1 AUC0-24 from a crossover study using a similar patient 
population with similar objectives.  From a review of studies on clinicaltrials.gov, there 
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were a number of estimates available of between-patient variability for baseline-adjusted 
FEV1 AUC0-24.  From the 12 studies reviewed, the mean coefficient of variation (CV) for 
the variable was 121%.  Within-patient variability is generally much less than 
between-patient variability.  As a starting point for the sample size estimation it was 
assumed that the within-patient variability would be about 50% of the between-patient 
variability, or a CV of 60%.  
The goal of the study is to complete 180 patients per protocol.  With a sample size in 
each of the 6 sequence groups of 30, for a total sample size of 180, a crossover design 
will have 90% power to reject both the null hypothesis that the ratio of the test mean to 
the standard mean is below 0.80 and the null hypothesis that the ratio of test mean to the 
standard mean is above 1.25 (ie, that the test and standard are not equivalent), in favor of 
the alternative hypothesis that the means of the 2 treatments are equivalent, assuming that 
the expected ratio of means is 1.00, the between-patient coefficient of variation is 1.21, 
the intra-patient coefficient of variation is 0.60.  In order to allow for a potential 30% 
premature withdrawal rate or loss from the PP population due to protocol deviations, 
240 patients will be randomized in total, 40 to each of the 6 treatment sequences. 
As no estimates of within-patient variability were available in the public domain, a 
blinded interim analysis will be conducted in order to assess the within-patient 
variability.  The blinded interim analysis will be done to ascertain if an increase in sample 
size is necessary maintain 90% power to complete the study with a 90% CI for the 
relative bioavailability of the Test (T) to the Reference (R) product inside of the 
pre-specified interval 0.80-1.25. 
11.3 POPULATIONS FOR ANALYSIS 
11.3.1 Intent-to-Treat (ITT) Population 
The ITT analysis set will adhere as closely as practically possible to the intention-to-treat 
(ITT) ideal, and will be based on data from all patients who were randomized, took at 
least one dose of study medication and contributed sufficient data for at least one efficacy 
endpoint to be calculated.  The ITT analysis set will be the primary analysis set used for 
the demonstration of the superiority of the active treatments to placebo.  In this 
population, treatment will be assigned based upon the treatment to which patients were 
randomized regardless of which treatment they actually received. 
11.3.2 Per-Protocol (PP) Population 
The PP analysis set will exclude patients from the ITT population who had major 
protocol deviations.  These patients will be identified before the study blind is broken. 
The PP analysis set will be the primary analysis set used for the determination of BE. 
11.3.3 Safety Population 
All patients who received at least one dose of any one of the randomized investigational 
products and for whom data have been collected after randomization will be included in 
the safety analysis set. 
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11.3.4 Part 2 of the Study (Open-Label) 
All patients who begin treatment during the open-label portion of the study will be 
included in the descriptive statistics provided for the open-label portion. 
11.4 INTERIM ANALYSIS 
A blinded interim look at the data will be made in order to check the assumption about 
intra-patient variability made when estimating sample size with the possibility of 
increasing sample size, if necessary, to maintain 90% power.  In particular, the sample 
size estimate is based on an assumed intra-patient variability to which sample size 
estimates are very sensitive.  As no estimates of intra-patient variability were available, 
the initial assumption was that the intra-patient CV would be approximately half of the 
inter-patient CV observed on average in a number of studies.  A blinded interim review 
of the data is planned to assess if this reduction is obtained.   
Based on this blinded interim look, the sample size may be revised upward if the 
assumption of the assumed CV is not observed.  The sample size will not be revised 
downward. The interim look is planned when 150 of the planned 240 randomized patients 
have completed Part 1 of the study. 
11.5 METHODS OF STATISTICAL ANALYSES 
11.5.1 Multiplicity 
The comparisons of interest are: 
1. The superiority comparison between Lupin Tiotropium Bromide Inhalation 
Powder, 18 mcg (T) and Placebo (P) 
2. The superiority comparison between SPIRIVA HANDIHALER, 18 mcg (R) and 
Placebo (P) 
3. The bioequivalence comparison between Lupin Tiotropium Bromide Inhalation 
Powder, 18 mcg (T) and SPIRIVA HANDIHALER, 18 mcg (R) 
As all 3 of these comparisons must be successfully achieved in order to demonstrate BE, 
no adjustment for multiplicity is required.  The order of testing will be according to the 
list above. 
11.5.2 Summarization of Data 
Aside from the calculation of the FEV1 AUC 0-24, summary statistics (mean, SD, median, 
min, max) will be provided by treatment for data from the serial spirometry 
measurements including tmax (time to maximum bronchodilator response) as well as for 
all of the individual measurement times.  Additionally, a figure illustrating the serial 
spirometry (FEV1 over time) by treatment group will be provided. 
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11.5.3 Missing Data 
For missing serial spirometry measurements: 
Linear interpolation between the 2 adjacent FEV1 measurements will be used to estimate 
missing spirometry measurements occurring between 2 available measurements.  The 
exception to this would be the unlikely event of missing measurements that occur near 
the peak of the FEV1-time curve.  In these cases the average percentage change from the 
preceding value for patients receiving the same treatment will be used.  This makes use of 
the response of other patients to the same treatment.  For analysis, the percentage will be 
expressed in terms of an FEV1 value. 
For missing measurements at the end of the time profile (ie, no available FEV1 value after 
a point in time): 
• For values at the end of the profile that were missing because rescue medication 
was taken, the minimum observed FEV1 value on that test day, including the 
predose value, will be used as the estimate.  This is similar to assuming that there 
would be no increase from baseline after the point that rescue medication was 
required. 
• For values at the end of the profile that were missing for reasons unrelated to the 
patient’s response to treatment, the average percentage change from the preceding 
values for patients receiving the same treatment will be used.  This makes use of 
the response of other patients to the same treatment.  For analysis, the percentage 
will be expressed in terms of an FEV1 value.  Two additional sensitivity analyses 
will be performed based on the following: (a) the AUC calculation will be based 
on the time interval up to the last non-missing time point and (b) the baseline 
value will be substituted for the missing values. 
• For values at the end of the profile that were missing for unknown reasons, the 
observed minimum FEV1 value on the day of testing, including the predose value, 
will be used as an estimate.  This conservatively assumes that there would be no 
increase from baseline after the point that the data were missing. 
Additional sensitivity analysis may be performed and will be described in the study SAP. 
If a patient contributes data to at least 2 of the crossover legs, data from that patient will 
be included in the analysis as the patient will have provided data for one of the treatment 
comparisons.  If a patient completes only 1 leg of the crossover, data from the patient will 
be listed but will not be included in summary statistics or the analysis.  There is no 
reasonable basis for imputing data for a completely missing leg of the crossover. 
11.5.4 Primary Variable 
The primary variable is the adjusted mean change in FEV1AUC0 -24h on the single-dose 
treatment days.  Baseline is defined as the average of the FEV1 values recorded at 
approximately 30 minutes and 15 minutes before dosing with study medication. 
This crossover study will follow a Williams design with 6 treatment sequences balanced 
for first order carryover effects (see Table 7-1). 
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A repeated measures crossover model consisting of effects of treatment, period, and 
sequence will be carried out. 
11.5.5 Establishing Superiority of Test (T) and Reference (R) to Placebo 
For the comparison of the Test (T) and Reference (R) products, study sensitivity will be 
demonstrated if the Test (T) and Reference (R) products are shown to be statistically 
superior to Placebo (P) (p <0.05 [two-tailed]).  For these comparisons, the mixed model 
analysis described in the previous section will be applied to the ITT population. 
11.5.6 Establishing Bioequivalence between Test (T) and Reference (R) products 
The analysis of the primary endpoint for BE will be the mixed model analysis performed 
on the PP Analysis Set which will include all patients in the ITT population except those 
who had major protocol deviations.  
Bioequivalence (BE) will be declared if the 90% CI of the T/R ratio is entirely contained 
within the BE interval, 0.80 to 1.25.  This is equivalent to meeting the requirements of the 
two one-sided tests described above.  The 90% CI on the ratio of the Test (T) to 
Reference (R) means will be constructed using Fieller’s theorem.   
11.5.7 Safety Analyses 
All randomized patients who receive at least one dose of at least one study treatment and 
for whom data have been collected after randomization will be included in the safety 
analysis set. 
Descriptive statistics will be provided for safety variables.  No formal hypothesis testing 
of safety data is planned.   
Summaries will be provided for the following safety variables: AEs, vital signs, physical 
examinations, 
HEENT 
and 
chest 
examinations, 
COPD 
exacerbations, 
and 
albuterol/salbutamol MDI use. 
11.5.7.1 Adverse events 
The number and percentage of patients experiencing at least one AE will be summarized 
by MedDRA, primary SOC, PT and LLT, by treatment and by intensity and relationship 
to study medication. 
In Part 1, the blinded, single dose crossover part of the study, AEs will be tabulated by 
the following periods: 
• double-blind treatment period 
• during washout 
• during follow-up 
Adverse events (AEs) occurring after a study treatment during the treatment day and the 
day immediate after the treatment will be assigned to the relevant study treatment group.  
Adverse events (AEs) that occur before randomization will be summarized separately and 
will be listed.  
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Narratives will be provided for SAEs. 
Adverse events (AEs) will be tabulated separately for Part 2 of the study.  For Part 2 of 
the study, AEs will be tabulated by the following periods: 
• During the open-label study 
• During follow-up (more than 24 hours after the last treatment day in the 
open-label study) 
11.5.7.2 Vital Signs 
Vital signs, including blood pressure, heart rate, respiratory rate and body temperature, 
will be collected at the screening visit (visit 1) and all subsequent investigational center 
visits.  Descriptive statistics for vital signs at screening and at treatment visits (visits 2 
through 4 or ET for Part 1 and visits 7, 9, and 10 or ET for Part 2) will be provided.   
For Part 1, the double-blind period, summary statistics will be provided by treatment 
received on the day of the measurement. 
Summary statistics will be provided separately for Part 2, the open label extension. 
11.5.7.3 Physical Examination 
For Part 1, physical examination findings at screening (visit 1) and visit 4 or ET will be 
summarized for any clinically significant findings. Significant changes from screening 
(visit 1) and the end of the double-blind period will be summarized.  Changes from 
screening (visit 1) to the end of the double-blind period will be presented in 3 by 3 shift 
tables, where the responses are normal, abnormal but clinically non-significant, or 
abnormal and clinically significant.  Each examination area, eg, skin, abdominal, will 
have a separate table.  Some patients may require 2 physical examinations before 
treatment starts.  If they do, the first one is the prescreening value and the one at visit 1 is 
the screening value.  Prescreening results will be listed only. 
For Part 2 of the study (open-label extension), findings at visit 10 or ET will be 
summarized for any clinically significant findings and significant changes from screening 
(visit 1) and the end of the open-label extension using the 3 by 3 shift tables described 
above. 
11.5.7.4 HEENT, Chest Examination, and Electrocardiograms (ECG) 
For Part 1, during the double-blind period, abbreviated physical examination findings 
(HEENT and chest examinations) and ECG results will be summarized for any clinically 
significant findings and significant changes from visit 2.   
For Part 2 of the study (open label extension), findings will be summarized for any 
clinically significant findings and significant changes from visit 2. 
HEENT and chest examination findings will be summarized by five 3 by 3 shift tables 
where the shift is from visit 2 to each of the 4 visits during treatment, 2 visits in Part 1 
and 2 visits in Part 2. 
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Electrocardiography (ECG) findings will be summarized by six 3 by 3 shift tables where 
the shift is from screening (visit 1) to each of the 6 visits during treatment, 3 visits in Part 
1 and 3 visits in Part 2. 
11.5.7.5 COPD Exacerbations 
COPD exacerbations will be summarized and/or listed separately for Part 1 and Part 2 of 
the study. 
11.5.8 Safety Spirometry 
Patients will be issued an ediary/electronic flow meter to measure FEV1 for monitoring 
disease stability.   
For Part 1 (commencing at the time of signing the ICF), FEV1 will be measured once 
daily: prior to dosing in the morning at approximately the same time each day. 
For Part 2, FEV1 will be measured twice daily at home: upon awakening in the morning 
immediately prior to dosing with study medication and at 2 (+2) hours after study 
medication administration. 
Values for each patient will be listed. 
11.5.9 EXACT/ER-S Scores 
EXACT scores will be recorded in the patient’s ediary once daily each evening before 
bedtime.  Values of the ER-S COPD for each patient will be listed. 
11.5.10Albuterol/Salbutamol Usage 
Albuterol/Salbutamol usage will be summarized and/or listed separately for Part 1 and 
Part 2 of the study. 
In addition, urine/serum pregnancy test, urine drug screen, clinical laboratory, drug 
accountability, smoking restriction, DPI training, and In-Check training data will also be 
listed. 
11.5.11Inhaler Robustness (Part 2) 
11.5.11.1 
Ruggedness of LUPINHALER during In-Patient Use 
Patients will be instructed to report any problems that they experience with their 
LUPINHALER during the open-label extension.  The number and percentage of patients 
who reported at least one issue with the LUPINHALER will be provided.  
Additionally, a listing of the individual issues will be provided.  The listing will describe 
the issue in the detail provided by the patient. These will also be summarized according 
to the following categories: 
• misuse episodes (eg, impact [problems with the device after it was dropped], 
moisture [fell in water, submersed], other) 
• issues identified (eg, mechanical problems, COPD worsening/seems ineffective, 
other) 
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11.5.11.2 
In Vitro Pharmaceutical Performance 
In vitro pharmaceutical performance of 100 inhalers post 72 days of in-patient use will be 
assessed.  The data resulting from the in vitro evaluation of the pharmaceutical 
performance will be presented in a separate report. 
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12 
STUDY ADMINISTRATION 
12.1 REGULATORY AND ETHICAL CONSIDERATIONS 
12.1.1 Regulatory Authority Approval 
This study will be conducted in accordance with Good Clinical Practice (GCP) 
requirements described in the current revision of International Conference on 
Harmonization of Technical Requirements of Pharmaceuticals for Human Use (ICH) 
Guidelines and all applicable regulations, including current US Code of Federal 
Regulations (CFR), Title 21, Parts 50, 54, 56, and 312 and Title 45, Part 164.  
Compliance with these regulations and guidelines also constitutes compliance with the 
ethical principles described in the current revision of the Declaration of Helsinki.  This 
study will also be carried out in accordance with local legal requirements. 
12.1.2 Ethics Approval 
It is the Investigator’s responsibility to ensure that, prior to initiating the study, this 
protocol is reviewed and approved by the appropriate local IRB/IEC.  A non-local 
IRB/IEC may be used if the site of the study is not under the auspices of an IRB/IEC. 
The IRB/IEC must also review and approve the site’s ICF, other written information 
provided to the patient, and all advertisements that may be used for patient recruitment.  
The Investigator will provide Lupin Inc. or designee with copies of these documents and 
of dated IRB/IEC approval(s) prior to the start of the study. 
If it is necessary to amend the protocol or the ICF during the study, the Investigator will 
be responsible for ensuring that the IRB/IEC reviews and approves these amended 
documents.  An IRB/IEC approval of the amended protocol and/or ICF must be obtained 
before implementation of the amended procedures and before new patients are consented 
to participate in the study using the amended version of the ICF.  The Investigator will 
forward copies of the dated IRB/IEC approval of the amended protocol and/or ICF to 
Lupin Inc. or designee as soon as available. 
12.1.3 Patient Informed Consent 
Before being admitted to the clinical study, all patients must consent to participate.  An 
ICF will be given to each patient, which will contain all US federally required elements, 
all ICH-required elements, and Health Insurance Portability and Accountability Act 
Authorization (HIPAA) information in language that is understandable to the patient.  
The consent should note that the Investigator is receiving compensation for the expenses 
of conducting the study. 
The process of obtaining the informed consent will be in compliance with all federal 
regulations, ICH requirements, and local laws. 
The Investigator or a designee will review the study and the ICF with each patient.  The 
review will include the nature, scope, procedures, and possible consequences of the 
patient's participation in the study.  The consent and review must be in a form 
understandable to the patient.  The Investigator or designee and the patient must both sign 
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and date the ICF after review and before the patient can participate in the study.  The 
patient will receive a signed and dated form, and the original will be retained in the site’s 
study files.  The Investigator or designee must emphasize to the patient that study 
participation is entirely voluntary and that consent regarding study participation may be 
withdrawn at any time without penalty or loss of benefits to which the patient is 
otherwise entitled. 
12.1.4 Investigator Reporting Requirements 
In accordance with applicable regulatory requirements, the Investigator is solely and 
exclusively obligated to keep the IRB/IEC informed of progress on this study, and/or 
provide periodic safety updates at his/her site, and notify the IRB/IEC of study closure. 
The Investigator will provide Lupin Inc. or designee with copies of all correspondence 
with, or from, the IRB/IEC that relates to study approvals, updates, or changes.  
Furthermore, the Investigator will be responsible for obtaining all IRB/IEC renewals 
according to applicable regulations for the duration of the study and to provide copies of 
any and all approval extensions to Lupin Inc. 
12.2 PROTOCOL AMENDMENTS 
Changes to the protocol can only be made by an approved protocol amendment.  Protocol 
amendments must be approved by Lupin Inc. and IRB/IEC prior to implementation. 
12.3 DECLARATION OF THE END OF THE CLINICAL TRIAL 
For clinical trial sites located in the EU, a declaration of the end of the clinical trial will 
be made according to the procedures outlined in Directive 2001/20/EC, Article 10(c) and, 
for those countries outside the EU, local regulations will be followed. 
12.4 STUDY MONITORING 
In accordance with applicable regulations, GCP, and the procedures of Lupin Inc., or its 
designee, the Study Monitor will periodically contact the site, including conducting on-
site visits.  The extent, nature, and frequency of on-site visits will be based on study 
complexity, enrollment rate, and data quality at the site.  Through frequent 
communications (eg, letter, e-mail, and telephone), the Study Monitor will ensure that the 
investigation is conducted according to protocol and regulatory requirements. 
During these contacts, the monitoring activities will include: 
• checking and assessing the progress of the study 
• reviewing study data collected to date for completeness and accuracy 
• conducting source document verification by reviewing each patient’s CRF against 
source documents (eg, medical records, ICF, laboratory results reports, raw data 
collection forms)  
• performing study medication accountability 
• identifying any issues and addressing resolutions 
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These activities will be done in order to verify that the: 
• Data are authentic, accurate, and complete. 
• Safety and rights of the patients are being protected. 
• Study is conducted in accordance with the currently approved protocol (and any 
amendments), GCP, and all applicable regulatory requirements. 
The Investigator will allow the Study Monitor direct access to all relevant documents, 
and allocate his/her time and the time of his/her staff to the Study Monitor to discuss 
findings and any relevant issues. 
In addition to contacts during the study, the Study Monitor will contact the site prior to 
the start of the study to discuss the protocol and data collection procedures with site 
personnel. 
12.5 QUALITY ASSURANCE 
At its discretion, Lupin Inc. or its designee may conduct a quality assurance audit of this 
study.  Auditing procedures of Lupin Inc. and/or its designee will be followed in order to 
comply with GCP guidelines and ensure acceptability of the study data for registration 
purposes.  If such an audit occurs, the Investigator will give the auditor direct access to 
all relevant documents, and will allocate his/her time and the time of his/her staff to the 
auditor as may be required to discuss findings and any relevant issues. 
Regulatory agencies (eg, FDA) may conduct an inspection of this study.  If such an 
inspection occurs, the Investigator will allow the inspector direct access to all source 
documents, CRFs, and other study documentation for source data check and/or on-site 
audit inspection.  The Investigator must allocate his/her time and the time of his/her staff 
to the inspector to discuss findings of any relevant issues. 
12.6 STUDY TERMINATION AND SITE CLOSURE 
Upon completion of the study, the following activities, when applicable, must be 
conducted by the Study Monitor in conjunction with the Investigator, as appropriate: 
• return all study equipment to Lupin Inc. or designee 
• data clarifications and/or resolutions 
• accounting, reconciliation, and final disposition of used and unused study 
medication 
• review of site study records for completeness 
• shipment of blood samples to the clinical laboratory, if applicable 
Lupin Inc. reserves the right to temporarily suspend or prematurely terminate this study 
for any reason. 
If the study is suspended or terminated for safety reason(s), Lupin Inc. will promptly 
inform the Investigator, and will also inform the regulatory authorities of the suspension 
or termination of the study and the reason(s) for the action.  The Investigator is 
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responsible for promptly informing the IRB/IEC, and providing the reason(s) for the 
suspension or termination of the study. 
If the study is prematurely discontinued, all study data must be returned to Lupin Inc. or 
its designee.  In addition, the site must conduct final disposition of all unused study 
medication in accordance with Lupin Inc. procedures for the study. 
12.7 SITE TERMINATION 
Lupin Inc. may, in its sole discretion, terminate a single study site for various reasons, 
including, but not limited to, the following: 
• failure of the Investigator to enroll patients into the study at a reasonable rate 
• failure of the Investigator to comply with pertinent ICH/GCP/FDA regulations  
• submission of knowingly false information from the research facility to Lupin 
Inc., Study Monitor, or FDA 
• insufficient adherence to protocol requirements 
If the participation of a study site is terminated for reasons other than safety (eg, 
uncorrected data acquisition or image quality issues), Lupin Inc. will issue a written 
notice to the Investigator.  The written notice will contain the reasons for taking such 
action.  If a study site is terminated for noncompliance, Lupin Inc. will also notify 
appropriate regulatory authorities.  Study termination and follow up will be performed in 
compliance with the conditions set forth in 21 CFR 312.50 and 21 CFR 312.56. 
12.8 RECORDS RETENTION 
In accordance with applicable regulatory requirements and following completion or 
termination of the study, the Investigator will retain a copy of all study records in a safe, 
secure, and accessible location for a minimum of 2 years after notification by Lupin Inc. 
that the investigations have been discontinued, or for 2 years after all marketing 
applications have been approved.  For EU submissions, retention of a minimum 5 years 
though it was post-submission is required.  Study records will include at a minimum the 
following: 
• signed ICFs for all patients 
• patient identification list 
• record of all communications between the Investigator and the IRB/IEC 
• record of all communications between the Investigator and Lupin Inc. or its 
designee 
• list of all Sub-Investigators and other key study personnel 
• copies of all financial records related to the study including: financial 
arrangements for the study; financial payments made by Lupin Inc. or its designee 
to the Investigator; and financial interests held by the Investigator in the product 
or in Lupin Inc. 
• copies of eCRFs for all patients  
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• all other source documents (eg, patient records, hospital records, laboratory 
reports, and drug accountability records) 
To avoid any possible errors, the Investigator will contact Lupin Inc. prior to the 
destruction of any study records.  The Investigator must immediately notify Lupin Inc. in 
the event of accidental loss or destruction of any study records. 
12.9 CONFIDENTIALITY OF INFORMATION 
Patient names will remain confidential and will not be supplied to Lupin Inc. or its 
designee.  Only the patient number and year of birth will be recorded in the CRF.  If the 
patient name appears on any other document collected (eg, hospital discharge summary), 
it must be obliterated from the document before the document is transmitted to Lupin Inc. 
or its designee.  All study findings will be stored in electronic databases.  The patients 
will give explicit written permission for representatives of Lupin Inc., regulatory 
authorities, and the IRB/IEC to inspect their medical records to verify the information 
collected.  Patients will be informed that all personal information made available for 
inspection will be handled in the strictest confidence and in accordance with all state, 
local, and federal data protection/privacy laws, including, without limitation, the HIPAA. 
When patients complete the study, all contact information will be purged from all study 
files, and all patient identifiers (other than an assigned patient number) will be obliterated 
from documentation confirming a clinical endpoint event. 
12.10 PAYMENT TO PATIENTS 
Patients may be compensated for participating in this study and the amount of payment 
will be stated in the ICF approved by the IRB/IEC.  Patients not completing this study for 
whatever reason will be paid on a pro rata basis. 
12.11 CLINICAL TRIAL REGISTRATION 
This clinical trial will be registered on the “clinicaltrials.gov” clinical trial registry 
website as required by 42 USC 282(j). 
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13 
REFERENCES 
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the 
diagnosis, management, and prevention of COPD. Updated 2016. http://www.goldcopd.org  
Barr RG, Bourbeau J, Camargo CA, Ram FS. Inhaled tiotropium for stable chronic obstructive 
pulmonary disease. Cochrane database of systematic reviews 2005:CD002876 
Cheyne L, Irvin-Sellers MJ, White J. Tiotropium versus ipratropium bromide for chronic 
obstructive pulmonary disease. Cochrane Database Syst Rev 2013 Sep 16;9:CD00955 
Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. 
PLoS Med 2006;3:e442 
Van den Boom G, van Schayck CP, van Mollen MP, et al. Active detection of chronic 
obstructive pulmonary disease and asthma in the general population. Results and economic 
consequences of the DIMCA program. Am J Respir Crit Care Med 1998;158:1730-8. 
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14 
APPENDICES 
• Appendix A: Study Medication Instructions for Use 
• Appendix B: Inhalation Training with In-Check DIAL 
• Appendix C: Evaluating Respiratory Symptoms (E-RS) Scale 
• Appendix D: Protocol Amendment 1 Summary of Changes 
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Appendix A: Study Medication Instructions for Use 
Patient Instructions for Investigational Product Administration of the Dry Powder Inhalers 
Two dry powder inhalers will be used in this study (see Figure A1 and Figure A2):  
For the run-in period, 1 inhaler (Figure A2) will be used to administer 2 inhalations from 
1 capsule of study medication (Lupin 18 mcg tiotropium bromide or placebo) once daily for 
14 +2 days. 
For Part 1 of the study, 2 inhalers (Figure A1 and Figure A2) will be used to administer a 
single-dose of study medication (18 mcg tiotropium bromide or placebo) at each treatment 
period (visits 2, 3, and 4).  A single-dose consists of 1 capsule per inhaler administered as 
2 inhalations per capsule.  Each capsule will be placed into the inhalers by unblinded study 
personnel as per the randomization schedule. 
For Part 2 of the study, 1 inhaler (Figure A2) will be used to administer 2 inhalations from 
1 capsule of study medication (Lupin 18 mcg tiotropium bromide) once daily for 72 +3 days. 
Placebo training inhalers will also be provided for training purposes during Part 1 of the study.   
YOUR STUDY INHALERS  
Figure A1 represents HANDIHALER and Figure A2 represents LUPINHALER.  These inhalers 
are for oral inhalation only.  Both INHALERS will be over-labeled with the appropriate 
kit/inhaler number. 
 
 
 
 
 
 
 
Figure A1 
Figure A2 
HANDIHALER 
 
 
 
 
LUPINHALER 
 
Each INHALER comes with capsules in blister packaging.  Use the INHALER provided with the 
designated capsule(s). 
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The parts of each INHALER include: 
(See Figure B1 for HANDIHALER and Figure B2 for LUPINHALER) 
1. Dust cap (lid)  
2. Mouthpiece 
3. Mouthpiece ridge 
4. Base 
5. Green piercing button 
6. Center chamber 
7. Air intake vents 
Figure B1 
 
 
    Figure B2 
 
 
Each tiotropium capsule is packaged in a blister (See Figure C).  
 
 
 
 
Figure C 
 
Each tiotropium capsule contains only a small amount of powder (See Figure D). 
Do not open the tiotropium capsule or it may not work. 
 
 
 
 
 
 
Figure D  
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FOR PATIENTS PARTICIPATING IN PART 1 DOUBLE-BLIND 
 
TAKING YOUR DOSE OF STUDY MEDICATION REQUIRES 4 MAIN STEPS. 
Note: Some of these steps will be performed by unblinded study personnel prior to you (the 
patient) receiving the INHALER. 
STEP 1. OPENING YOUR INHALER: 
Only unblinded study personnel should open the kits and prepare the INHALERS for the Part 1 
double-blind treatment.  Opening of the kit and preparation of the INHALERS should be done in 
a blinded study medication location away from the view of blinded study personnel and you.  
After unblinded study personnel has removed your INHALER from the pouch: 
• Unblinded study personnel will open the dust cap (lid) by pressing the green piercing 
button (See Figure E1 for HANDIHALER and Figure E2 for LUPINHALER). 
 
 
 
 
 
 
 
 
Figure E1 
 
 
   Figure E2 
• Unblinded study personnel will pull the dust cap (lid) upwards away from the base to 
expose the mouthpiece (See Figure F1 for HANDIHALER and Figure F2 for 
LUPINHALER). 
 
 
 
 
 
 
 
Figure F1 
    Figure F2 
• Unblinded study personnel will open the mouthpiece by pulling the mouthpiece ridge up 
and away from the base so center chamber is showing (See Figure G1 for 
HANDIHALER and Figure G2 for LUPINHALER). 
 
 
 
 
 
 
 
Figure G1    
 
 
Figure G2 
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STEP 2. INSERTING THE CAPSULE INTO YOUR INHALER: 
Unblinded study personnel will separate the blisters from the blister card by tearing along the 
perforated line (See Figure H). 
 
 
 
 
 
 
 
Figure H 
 
Unblinded study personnel will remove the capsule from the blister: 
• Do not cut the foil or use sharp instruments to take out the capsule from the blister. 
• Bend one of the blister corners with an arrow and separate the aluminum foil layers. 
• Peel back the printed foil until you see the whole capsule (See Figure J). 
• If you have opened more than 1 blister to the air, the extra capsule should not be used. 
 
 
 
 
 
 
 
 
 
Figure J 
 
 
• Unblinded study personnel will place the capsule in the center chamber of your 
INHALER (See Figure K1 for HANDIHALER and Figure K2 for LUPINHALER). 
 
 
 
 
 
 
 
 
 
Figure K1 
 
 
    Figure K2 
 
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• Unblinded study personnel will close the mouthpiece firmly against the base until he/she 
hears a click.  Unblinded study personnel will leave the dust cap (lid) open  
(See Figure L1 for HANDIHALER and Figure L2 for LUPINHALER). 
 
 
 
 
 
 
 
 
 
Figure L1 
 
 
    Figure L2 
 
STEP 3A. PIERCING THE CAPSULE: 
• Unblinded study personnel will hold your INHALER with the mouthpiece pointed up  
(See Figure M1 for HANDIHALER and Figure M2 for LUPINHALER). 
   
 
 
 
 
 
 
 
Figure M1 
 
 
   Figure M2 
    
• Unblinded study personnel will press the green piercing button once until it is flat (flush) 
against the base, then release.  This is how to make holes in the capsule so that you get 
study medication when you breathe in. 
• Do not press the green button more than one time. 
• Do not shake the INHALER. 
• The piercing of the capsule may produce small pieces of the capsule.  Some of these 
small pieces may pass through the screen of the INHALER into the mouth or throat when 
you breathe in your medicine.  This is normal.  The small pieces of the capsule should not 
harm you. 
STEP 3B. APPLYING TAPE TO MASK THE CHAMBER WINDOW 
• After piercing the capsule, unblinded study personnel will apply an opaque label/tape to 
cover the chamber window to prevent identification of the capsules, numbering the 
inhaler dosing order based on even/odd calendar days as described in the pharmacy 
manual. 
• Unblinded study personnel will bring the INHALERS to the patient dosing location 
leaving the inhaler kit carton, capsule blisters in the blinded study medication location. 
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STEP 4. TAKING YOUR DOSE OF STUDY MEDICATION: 
Blinded study personnel will hand you the INHALER in a horizontal position.  Keep the 
INHALER in the horizontal position. 
 
Breathe out completely in 1 breath, emptying your lungs of any air  
(See Figure N). 
 
Important: Do not breathe into your INHALER. 
 
 
 
 
 
 
 
 
 
 
Figure N 
 
 
With your next breath, take your study medication: 
• Hold your head in an upright position while you are looking straight ahead  
(See Figure P1 for HANDIHALER and Figure P2 for LUPINHALER). 
• Raise your INHALER to your mouth in a horizontal position.  Do not block the air intake 
vents. 
• Close your lips tightly around the mouthpiece. 
• Breathe in deeply until your lungs are full.  You should hear or feel the capsule 
vibrate (rattle) (See Figure P1 for HANDIHALER and Figure P2 for LUPINHALER). 
• Hold your breath for a few seconds and, at the same time, take your INHALER out of 
your mouth. 
• Breathe normally again. 
 
 
 
 
 
 
 
Figure P1 
 
 
   Figure P2  
The rattle tells you that you breathed in correctly.  If you do not hear or feel a rattle, see the 
section, “If you do not hear or feel the capsule rattle as you breathe in your study medication.”
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To get the full amount from the capsule, you must again, breathe out completely  
(See Figure Q)  
 
 
 
 
 
 
 
 
 
Figure Q 
 
then for a second time, breathe in (See Figure R1 for HANDIHALER and Figure R2 for 
LUPINHALER) from the same capsule. 
Important: Do not press the green piercing button again.  Do not breathe into your INHALER. 
Remember: To get your full amount from the capsule, you must breathe in 2 times from the same 
capsule.  Make sure you breathe out completely each time before you breathe in from your 
INHALER. 
 
 
 
 
 
 
 
 
 
 
Figure R1 
 
 
   Figure R2 
 
After completing 2 inhalations from your 1st INHALER, hand the INHALER to unblinded study 
personnel.  Blinded study personnel will collect the INHALER, and close the INHALER. 
 
Repeat Step 4 with the 2nd INHALER to take your 2nd capsule.  
 
Every attempt should be made to administer the powder contents from each of the 
2 capsules (2 inhalations/capsule for a total of 4 inhalations) within 2 minutes. 
 
After you have dosed with both INHALERS, unblinded study personnel will return the 
INHALERS to the blinded study medication location and deposit each used INHALER 
containing the used capsule along with unused capsule blisters into the pouch and carton. 
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IF YOU DO NOT HEAR OR FEEL THE CAPSULE AS YOU BREATHE IN YOUR STUDY 
MEDICATION: 
Do not press the green piercing button again. 
Blinded study personnel will hold your INHALER with the mouthpiece pointed up and tap your 
INHALER gently on a table (See Figure S1 for HANDIHALER and Figure S2 for 
LUPINHALER). 
 
 
 
 
 
 
 
 
Figure S1 
 
 
   Figure S2 
Blinded study personnel will check to see that the mouthpiece is completely closed.  Breathe out 
completely before deeply breathing in again with the mouthpiece in your mouth  
(See Figure R1 for HANDIHALER and Figure R2 for LUPINHALER). 
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FOR PATIENTS PARTICIPATING IN TRAINING/RUN-IN/PART 2 
 
TAKING YOUR DOSE OF STUDY MEDICATION REQUIRES 4 MAIN STEPS. 
 
STEP 1. OPENING YOUR INHALER: 
After study personnel has removed your INHALER from the pouch: 
• Open the dust cap (lid) by pressing the green piercing button (See Figure E). 
 
 
 
 
 
 
 
 
Figure E 
 
• Pull the dust cap (lid) upwards away from the base to expose the mouthpiece  
(See Figure F). 
 
 
 
 
 
 
 
 
Figure F 
 
• Open the mouthpiece by pulling the mouthpiece ridge up and away from the base so 
center chamber is showing (See Figure G). 
 
 
 
 
 
 
 
Figure G 
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STEP 2. INSERTING THE CAPSULE INTO YOUR INHALER: 
Each day, separate only 1 blister from the blister card by tearing along the perforated line  
(See Figure H). 
 
 
 
 
 
 
Figure H 
 
Remove the capsule from the blister: 
• Do not cut the foil or use sharp instruments to take out the capsule from the blister. 
• Bend one of the blister corners with an arrow and separate the aluminum foil layers. 
• Peel back the printed foil until you see the whole capsule (See Figure J). 
• If you have opened more than 1 blister to the air, the extra capsule should not be used. 
 
 
 
 
 
 
 
 
 
Figure J 
 
 
• Place the capsule in the center chamber of your INHALER (See Figure K). 
 
 
 
 
 
 
 
 
 Figure K 
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• Close the mouthpiece firmly against the base until you hear a click.  Leave the dust cap 
(lid) open (See Figure L). 
 
 
 
 
 
 
 
 
  
  Figure L 
 
 
STEP 3. PIERCING THE CAPSULE: 
• Hold your INHALER with the mouthpiece pointed up (See Figure M). 
   
 
 
 
 
 
 
 
 
 
   Figure M 
    
 
• Press the green piercing button once until it is flat (flush) against the base, then release.  
This is how to make holes in the capsule so that you get study medication when you 
breathe in. 
• Do not press the green button more than one time. 
• Do not shake the INHALER. 
• The piercing of the capsule may produce small pieces of the capsule.  Some of these 
small pieces may pass through the screen of the INHALER into the mouth or throat when 
you breathe in your study medication.  This is normal.  The small pieces of the capsule 
should not harm you. 
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STEP 4. TAKING YOUR FULL DAILY DOSE OF STUDY MEDICATION 
(2 INHALATIONS FROM THE SAME CAPSULE): 
 
Breathe out completely in 1 breath, emptying your lungs of any air (See Figure N). 
 
Important: Do not breathe into your INHALER. 
 
 
 
 
 
 
 
 
 
Figure N 
 
With your next breath, take your study medication: 
• Hold your head in an upright position while you are looking straight ahead  
(See Figure P). 
• Raise your INHALER to your mouth in a horizontal position.  Do not block the air intake 
vents. 
• Close your lips tightly around the mouthpiece. 
• Breathe in deeply until your lungs are full.  You should hear or feel the capsule 
vibrate (rattle) (See Figure P). 
• Hold your breath for a few seconds and, at the same time, take your INHALER out of 
your mouth. 
• Breathe normally again. 
 
 
 
 
 
 
 
 Figure P  
 
The rattle tells you that you breathed in correctly.  If you do not hear or feel a rattle, see the 
section, “If you do not hear or feel the capsule rattle as you breathe in your study medication.” 
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To get the full amount from the capsule, you must again, breathe out completely  
(See Figure Q)  
 
 
 
 
 
 
 
 
 
 
Figure Q 
 
then for a second time, breathe in (See Figure R) from the same capsule.  
Important: Do not press the green piercing button again.  Do not breathe into your INHALER. 
Remember: To get your full amount from the capsule, you must breathe in 2 times from the same 
capsule.  Make sure you breathe out completely each time before you breathe in from your 
INHALER. 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Figure R 
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CARING FOR AND STORING YOUR INHALER: 
• After taking your daily dose, open the mouthpiece and tip out the used capsule into your 
trash can, without touching it. 
• Remove any capsule pieces or powder buildup by turning your INHALER upside down 
and gently, but firmly, tapping it (See Figure S).  Then, close the mouthpiece and dustcap 
for storage. 
 
 
 
 
 
  Figure S 
• Do not store your INHALER and capsules (blisters) in a damp moist place.  Always store 
capsules in the sealed blisters. 
 
IF YOU DO NOT HEAR OR FEEL THE CAPSULE AS YOU BREATHE IN YOUR STUDY 
MEDICATION: 
• Do not press the green piercing button again. 
• Hold your INHALER with the mouthpiece pointed up and tap your INHALER gently on 
a table (See Figure T). 
 
 
 
 
 
 
 
 
 
 
Figure T 
 
• Check to see that the mouthpiece is completely closed.  Breathe out completely before 
deeply breathing in again with the mouthpiece in your mouth (See Figure R). 
• If you still do not hear or feel the capsule rattle after repeating the above steps: 
o Throw away the used capsule. 
o Open the base by lifting the green piercing button and check the center chamber 
for pieces of the capsule. 
o Capsule pieces in the center chamber can cause a capsule not to rattle. 
o Turn your INHALER upside down and gently, but firmly, tap to remove the 
capsule pieces. Call your study doctor for instructions. 
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CLEANING YOUR INHALER: 
• Clean your INHALER device as needed (See Figure U). 
o It takes 24 hours to air dry your INHALER after you clean it. 
o Do not use cleaning agents or detergents. 
o Do not place your INHALER in the dishwasher for cleaning. 
 
 
 
 
 
 
 
 
Figure U 
• Cleaning Steps: 
o Open the dust cap and mouthpiece. 
o Open the base by lifting the green piercing button. 
o Look in the center chamber for capsule pieces or powder buildup.  If seen, tap out. 
o Rinse your INHALER with warm water, pressing the green piercing button a few 
times so that the center chamber and the piercing needle are under the running 
water.  Check that any powder buildup or capsule pieces are removed. 
o Dry your INHALER well by tipping the excess water out on a paper towel. 
Air-dry afterwards, leaving the dust cap, mouthpiece, and base open by fully 
spreading it out so that it dries completely. 
o Do not use a hair dryer to dry your INHALER. 
o Do not use your INHALER when it is wet.  If needed, you may clean the outside 
of the mouthpiece with a clean damp cloth. 
o Document in your diary when cleaning of the INHALER has been performed. 
 
IMPORTANT INFORMATION ABOUT USING YOUR INHALER: 
1. Do not swallow capsules. 
2. Capsules should only be used with the INHALER and inhaled through your mouth (oral 
inhalation). 
3. Do not use your INHALER to take any other medicine. 
4. Do not store capsules in the INHALER. 
5. Store capsules in the sealed blister package at room temperature between 68°F to 77°F 
(20°C to 25°C). 
6. Keep capsules away from heat and cold (do not freeze). 
7. Store capsules in a dry place.  Do not use any unused capsules that have been open to air. 
8. Ask your study doctor if you have any questions about storing your capsules. 
9. Keep the INHALER and capsules out of the reach of children. 
10. Do not let the powder from the capsule get into your eyes. 
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Appendix B: Inhalation Training with In-Check DIAL 
The In-Check DIAL is an inhalation airflow meter that can help educate and assess patients who 
use inhaler devices.  It simulates the internal resistance of several common inhaler devices, and 
measures inspiratory flow.  Inspiratory flow rate measurements will be obtained at screening and 
visits 2, 3, and 4 using the In-Check DIAL device.  
How to use the In-Check DIAL 
1.  Reset the In-Check DIAL.  The cursor should be reset to zero through a “tap and turn” 
maneuver which releases a seated magnet from the top of the DIAL and pushes the cursor 
back. The DIAL should then be turned upside down to reseat the magnet so as not to get in 
the way of an accurate measurement. 
 
2.    Align the scale with the inhaler device.  With the triangular pointer on top of the scale, align 
the “dial” portion of the device for use with HANDIHALER adapter by setting the device to 
no resistance circle (pMDI) icon - an audible "click" should be heard.   
 
 
 
 
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3.   Attach a clean mouthpiece.  Attach the HANDIHALER resistance adapter (blue transparent 
cylinder provided separately in a sealed plastic bag) to mimic SPIRIVA HANDIHALER 
resistance.  Insert a disposable one-way valved inspiratory mouthpiece into the wider end 
of the blue transparent adapter. 
 
 
4.   Ask the patient to exhale slowly and fully. 
 
 
 
 
 
 
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5.   Seal lips around the mouthpiece. According to the inhaler setting (no resistance circle 
[pMDI] icon) and HANDIHALER resistance adapter), instruct the patient to inhale deeply.  
 
6.   Record the inspiratory flow from the position of the red cursor against the scale.  Reset, and 
repeat until 3 successful inspiratory flow rates (≥40 L/min) are achieved.  Record the three 
(3) inspiratory flow rates on the patient’s source.  
 
 
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Appendix C: EXACT DAILY DIARY 
Instructions: Please complete your diary every evening, just before you go to bed.  As you 
answer the following questions, please select the option that best describes your experience. 
The ediary will be programmed to display your ER-S: COPD daily respiratory symptoms (RS) 
Total score.  A baseline score will be obtained from the first available evening session after the 
screening visit (visit 1) for use during the screening and run-in periods and from the latest 
available evening session before the randomization visit (visit 2) for use during the double-blind 
and open-label treatment periods.  If at any time, there is increase in the daily RS Total score of 
≥2 from baseline, the ediary will alert you to notify investigational center personnel to discuss 
your current health status. 
1. Did your chest 
feel congested 
today? 
Not at all 
Slightly 
Moderately 
Severely 
Extremely 
2. How often did 
you cough today?  
Not at all 
Rarely 
Occasionally 
Frequently 
Almost constantly 
3. How much 
mucus (phlegm) 
did you bring up 
when coughing 
today? 
None at all  
A little 
Some 
A great deal 
A very great deal 
4. How difficult 
was it to bring up 
mucus (phlegm) 
today? 
Not at all   
Slightly   
Moderately   
Quite a bit   
Extremely   
5. Did you have 
chest discomfort 
today? 
Not at all   
Slight   
Moderate   
Severe   
Extreme   
 
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6. Did your chest 
feel tight today? 
Not at all 
Slightly 
Moderately 
Severely 
Extremely 
7. Were you 
breathless today? 
Not at all 
Slightly 
Moderately 
Severely 
Extremely 
8. Describe how 
breathless you were 
today: 
Unaware of breathlessness 
Breathless during strenuous activity 
Breathless during light activity 
Breathless when washing or dressing 
Present when resting  
9. Were you short of 
breath today when 
performing your 
usual personal care 
activities like 
washing or 
dressing? 
Not at all 
Slightly 
Moderately 
Severely 
Extremely 
Too breathless to do these 
10. Were you short 
of breath today 
when performing 
your usual indoor 
activities like 
cleaning or 
household work? 
Not at all 
Slightly 
Moderately 
Severely 
Extremely 
Too breathless to do these 
 
 
 
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11. Were you short 
of breath today 
when performing 
your usual activities 
outside the home 
such as yard work or 
errands? 
Not at all 
Slightly 
Moderately 
Severely 
Extremely 
Too breathless to do these 
12. Were you tired 
or weak today? 
Not at all 
Slightly 
Moderately 
Severely 
Extremely 
13. Last night, was 
your sleep 
disturbed? 
Not at all 
Slightly 
Moderately 
Severely 
Extremely 
14. How scared or 
worried were you 
about your lung 
problems today? 
Not at all 
Slightly 
Moderately 
Severely 
Extremely 
Copyright 
EXACT© 2013, Evidera, Inc. All rights reserved. 
EXACT version 1.1-English (universal) 9/9/2009 
*The EXACT instrument and scoring program are owned by Evidera.  The questions listed above may be displayed 
in another format as per the formal licensing agreement with the ediary vendor. 
 
 
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APPENDIX D: PROTOCOL AMENDMENT 1 SUMMARY OF CHANGES 
Protocol Amendment 1 incorporates the following changes.  The revisions listed below have 
been made to the protocol and synopsis as appropriate, and are considered substantial.  Revised 
or new text is presented in bold italics and deletions are struck through.  Minor typographical and 
formatting errors were corrected throughout the protocol.   
The primary reasons for this amendment are: 
• To incorporate the administrative letter dated 27 Feb 2017, Clarification of the roles of 
the unblinded/blinded study personnel during study medication administration in Part 1, 
updates to the study medication and In-Check DIAL instructions for use, and clarification 
of clinical laboratory results prior to run-in. 
‒ 
Roles of the unblinded/blinded study personnel: Unblinded study personnel will prepare 
double-blind study medication and dispense the inhalers to blinded study personnel and 
observe dose administration in Part 1.  Blinded study personnel will perform study 
medication training during all parts of the study 
‒ 
In-Check DIAL: A new release of the In-Check DIAL device was issued prior to study 
initiation (ie, new dial top developed to group inhalers by resistance instead of device 
type); therefore, updated the instructions for use accordingly. 
‒ 
Clinical laboratory results: Based on the study visit schedule, the clinical laboratory results 
may not be available prior to a patient entering run-in; therefore, footnote #5 in the 
Schedule of Events was updated to state the results must be available and evaluated prior to 
randomization. 
• To incorporate the administrative letter dated 10 Mar 2017, Clarification of the 
dispensation of the ediary/electronic flow meter and safety monitoring during the 
screening period. 
‒ 
Ediary: Diary collection will begin at the time of signing the ICF.  COPD symptom scores 
(EXACT), albuterol/salbutamol MDI usage, and once daily (morning) FEV1 measurements 
at home using will be collected using the ediary/electronic flow meter during the screening 
period. 
‒ 
Screening period/screening visit assessments:  The screening period may occur up to 30 
days prior to the start of the run-in period.  Procedures for the screening visit (visit 1), with 
the exception of signing of the ICF, assigning a patient number, performing a pre-washout 
physical examination, and dispensing/completing the ediary, cannot occur until appropriate 
medication washouts have been completed in accordance with the study protocol. 
• To prohibit caffeine-containing medication for at least 6 hours prior to spirometry 
assessments at any scheduled visit (visit 1 through visit 4).  
 
 
 
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Study Centers, Synopsis (page 8) 
Original text: 
The study is planned to be conducted at approximately 60 investigational centers in the United States of 
America (USA).  Additional centers in the USA may be added as needed. 
Revised text: 
The study is planned to be conducted at approximately 60 40 investigational centers in the United States 
of America (USA).  Additional centers in the USA may be added as needed. 
Rationale for change: Based on enrollment projections, 40 investigational centers were selected to 
participate in the study. 
 
 
Study Design Overview, Synopsis (page 9) and Section 5.1.1 Part 1: Double-Blind Treatment Period 
(page 26) 
Original text: 
The screening period, of up to 30 days, allows for adequate washout of the following COPD therapies, 
along with other prohibited medications per protocol: 
• 
long-acting anti-muscarinic agent (LAMA) medications (including mono products and 
combination products containing LAMAs [eg, LAMA/LABA]) will not be permitted within 
21 days of the screening visit (visit 1) 
• 
long-acting beta agonist (LABA) mono products will not be permitted within 7 days of the 
screening visit (visit 1) 
• 
inhaled corticosteroid (ICS) mono products and ICS/LABA combination products will not be 
permitted within 30 days of the screening visit (visit 1) 
Revised text: 
The screening period, of up to 30 days, allows for adequate washout of the following COPD therapies, 
along with other prohibited medications per protocol: 
• 
long-acting anti-muscarinic agent (LAMA) medications (including mono products and 
combination products containing LAMAs [eg, LAMA/LABA]) will not be permitted within 
21 days of the screening visit (visit 1) 
• 
long-acting beta agonist (LABA) mono products will not be permitted within 7 days of the 
screening visit (visit 1) 
• 
inhaled corticosteroid (ICS) mono products and ICS/LABA combination products will not be 
permitted within 30 days of the screening visit (visit 1) 
If a patient is washing out of ICS (monotherapy) or ICS/LABA combination therapy as stated above, 
an additional 3 day window is permitted to complete the assessments for the screening visit (visit 1). 
Rationale for change: For patients on ICS (monotherapy) or ICS/LABA combination therapy additional 
time may be needed to complete all screening assessments prior to the run-in period; therefore, the 
window has been extended. 
 
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Synopsis, Study Design Overview (page 10) and Section 5.1.1 Part 1: Double-Blind Treatment 
Period (page 27) 
Original text: 
In order to maintain the patient blind, a specified member of the investigational center (ie, unblinded 
administrator) will load and dispense the study medication to the patient and instruct the patients to take 2 
full inhalations from each of 2 inhalers.  The unblinded administrator will also apply an opaque covering 
to the chamber windows prior to patient administration to obstruct capsule identification in each inhaler.  
The unblinded administrator will check each inhaler after each dose (2 inhalations) is administered to 
ensure that the capsule powder has been evacuated.  Any instances where the capsule powder is not 
evacuated should be documented. 
Revised text: 
In order to maintain the patient blind, a specified member of the investigational center (ie, unblinded 
administrator) will load and dispense the study medication to the patient and instruct the patients to take 2 
full inhalations from each of 2 inhalers.  The unblinded administrator will also apply an opaque covering 
to the chamber windows prior to patient administration to obstruct capsule identification in each inhaler. 
The unblinded administrator will check each inhaler after each dose (2 inhalations) is administered to 
ensure that the capsule powder has been evacuated.  Any instances where the capsule powder is not 
evacuated should be documented. 
Rationale for change:  Because the amount of powder is not visible through the chamber window, it is 
not feasible to check the remaining powder content via the chamber window through visual inspection.  
Therefore, this step has been removed.  
 
 
Synopsis, Study Design Overview (page 12), Section 5.1.2 Part 2: Open-Label Extension (page 29), 
and Section 9.3.4.1 Visit 5 (Day 43) (page 67) 
Original text: 
If at any time patients experience a perceived issue with their inhaler, the ediary system will alert the 
investigational center who will arrange the necessary corrective action, if required.  The investigational 
center should endeavor to complete an inhaler report worksheet within 24 hours of notification of an 
issue. 
Revised text: 
If at any time patients experience a perceived issue with their inhaler, the ediary system will alert the 
investigational center who will arrange the necessary corrective action, if required.  The investigational 
center should endeavor to complete an inhaler report worksheet the electronic case report form (eCRF) 
within 24 hours of notification of an issue.  
Rationale for change: Clarification.  Any identified issues with study medication will be recorded in the 
electronic data capture (EDC) system. 
 
 
Synopsis, Study Design Overview (page 12) and Section 5.1.2 Part 2: Open-Label Extension 
(page 29) 
Original text: 
Safety will be monitored throughout Part 1 and Part 2 of the study by vital signs measurements, 
albuterol/salbutamol MDI and concomitant medication usage, physical examinations, head, ears, eyes, 
nose, throat (HEENT)/chest examinations, spirometry (FEV1) measurements, electrocardiography 
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(ECGs), ER-S: COPD scores (derived from the EXACT), COPD exacerbations, and adverse events 
(AEs). 
Revised text: 
Safety will be monitored throughout Part 1 and Part 2 of the study by vital signs measurements, 
albuterol/salbutamol MDI and concomitant medication usage, physical examinations, head, ears, eyes, 
nose, throat (HEENT)/chest examinations, spirometry (FEV1) measurements, electrocardiography 
(ECGs), ER-S: COPD scores (derived from the EXACT), COPD exacerbations, and adverse events 
(AEs).  During the screening and run-in periods, safety will be assessed via FEV1 measurements, 
ER-S: COPD scores, and monitoring of AEs and COPD exacerbations. 
Rationale for change: Clarification.  Safety is assessed during the screening and run-periods via FEV1 
measurements, COPD symptom scores, and monitoring of AEs and COPD exacerbations. 
 
 
Synopsis, Inclusion criteria (page 13), Section 6.1 Inclusion Criteria (pages 30-31), Schedule of 
Assessments, footnote 13 (page 52) 
Original text: 
9. Patient has demonstrated ≥15% reversibility of FEV1 within 30 or 60 minutes following 68 mcg of 
ipratropium bromide inhalation (pMDI) at the screening visit (visit 1).  Patients who do not 
demonstrate a positive improvement of at least 15% in FEV1 measured at 30 or 60 minutes post 
inhalation will not be eligible to participate in the study.  However, based on Investigator judgment, 
patients will be allowed to retest once no sooner than 24 hours and no later than 2 weeks after the 
initial failure (see section 9.3.6).  Reversibility values of 14.50-14.99 will be rounded to 15. 
Revised text: 
9. Patient has demonstrated ≥15% reversibility of FEV1 within 30 or 60 minutes following 68 mcg of 
ipratropium bromide inhalation (pMDI) at the screening visit (visit 1).  If required, spacers are 
permitted for use during reversibility testing for ipratropium administration.  Patients who do not 
demonstrate a positive improvement of at least 15% in FEV1 measured at 30 or 60 minutes post 
inhalation will not be eligible to participate in the study.  However, based on Investigator judgment, 
patients will be allowed to retest once no sooner than 24 hours and no later than 2 weeks after the 
initial failure (see section 9.3.6).  Reversibility values of 14.50-14.99 will be rounded to 15. 
Rationale for change: Clarification.  Spacers will be permitted for use during reversibility testing. 
 
 
Exclusion criterion #15, Synopsis (page 15) and Section 6.2 Exclusion Criteria (page 33) 
Original text: 
15. Positive urine drug screen at the screening visit (visit 1).  If a patient has a positive urine drug 
screen for a class of drug which is consistent with a medication that the patient is currently 
prescribed, the patient can be considered eligible for the study after the prescription is confirmed 
by the Investigator. 
Revised text: 
15. Positive urine drug screen at the screening visit (visit 1).  If a patient has a positive urine drug 
screen for a class of drug which is consistent with a medication that the patient is currently 
prescribed (excluding inhaled marijuana), the patient can be considered eligible for the study 
after the prescription is confirmed by the Investigator. 
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Rationale for change: Clarification. Inhaled marijuana has been previously established as a prohibited 
medication as indicated in Table 8-1; therefore use is prohibited even if prescribed. 
 
 
Synopsis, Randomization Criteria (page 16) and Section 6.3 Randomization Criteria (page 34) 
Original text: 
5. Patient has withheld all inhaled SABAs for at least 6 hours and SAMAs for at least 8 hours prior to 
lung function assessments at randomization (visit 2). 
Revised text: 
5. Patient has withheld all inhaled SABAs for at least 6 hours and SAMAs for at least 8 hours prior to 
lung function assessments at randomization (visit 2). 
Rationale for change: Typographical error.  At visit 2, patients will withhold SABAs for at least 6 hours 
and SAMA for at least hours prior to lung function assessments. 
 
 
Randomization criterion #9, Synopsis (page 16) and Section 6.3 Randomization Criteria (page 34) 
Original text: 
9. Patient has demonstrated compliance to placebo run-in medication within the margins of at least 
≥75% and ≤125% of projected use.  
Revised text: 
9. Patient has demonstrated ediary compliance to placebo run-in medication within the margins of at 
least ≥75% and ≤125% of projected use.  
Rationale for change: Clarification.  Compliance to placebo run-in medication will be calculated and 
verified via the ediary.   
 
 
Section 3.2 Clinical Experience with Tiotropium Bromide Inhalation Powder Administered by a 
Dry Powder Inhaler (DPI) (pages 22-23) 
Original text: 
To date, one clinical study (Study LBC-P-055-15) with Lupin Tiotropium Bromide Inhalation Powder has 
been conducted. 
Revised text: 
To date, one 2 clinical study studies (Study LBC-P-055-15 and LBC-P-006-15) with Lupin Tiotropium 
Bromide Inhalation Powder has have been conducted. 
Study LBC-P-0006-15 was a randomized, open-label, single-dose, 3-period Phase 1, PK crossover study 
being conducted in healthy male subjects 18-45 years of age under fasting conditions.  The primary 
objective of the study was to assess the systemic levels and relative bioavailability of a single orally-
administered dose of tiotropium (18 mcg), from 2 different batches of Lupin tiotropium capsules 
18 mcg (×1 capsule) via the LUPINHALER, and 1 batch of SPIRIVA capsules 18 mcg (×1 capsule) via 
the HANDIHALER. 
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Preliminary safety results from this study indicate that Tiotropium Bromide Inhalation Powder was 
well tolerated by the healthy subjects, ages 18 to 45 years.  No SAEs were reported.  The final statistical 
analyses and PK results are not available at this time. 
Rationale for change: Informational update.  A 2nd PK study was conducted to assess the PK profiles of 
different batches of Lupin Tiotropium Bromide Inhalation Powder with SPIRIVA HANDIHALER. 
 
 
Section 4.4.3 Other Endpoints (page 25) 
Original text: 
For a subset of the LUPINHALERs used during the open-label extension (Part 2), the following 
endpoints will be assessed: 
• 
ruggedness of the LUPINHALER during 72 days of in-patient use 
• 
percent (%) of overall inhalers with reported problems or malfunctions; comprised of 
problems/malfunctions encountered with the device (eg, lack of efficacy, mechanical 
problems, problems with device after it has been dropped) during 72 days of in-patient use 
• 
in vitro pharmaceutical performance of 100 inhalers post 72 days of in-patient use 
The data resulting from the in vitro evaluation of the pharmaceutical performance will be 
presented in a separate report. 
Revised text: 
For a subset of the LUPINHALERs used during the open-label extension (Part 2), the following 
endpoints will be assessed: 
• 
ruggedness of the LUPINHALER during 72 days of in-patient use 
• 
percent (%) of overall inhalers with reported problems or malfunctions; comprised of 
problems/malfunctions encountered with the device (eg, lack of efficacy, mechanical 
problems, problems with device after it has been dropped) misuse episodes (eg, impact 
and moisture) and issues identified (eg, mechanical problems and COPD 
worsening/seems ineffective) during 72 days of in-patient use 
• 
in vitro pharmaceutical performance of 100 inhalers post 72 days of in-patient use 
The data resulting from the in vitro evaluation of the pharmaceutical performance will be 
presented in a separate report. 
Rationale for change: Clarification.  Ruggedness of the LUPINHALER will be summarized into 2 main 
categories with additional subclassification. 
 
 
Section 6.5 Withdrawal Criteria (pages 35-36) 
Original text: 
The following alert criteria should be evaluated by the Investigator for consideration of whether the 
patient should be withdrawn from the study. 
These criteria would include the following:  
• 
COPD exacerbation during Part 2 that prohibits the patient from administering their study 
medication (Lupin Tiotropium Bromide Inhalation Powder) once daily 
• 
use of medication for respiratory symptoms not allowed by the study protocol 
• 
viral or bacterial respiratory infection during Part 1 which results in an increase in the symptoms 
of COPD from the patient’s normal baseline level 
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• 
prior to randomization (Part 1): a decrease in FEV1 of more than 20% from the predose FEV1 at 
the screening visit (visit 1) 
• 
post randomization (Part 1 and Part 2): more than 3 occurrences of a decrease in FEV1 of more 
than 20% from the predose FEV1 at the randomization visit (visit 2)  
• 
>20% decrease from the mean morning baseline FEV1 on more than 3 of the last 7 (rolling) days 
during Part 1 or 2  
• 
viral or bacterial respiratory infection during Part 2 which results in an increase in the symptoms 
of COPD from the patient’s normal baseline level 
• 
increase of ≥2 on the ER-S: COPD daily respiratory symptoms (RS) Total Score during Part 1 or 
2 
• 
≥12 or more albuterol/salbutamol puffs per day on more than 2 of the last 7 (rolling) days during 
Part 1 or 2 
Revised text: 
These criteria would include the following:  
• 
COPD exacerbation during Part 2 that prohibits the patient from administering their study 
medication (Lupin Tiotropium Bromide Inhalation Powder) once daily 
• 
use of medication for respiratory symptoms not allowed by the study protocol 
• 
viral or bacterial respiratory infection during Part 1 which results in an increase in the symptoms 
of COPD from the patient’s normal baseline level 
• 
prior to randomization (Part 1): a decrease in FEV1 of more than 20% from the predose FEV1 at 
the screening visit (visit 1) 
• 
post randomization (Part 1 and Part 2): more than 3 occurrences of a decrease in FEV1 of more 
than 20% from the predose FEV1 at the randomization visit (visit 2)  
• 
>20% decrease from the mean morning baseline FEV1 on more than 3 of the last 7 (rolling) days 
during Part 1 (commencing once the predose pre-bronchodilator study qualifying FEV1 (ie, 
pre-PFT) is performed at the screening visit [visit 1])) or Part 2  
• 
viral or bacterial respiratory infection during Part 2 which results in an increase in the symptoms 
of COPD from the patient’s normal baseline level 
• 
increase of ≥2 on the ER-S: COPD daily respiratory symptoms (RS) Total Score during Part 1 
(commencing at the start of the screening period) or Part 2 
• 
≥12 or more albuterol/salbutamol puffs per day on more than 2 of the last 7 (rolling) days during 
Part 1 (commencing at the start of the screening period) or Part 2. 
Rationale for change: Clarification.  Diary collection begins at the time of signing the ICF.  
eDiaries/electronic flow meters will be dispensed on the 1st day of the screening period prior to patients 
beginning any medication washout, to assist with safety monitoring throughout the screening period.  
FEV1 monitoring, COPD symptom scores, and rescue use will be recorded in the ediary/electronic flow 
meter.  The FEV1 withdrawal criteria for verifying stability will commence at once the pre-PFT is 
performed at visit 1.  
 
 
Section 7.4 Ancillary Supplies (page 38) 
Original text: 
ediary/electronic flow meter 
For Part 1 and Part 2 of the study, patients will be issued an ediary/electronic flow meter to record COPD 
symptom scores (EXACT), albuterol/salbutamol MDI and study medication usage, and FEV1 
measurements at home.  In addition device robustness data will be tracked via the ediary system. 
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Revised text: 
For the screening period, run-in period, Part 1 and Part 2 of the study, patients will be issued an 
ediary/electronic flow meter to record COPD symptom scores (EXACT); albuterol/salbutamol MDI 
usage; and study medication usage (run-in and Part 2 only); and FEV1 measurements at home.  Diary 
collection begins at the time of signing the ICF.  eDiaries/electronic flow meters will be dispensed on 
the 1st day of the screening period prior to patients beginning any medication washout, to assist with 
safety monitoring throughout the screening period. 
In addition device robustness data will be tracked via the ediary system. 
Rationale for change: Clarification.  Diary collection begins at the time of signing of ICF to assess the 
safety of patients during the screening period.  
 
 
Section 7.6 Method of Assigning Patients to Treatment Sequences (page 40) 
Original text: 
Additionally, on each study day, as this is a double-dummy study, the order of administration of the 
LUPINHALER and HANDIHALER will be randomly assigned via a randomization schedule separate 
from the main crossover randomization schedule. 
Revised text: 
Additionally, on each study day, as this is a double-dummy study, the order of administration of the 
LUPINHALER and HANDIHALER will be randomly assigned via a randomization schedule separate 
from the main crossover randomization schedule based on even/odd calendar days.  On odd calendar 
days (eg, 1, 3, 5, 29, 31), the LUPINHALER will be dosed first.  On even calendar days (eg, 2, 4, 6, 28, 
30), the HANDIHALER will be dosed first. 
Rationale for change: Implementing a randomization schedule for the order of inhaler 
administration for each patient for each day would not be practical.  The method described 
assures that the same inhaler is not administered first on each day of the study for each patient. 
 
 
Section 7.7.1 Blinding Part 1 (pages 40-41) 
Original text: 
The unblinded administrator will collect the study medication from the pharmacy, remove the capsule 
from the relevant blister strips and prepare the inhalers out of sight of the patient.  The unblinded 
administrator will then obscure the observation windows in the device with opaque tape and ask the 
patient to complete dosing as per the instructions for use (Appendix A).  After the 2nd inhalation the 
unblinded administrator will unmask the inhaler, review the capsule to ensure the dose has been properly 
administered and re-attach the tape to mask the window.  The same process will be repeated for the other 
inhaler until 2 inhalations from each capsule have been completed through both test and reference 
inhalers.   
As indicated in the randomization scheme (Table 7-1), at each treatment visit the patient will receive 
either: 
• one active dose from 1 of the 2 inhalers; other inhaler contain placebo dose 
• 2 placebo doses  
Training of the patient on inhaler technique and dosing of the study medication and drug accountability 
should be undertaken exclusively by the unblinded administrator so that the core study team who are 
responsive for efficacy and safety assessments are unaware of the inhalers administered.   
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The patient will self-administer the medication at the investigational center on each study day guided by 
this unblinded study team member.  FEV1 testing will continue postdose by the blinded study team. 
Revised text: 
The unblinded administrator will collect the study medication from the pharmacy, remove the capsule 
from the relevant blister strips and prepare the inhalers out of sight of the patient.  The unblinded 
administrator will then obscure the observation windows in the device with opaque tape and ask dispense 
to blinded study personnel, who will assist the patient to complete dosing as per the instructions for use 
(Appendix A).  After the 2nd inhalation the unblinded administrator will unmask the inhaler, review the 
capsule to ensure the dose has been properly administered and re-attach the tape to mask the window.  
The same process will be repeated for the other inhaler until 2 inhalations from each capsule have been 
completed through both test and reference inhalers.   
As indicated in the randomization scheme (Table 7-1), at each treatment visit the patient will receive 
either: 
• one active dose from 1 of the 2 inhalers; other inhaler contain placebo dose 
• 2 placebo doses  
Training of the patient on inhaler technique and dosing of the study medication and drug accountability 
should be undertaken exclusively by the unblinded administrator will be undertaken by blinded study 
personnel.  The unblinded administrator will acknowledge all shipments, prepare blinded study 
medication, and dispense the blinded study medication to the blinded study personnel so that the core 
study team who are responsive for efficacy and safety assessments are unaware of the inhalers 
administered.  In addition, the unblinded administrator will witness dose administration in the double-
blind portion of Part 1. 
The patient will self-administer the medication at the investigational center on each study day guided by 
this unblinded study team member.  FEV1 testing will continue postdose by the blinded study team. 
Rationale for change: Clarification.  To define the roles of the unblinded and blinded study personnel 
during administration of study mediation in Part 1 Double-Blind.  Unblinded study personnel will 
prepare double-blind study medication and dispense the inhalers to blinded study personnel and observe 
dose administration in Part 1.  Blinded study personnel will perform study medication training during all 
parts of the study and assist with dosing of the patients in Part 1. 
 
 
Section 7.7.2 Blinding Part 2 (page 41) 
Original text: 
Part 2 will be conducted via an open-label design; therefore, no blinding is required.  Used inhalers and 
unused/used capsules will be returned to the investigational center. 
Revised text: 
Part 2 will be conducted via an open-label design; therefore, no blinding is required.  Used inhalers and 
unused/used capsules will be returned to the investigational center. 
Rationale for change: Only the unused capsules in Part 2 will be returned to the investigational center.  
Used capsules will be discarded in the patient’s trash. 
 
 
Section 7.9 Dosing Procedures (page 42) 
Original text: 
For Part 1, prior to study visits 2 through 4, patients should refrain from using albuterol/salbutamol MDI 
and other prohibited medication; patients should not smoke at least 1 hour prior to lung function 
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assessments during the visits; and patients should adhere to the dietary restrictions as per protocol (see 
section 8.2).  Patients will be trained on the correct use of the study medication.  Patients will administer 
2 inhalations from each of 2 inhalers of the assigned study medication in the morning with the assistance 
of the unblinded administrator.  Dosing at visits 2-4 must be administered by the unblinded site staff 
member.  Patients may stay overnight at the investigational center or at nearby housing facility (eg, hotel) 
to complete the FEV1 serial measurements over a 24-hour period.  In certain cases, the patient may return 
home after the 12 hour FEV1 measurement and return for the 23 and 24 FEV1 measurements, at the 
discretion of the Investigator.   
After administration of study medication, the patient will enter a washout period of 21 days + 3 days 
between treatment periods, where the patient may continue to use albuterol/salbutamol MDI and other 
medications permitted per protocol (see section 8).  For visits 2 through 4, patients should present at the 
investigational center so that the start of lung function testing will be within ±1 hour from the lung 
function testing at visit 1. 
For Part 2 of the study, patients will be trained on the correct use of the DPI by the unblinded 
administrator.  The dose should be taken at home in the morning.  Predose FEV1 measurements should be 
performed upon awakening in the morning immediately prior to dosing with the study medication; 
postdose FEV1 measurements are to be performed 2 (+2) hours after study medication administration. 
Revised text: 
For Part 1, prior to study visits 2 through 4, patients should refrain from using albuterol/salbutamol MDI 
and other prohibited medication; patients should not smoke at least 1 hour prior to lung function 
assessments during the visits; and patients should adhere to the dietary restrictions as per protocol (see 
section 8.2).  Patients will be trained on the correct use of the study medication.  Patients will administer 
2 inhalations from each of 2 inhalers of the assigned study medication in the morning with the assistance 
of the unblinded administrator.  Dosing at visits 2-4 must be administered by the unblinded site staff 
member.  Patients may stay overnight at the investigational center or at nearby housing facility (eg, hotel) 
to complete the FEV1 serial measurements over a 24-hour period.  In certain cases, the patient may return 
home after the 12 hour FEV1 measurement and return for the 23 and 24 FEV1 measurements, at the 
discretion of the Investigator.   
After administration of study medication, the patient will enter a washout period of 21 days + 3 days 
between treatment periods, where the patient may continue to use albuterol/salbutamol MDI and other 
medications permitted per protocol (see section 8).  For visits 2 through 4, patients should present at the 
investigational center so that the start of lung function testing will be within ±1 hour from the lung 
function testing at visit 1. 
For Part 2 of the study, patients will be trained on the correct use of the DPI by the unblinded 
administrator study personnel.  The dose should be taken at home in the morning.  Predose FEV1 
measurements should be performed upon awakening in the morning immediately prior to dosing with the 
study medication; postdose FEV1 measurements are to be performed 2 (+2) hours after study medication 
administration. 
Rationale for change: Clarification.  To define the roles of the unblinded and blinded study personnel 
during administration of study mediation in Part 1 Double-Blind.  Unblinded study personnel will 
prepare double-blind study medication and dispense the inhalers to blinded study personnel and observe 
dose administration in Part 1.  Blinded study personnel will perform study medication training during all 
parts of the study and assist with dosing of the patients in Part 1. 
 
 
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Section 7.10 Study Medication Accountability (page 42) 
Original text: 
At study conclusion, all used and unused study medication, albuterol/salbutamol medication, and placebo 
trainers must be returned to the Sponsor or Sponsor’s designee.  Documented evidence of destruction 
should be made available to the Sponsor. 
Revised text: 
At study conclusion, all used and unused study medication (with the exception of used capsules during 
the run-in period and open-label extension), albuterol/salbutamol medication, and placebo trainers must 
be returned to the Sponsor or Sponsor’s designee.  Documented evidence of destruction should be made 
available to the Sponsor. 
Rationale for change: Only the unused capsules in the run-in period and Part 2 will be returned to the 
investigational center.  Used capsules will be discarded in the patient’s trash. 
 
Table 8-1 Prohibited Concomitant Medications (page 45) 
Original text: 
Type of medication 
Washout period before the screening visit (visit 1) 
and throughout the study (unless otherwise specified) 
Prohibited 
Beta-adrenergic receptor blocking agents 
14 days 
Drugs 
of 
abuse 
(cannabinoids, 
amphetamines, 
barbiturates, cocaine, benzodiazepines, methadone, 
and opiates)a  
A negative test is required at the screening visit and use 
is prohibited throughout the study. 
a. 
If a patient has a positive urine drug screen for a class of drug which is consistent with a medication that the 
patient is currently prescribed, the patient can be considered eligible for the study after the prescription is 
confirmed by the Investigator. 
Revised text: 
Type of medication 
Washout period before the screening visit (visit 1) 
and throughout the study (unless otherwise specified) 
Prohibited 
Beta-adrenergic receptor blocking agents a 
14 days 
Drugs 
of 
abuse 
(cannabinoids, 
amphetamines, 
barbiturates, cocaine, benzodiazepines, methadone, 
and opiates) a b 
A negative test is required at the screening visit and use 
is prohibited throughout the study. 
a. 
Cardioselective beta blockers are permitted as long as therapy was initiated at least 7 days before the 
screening visit (visit 1) and is expected to remain at a stable dose throughout the study. 
b. If a patient has a positive urine drug screen for a class of drug which is consistent with a medication that the 
patient is currently prescribed (excluding inhaled marijuana), the patient can be considered eligible for the 
study after the prescription is confirmed by the Investigator.  Inhaled marijuana is not permitted even if 
prescribed. 
Rationale for change: Cardioselective beta blockers are permitted if therapy initiated at least 7 days 
prior to the screening visit (visit 1) and the patient remains on a stable dose throughout the study.  
Inhaled marijuana has been previously established as a prohibited medication as indicated in Table 8-1; 
therefore use is prohibited even if prescribed. 
 
 
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Section 8.1.1 Washout Restrictions during Part 1 of the Study Only (page 46) 
Original text: 
Patients should refrain from taking the following medications from the specified time points below prior 
to spirometry assessments at each clinic visit (both days of each inpatient visit) during Part 1 of the study: 
• 
SABAs  
 
 
 
 
 
  6 hours 
• 
SAMAs: 
 
 
 
 
 
  8 hours  
• 
short-acting forms of theophylline:  
 
 
12 hours  
• 
twice-a-day controlled-release forms of theophylline:  
24 hours 
• 
once-a-day controlled-release forms of theophylline: 
36 hours 
Revised text: 
Patients should refrain from taking the following medications from the specified time points below prior 
to spirometry assessments at each clinic visit (both days of each inpatient visit) during Part 1 of the study: 
• 
SABAs  
 
 
 
 
 
   
  6 hours 
• 
SAMAs: 
 
 
 
 
 
   
  8 hours  
• 
short-acting forms of theophylline:  
 
 
 
12 hours  
• 
twice-a-day controlled-release forms of theophylline:  
 
24 hours 
• 
once-a-day controlled-release forms of theophylline: 
 
36 hours 
• 
caffeine-containing medications (eg, MIDOL®, EXCEDRIN®)   6 hours 
Rationale for change: Caffeine could impact lung function and is therefore restricted with appropriate 
washout. 
 
 
Schedule of Events (page 52) 
Original text: 
5) The screening visit (visit 1) may take place over several days beginning on day -44 to -14 dependent on 
the patient’s washout. All results must be available and evaluated prior to commencing the run-in 
period.  
Revised text: 
5) The screening visit (visit 1) may take place over several days beginning on day -44 to -14 dependent on 
the patient’s washout.  If a patient is washing out of ICS (monotherapy) or ICS/LABA combination 
therapy, an additional 3 days is permitted to complete the assessments for the screening visit 
(visit 1).  All results, with the exception of the clinical laboratory assessments, must be available and 
evaluated prior to commencing the run-in period.  The clinical laboratory results must be available 
and evaluated prior to randomization.  The procedures for the screening visit (visit 1), with the 
exception of signing of the ICF, performing a pre-washout physical examination, and 
dispensing/completing the ediary, cannot occur until appropriate medication washouts have been 
completed in accordance with the protocol.  Once the washout requirements have been met, the 
screening visit (visit 1) should immediately precede the start of the run-in period.  If a patient does 
not require washout, and the patient passes all entry criteria at the screening visit (visit 1), the 
patient will be eligible to enter the run-in period on the same day as the screening visit (visit 1).  The 
patient must successfully complete the visit 1 procedures/assessments prior to entering the run-in 
period. 
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Rationale for change: Clarification. Clinical laboratory results may not be available prior to a patient 
entering run-in; however, the results must be reviewed and evaluated for clinical significance prior to 
patient randomization.  Diary collection begins at the time of signing of ICF to assess the safety of 
patients during the screening period.  For patients on ICS (monotherapy) or ICS/LABA combination 
therapy additional time may be needed to complete all screening assessments prior to the run-in period; 
therefore, the window has been extended. 
 
 
Schedule of Events (page 52) 
Original text: 
14) A stability limit will be established at the screening visit to determine alert criteria for worsening 
COPD during the screening and run-in periods, and will be calculated by selecting the best pre-
bronchodilator qualifying FEV1 measurement at the screening visit using the onsite spirometer x 
80%. 
Revised text: 
14) A stability limit will be established at the screening visit (visit 1) to determine alert criteria for 
worsening COPD during the screening and run-in periods, and will be calculated by selecting the best 
pre-bronchodilator qualifying FEV1 measurement at the screening visit using the onsite spirometer x 
80%. 
Rationale for change: Clarification. A stability limit will be established at visit 1 using the onsite 
spirometry to monitor a patient’s COPD status between visit 1 and the run-in period. 
 
 
Schedule of Events (page 53) 
Original text: 
17) Predose FEV1 will be measured at 30 and 15 minutes before administration of study medication.  
Serial FEV1 spirometry measured at 0 hours (within 30 and 15 minutes prior to study medication 
administration [equivalent to the predose FEV1]), and at 5 and 30 minutes postdose, and at 1, 2, 4, 6, 
8, 10, 12, 23, and 24 hours postdose.  The following windows are permitted: +5 minutes for predose 
measurements (-30 and -5 minutes); ±5 minutes for 0.5-6 hours, and ±15 minutes for 8-24 hours.  
Revised text: 
17) Predose FEV1 will be measured at 30 and 15 minutes before administration of study medication.  
Serial FEV1 spirometry measured at 0 hours (within 30 and 15 minutes prior to study medication 
administration [equivalent to the predose FEV1]), and at 5 and 30 minutes postdose, and at 1, 2, 4, 6, 
8, 10, 12, 23, and 24 hours postdose.  The following windows are permitted: +5 minutes for predose 
measurements (-30 and -5 minutes) and 5 minute postdose measurement; ±5 minutes for 0.5-6 hours, 
and ±15 minutes for 8-24 hours. 
Rationale for change: Added a collection time window of +5 minutes for the 5 minute postpose FEV1 
measurement. 
 
 
Schedule of Events (page 53) 
Original text: 
20) Administration of study medication at the investigational center will occur in the presence of the 
unblinded a staff member.  
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Revised text: 
20) Administration of study medication at the investigational center will occur in the presence of the 
unblinded and blinded staff members. 
Rationale for change: Clarification. To define the roles of the unblinded and blinded study personnel 
during administration of study mediation in Part 1 Double-Blind.  Unblinded study personnel will 
prepare double-blind study medication and dispense the inhalers to blinded study personnel and observe 
dose administration in Part 1.  Blinded study personnel will perform study medication training during all 
parts of the study and assist with dosing of the patients in Part 1. 
 
 
Section 9.2.1.1 Spirometry (page 54) 
Original text: 
Spirometry testing will be performed by experienced research staff who have passed a proficiency process 
to ensure understanding of the equipment used and forced spirometry technique.  To collect data in a 
consistent manner, the same staff member will conduct all spirometry assessments for the same patient 
whenever possible.  The same spirometer should be used on a patient throughout the study 
Revised text: 
Spirometry testing will be performed by experienced research staff who have passed a proficiency process 
to ensure understanding of the equipment used and forced spirometry technique.  To collect data in a 
consistent manner, the same staff member will conduct all spirometry assessments for the same patient 
whenever possible.  The same spirometer should be used on a patient throughout the study.  Onsite 
spirometry assessments (baseline/study qualifying/reversibility) must occur after washout of the 
protocol prohibited and restricted medications. 
Rationale for change: Clarification.  To emphasize spirometry assessments must occur after washout of 
prohibited and restricted medications. 
 
 
Section 9.2.1.1 Spirometry (page 54) 
Original text: 
The following windows are permitted: +5 minutes for predose measurements (-30 and -15 minutes); 
±5 minutes for 0.5-6 hours, and ±15 minutes for 8-24 hours.  
Revised text: 
The following windows are permitted: +5 minutes for predose measurements (-30 and -15 minutes) and 
5 minute postdose measurement, ±5 minutes for 0.5-6 hours, and ±15 minutes for 8-24 hours. 
Rationale for change: Added a collection time window of +5 minutes for the 5 minute postpose FEV1 
measurement. 
 
 
Section 9.2.1.1 Spirometry (pages 54-55) 
Original text: 
Reversibility Testing 
For reversibility testing, patients will receive 68 mcg of ipratropium bromide inhalation pMDI as 
4 actuations of 17 mcg/actuation (ex-mouthpiece); given at approximately 30 second intervals.  All 
actuations are to be completed within 3 minutes of the 1st actuation.  The ATS/ERS criteria will be 
followed for spirometry measures.  Patients who do not demonstrate a positive improvement of at least 
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15% in FEV1 measured at 30 or 60 minutes (±5 minutes) post inhalation will not be eligible to participate 
in the study (except as permitted per the retest specified below).  Reversibility values of 14.50-14.99 will 
be rounded to 15.  
Revised text: 
Reversibility Testing 
For reversibility testing, patients will receive 68 mcg of ipratropium bromide inhalation pMDI as 
4 actuations of 17 mcg/actuation (ex-mouthpiece); given at approximately 30 second intervals.  If 
required, spacers are permitted for use during reversibility testing for ipratropium bromide 
administration.  All actuations are to be completed within 3 minutes of the 1st actuation.  The ATS/ERS 
criteria will be followed for spirometry measures.  Patients who do not demonstrate a positive 
improvement of at least 15% in FEV1 measured at 30 or 60 minutes (±5 minutes) post inhalation will not 
be eligible to participate in the study (except as permitted per the retest specified below).  Reversibility 
values of 14.50-14.99 will be rounded to 15.  
Rationale for change: Clarification.  Spacers will be permitted for use during reversibility testing. 
 
 
Section 9.2.1.1 Spirometry (page 55) 
Original text: 
FEV1 Stability Limits 
FEV1 stability limits will be calculated for each patient at the screening visit (visit 1) using the onsite 
spirometer and the randomization visit (visit 2), using both the home device and onsite spirometer. 
Screening Visit: 
The stability limit established at the screening visit will be used to determine alert criteria for worsening 
COPD during the screening and run-in periods.  The FEV1 stability limit at the screening visit will be 
calculated as follows: 
Best pre-bronchodilator qualifying FEV1 measurement at the screening visit using the onsite spirometer 
× 80%. 
Randomization Visit 
Two stability limits will be re-established at the randomization visit (visit 2) for use during the double-
blind and open-label treatment periods using the following equations: 
• 
Investigational Center Stability Limits (for use with onsite spirometer): 
mean FEV1 of the predose pre-bronchodilator qualifying FEV1 measurements (-30 and -15 min) 
using the onsite spirometer × 80% 
• 
At Home Stability Limits (for use with the electronic flow meter [home device]): 
mean of the best predose FEV1 measurements on the last 3 days before randomization on the 
home device × 80% 
If a patient falls below any of the above FEV1 stability limits, an alert will be triggered to the patient and 
investigational center personnel.  
Revised text: 
FEV1 stability limits will be calculated for each patient at the screening visit (visit 1) using the onsite 
spirometer and the randomization visit (visit 2) using both the home device and onsite spirometer. 
Screening Visit: 
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The stability limit established at the screening visit will be used to determine alert criteria for worsening 
COPD during the screening and run-in periods.  The FEV1 stability limit at the screening visit will be 
calculated as follows: 
Best pre-bronchodilator qualifying FEV1 measurement at the screening visit (visit 1) using the onsite 
spirometer × 80%. 
Randomization Visit 
Two stability limits will be re-established at the randomization visit (visit 2) for use during the 
double-blind and open-label treatment periods using the following equations: 
• 
Investigational Center Stability Limits (for use with onsite spirometer at the double-blind visits 
only): 
mean FEV1 of the predose pre-bronchodilator qualifying FEV1 measurements (-30 and -15 min) 
using the onsite spirometer × 80% 
• 
At Home Stability Limits (for use with the electronic flow meter [home device]): 
mean of the best predose FEV1 measurements on the last 3 days before randomization on the 
home device × 80% 
If a patient falls below any of the above FEV1 stability limits, an alert will be triggered to the patient and 
investigational center personnel.  
Note: If the reschedule icon on the site spirometer is chosen for the screening visit (visit 1) or visit 2, and 
therefore, visit 1 or visit 2 is performed again, the FEV1 stability limit will be updated accordingly.  If 
V1_RETEST on the site spirometer is performed, the stability limit will not be updated. 
Rationale for change: Clarification.  To specify that the predose spirometry conducted at the screening 
visit (visit 1) is used to define the stability limits between visit 1 and the run-in period and the predose 
spirometry at visit 2 is used to define the stability limits for the double-blind and open-label portions of 
the study.  If the reschedule icon is selected at visit 1 or visit 2, the stability limit will be updated 
accordingly. 
 
 
Section 9.2.2.3 Spirometry (Part 1 and 2) (page 56) 
Original text: 
Patients enrolled in Part 1 and Part 2 of the study will be issued with an ediary/electronic flow meter to 
assess their lung function (FEV1). 
Revised text: 
Patients enrolled in Part 1 and Part 2 of the study will be issued with an ediary/electronic flow meter to 
assess their lung function (FEV1).  FEV1 collection begins at the time of signing the ICF, and then 
continues throughout Part 1 and Part 2, per the randomization scheme. 
Rationale for change: Clarification.  Diary collection, including FEV1 measurements, begins at the time 
of signing the ICF and continues throughout the study. 
 
 
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Section 9.2.2.4 Adverse Events (Part 1 and Part 2) (page 57) 
Original text: 
All AE/SAEs (including treatment-emergent AEs) will be assessed throughout the study visits and 
followed to resolution/satisfaction.  Adverse events (AEs) will be recorded after the patient has signed the 
informed consent form (ICF). 
Revised text: 
All AE/SAEs (including treatment-emergent AEs) will be assessed throughout the study visits and 
followed to resolution/satisfaction.  Adverse events (AEs) will be recorded after the patient has signed the 
informed consent form (ICF) and captured via patient interview during the onsite or telephone visits. 
Rationale for change: Clarification.  Adverse events (AEs) experienced in the outpatient portion of the 
study will be collected via telephone contact or at the investigational center visits. 
 
 
Section 9.2.2.5 Monitoring of COPD Exacerbations (Part 1 and Part 2) (page 57) 
Original text: 
Collection of COPD exacerbations will begin at the time of consent and will continue through the final 
visits in Part 1 and Part 2 of the study. 
Revised text: 
Collection of COPD exacerbations will begin at the time of consent and will continue through the final 
visits in Part 1 and Part 2 of the study.  COPD exacerbations will be captured via patient interview 
during the onsite or telephone visits. 
Rationale for change: Clarification.  COPD exacerbations experienced in the outpatient portion of the 
study will be collected via telephone contact or at the investigational center visits. 
 
 
Section 9.2.2.6 COPD Symptom Scores (Part 1 and 2) (pages 57-58) 
Original text: 
During Part 1 and Part 2 of the study, as indicated in, Schedule of Events, Table 9-1, patients will assess 
and record their COPD symptoms scores once daily in the evening before bedtime using the EXACT.   
The ER-S: COPD (derived from the EXACT score) will be used to assess disease stability throughout the 
study.  A baseline score will be obtained from the first available evening session after the screening visit 
(visit 1) for use during the screening and run-in periods and from the latest available evening session 
before the randomization visit (visit 2) for use during the double-blind and open-label treatment periods.  
If at any time, there is increase in the ERS-COPD daily RS-Total score of ≥2 from baseline, the ediary 
will alert the patient to notify the investigational center personnel to discuss the patient’s current health 
status.  The Investigator will need to determine if the patient is able to continue participating in the study 
as per the withdrawal criteria in section 6.5.   
Revised text: 
During Part 1 (commencing at the time of consent) and Part 2 of the study, as indicated in, Schedule of 
Events, Table 9-1, patients will assess and record their COPD symptoms scores once daily in the evening 
before bedtime using the EXACT. 
The ER-S: COPD (derived from the EXACT score) will be used to assess disease stability throughout the 
study.  A baseline score will be obtained from the first available evening session after the screening visit 
(visit 1) signing the ICF for use during the screening and run-in periods and from the latest available 
evening session before the randomization visit (visit 2) for use during the double-blind and open-label 
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treatment periods.  If at any time, there is increase in the ERS-COPD daily RS-Total score of ≥2 from 
baseline, the ediary will alert the patient to notify the investigational center personnel to discuss the 
patient’s current health status.  The Investigator will need to determine if the patient is able to continue 
participating in the study as per the withdrawal criteria in section 6.5. 
Rationale for change: Clarification.  Diary collection, including COPD symptom scores (ie, EXACT), 
begins at the time of signing the ICF and continues throughout the study. 
 
 
Section 9.2.2.7 Electrocardiography (Part 1 and 2) (page 58) 
Original text: 
A 12-lead ECG will be performed for Part 1 and Part 2 as indicated in Schedule of Events, Table 9-1.  
For Part 1, the ECGs will be collected prior to lung function assessments.  Procedures for conducting 
ECGs are described in the ECG manual.  A qualified physician at a central diagnostic center will be 
responsible for interpreting the ECG.  However, at the screening visit (visit 1), the Investigator will 
preliminarily interpret the ECG to determine if the patient is eligible to proceed with screening 
assessments; final interpretation of the ECG will the responsibility of the central ECG reader.  The 
Investigator is responsible for determining whether an abnormality is clinically relevant. 
Revised text: 
A 12-lead ECG will be performed for Part 1 and Part 2 as indicated in Schedule of Events, Table 9-1.  
For Part 1, the ECGs will be collected prior to lung function assessments.  Procedures for conducting 
ECGs are described in the ECG manual.  The patient should be in a supine position and resting for at 
least 5 minutes.  A qualified physician at a central diagnostic center will be responsible for interpreting 
the ECG.  However, at the screening visit (visit 1), the Investigator will preliminarily interpret the ECG to 
determine if the patient is eligible to proceed with screening assessments; final interpretation of the ECG 
will the responsibility of the central ECG reader.  The Investigator is responsible for determining whether 
an abnormality is clinically relevant. 
Rationale for change: Clarification.  Electrocardiograms should be performed in a supine position after 
at least 5 minutes of rest. 
 
 
Section 9.2.3.4 Urine Drug Screening (page 59) 
Original text: 
Urine drug screening will be performed via a urine dipstick at the investigational center as indicated in 
Schedule of Events, Table 9-1 or at any time during the study should the Investigator deem it is 
warranted.  A positive finding during the screening visit (visit 1) will prevent the patient from 
participating in the study, and a positive finding after the screening visit will require immediate Sponsor 
notification, and may result in discontinuation of study medication and termination from the study (if not 
related to a currently prescribed medication as described below).   
If a patient has a positive urine drug screen for a class of drug which is consistent with a medication that 
the patient is currently prescribed, the patient can be considered eligible for the study after the 
prescription is confirmed by the Investigator.   
Additional details are provided in the laboratory instruction manual. 
Revised text: 
Urine drug screening will be performed via a urine dipstick at the investigational center as indicated in 
Schedule of Events, Table 9-1 or at any time during the study should the Investigator deem it is 
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warranted.  A positive finding during the screening visit (visit 1) will prevent the patient from 
participating in the study, and a positive finding after the screening visit will require immediate Sponsor 
notification, and may result in discontinuation of study medication and termination from the study (if not 
related to a currently prescribed medication as described below).   
If a patient has a positive urine drug screen for a class of drug which is consistent with a medication that 
the patient is currently prescribed (excluding inhaled marijuana), the patient can be considered eligible 
for the study after the prescription is confirmed by the Investigator.  Inhaled marijuana is not permitted 
even if prescribed. 
Additional details are provided in the laboratory instruction manual. 
Rationale for change: Benzodiazepines and barbiturates could impact lung function and are therefore 
prohibited with appropriate washout.  Inhaled marijuana has been previously established as a prohibited 
medication as indicated in Table 8-1; therefore it was included as a clarification. 
 
 
Section 9.3 STUDY VISITS (page 59) 
Original text: 
The study consists of 2 parts.  Part 1 (double-blind treatment period) consists of a screening visit (visit 1), 
3 treatment periods at the investigational center, and a follow-up telephone call at the end of the 
double-blind treatment period for only those patients participating in Part 1.  
Revised text: 
The study consists of 2 parts.  Part 1 (double-blind treatment period) consists of a screening visit (visit 1) 
period, 3 double-blind treatment periods at the investigational center, and a follow-up telephone call at 
the end of the double-blind treatment period for only those patients participating in Part 1 
Rationale for change: Clarification.  To indicate the study includes a screening period which is 30 days 
(day -44 to day -14) before the start of the run-in period, which may be used to washout of COPD and 
other medications per protocol. 
 
 
Section 9.3.1 Screening Period (page 60) 
Original text: 
At the screening visit (visit 1), a signed and dated ICF will be obtained before screening procedures 
commence.  The screening visit (visit 1) will be conducted up to 30 days (day -44 to day -14) before the 
start of the run-in period.  The following procedures and assessments will be conducted at the screening 
visit (visit 1): 
Revised text: 
At the screening visit (visit 1) During the screening period, a signed and dated ICF will be obtained first 
before screening procedures commence.  The screening visit (visit 1) period may be conducted up to 30 
days (day -44 to day -14) before the start of the run-in period.  The screening period begins once the ICF 
is signed, and ends at the start of the run-in period.  The screening period may take place over several 
days beginning on day –44 to day –14 dependent on the patient’s washout.  If a patient is washing out 
of ICS (monotherapy) or ICS/LABA combination therapy, an additional 3 days is permitted to complete 
the assessments for the screening visit (visit 1).  The screening visit (visit 1) should immediately 
precede the start of the run-in period.  If a patient does not require washout, and the patient passes all 
entry criteria at the screening visit (visit 1), the patient will be eligible to enter the run-in period on the 
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same day as the screening visit (visit 1). The patient must successfully complete the visit 1 
procedures/assessments prior to entering the run-in period. 
The procedures for the screening visit (visit 1), with the exception of signing of the ICF, assigning a 
patient number, performing a pre-washout physical examination, and dispensing/completing the 
ediary, cannot occur until appropriate medication washouts have been completed in accordance with 
the protocol.  Once the washout requirements have been met, the screening visit (visit 1) should 
immediately precede the start of the run-in period. 
The following procedures and assessments will be conducted at the screening visit (visit 1) with the 
exception of the procedures listed above if medication washout is required: 
Rationale for change: Clarification.  To differentiate the screening period and the screening visit, and 
define the procedures to be performed at each of these visits.  The screening period may occur up to 30 
days (day -44 to day -14) before the start of the run-in period to washout of COPD and other medications 
per protocol.  The screening visit cannot occur until the appropriate washout requirements have been 
met.  For patients on ICS (monotherapy) or ICS/LABA combination therapy additional time may be 
needed to complete all screening assessments prior to the run-in period; therefore, the window has been 
extended. 
 
 
Section 9.3.1 Screening Period (pages 61-62) 
Original text: 
The patient will continue using an ediary/electronic flow meter for use throughout the screening period 
and asked to measure their lung function (FEV1) in the morning prior to dosing with COPD medication 
(as applicable) at approximately the same time each day.  Patients will be asked to record EXACT 
symptom scores (see Appendix C) and albuterol/salbutamol MDI/study medication use in their ediary. 
Revised text: 
The patient will continue begin using an ediary/electronic flow meter for use throughout the screening 
period, if applicable, and asked to measure their lung function (FEV1) in the morning prior to dosing with 
COPD medication (as applicable) at approximately the same time each day.  Patients will be asked to 
record EXACT symptom scores (see Appendix C) and albuterol/salbutamol MDI/study medication use 
in their ediary during the screening period, if applicable. 
Rationale for change: Clarification.  To define the procedures to be conducted during the screening 
period. 
 
 
Section 9.3.2 Run-in Period (page 62) 
Original text: 
The patient will continue using an ediary/electronic flow meter for use throughout the run-in period and 
asked to measure their lung function (FEV1) in the morning prior to dosing with placebo LUPINHALER 
at approximately the same time each day.  Patients will be asked to record EXACT symptom scores (see 
Appendix C), and albuterol/salbutamol MDI/study medication use in their ediary. 
Revised text: 
The patient will continue using an ediary/electronic flow meter for use throughout the run-in period and 
asked to measure their lung function (FEV1) in the morning prior to dosing with placebo LUPINHALER 
at approximately the same time each day.  Patients will be asked to record EXACT symptom scores (see 
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Appendix C) once daily in the evening before bedtime, and albuterol/salbutamol MDI/study medication 
use in their ediary. 
Rationale for change: Clarification.  To indicate the EXACT is performed once daily in the evening 
before bedtime. 
 
 
Section 9.3.3.1 Visit 2, Day 0 (page 63), Section 9.3.3.2 Visit 3, Day 21 (+3 days) (page 64), 
Section 9.3.3.3 Visit 4, Day 42 (+3 days) (page 65) 
Original text: 
• administration of study medication at the investigational center under supervision of 
unblinded study personnel 
Revised text: 
• administration of study medication at the investigational center under supervision of 
unblinded study personnel 
Rationale for change: Unblinded study personnel will prepare double-blind study medication and 
dispense the inhalers to blinded study personnel and observe dose administration in Part 1.  Blinded 
study personnel will perform study medication training during all parts of the study and assist with 
dosing of the patients in Part 1. 
 
 
Section 9.3.3.1 Visit 2, Day 0 (page 63) 
Original text: 
The patient will continue using the ediary/electronic flow meter throughout the Part 1 and asked to 
measure their lung function (FEV1) in the morning prior to administering COPD medication at 
approximately the same time each day.  Patients should not perform FEV1 measurements on the home 
device prior to day 1, visit 3 (both day 21 and day 22) and visit 4 (both day 42 and 43).  Patients will be 
asked to record EXACT symptom scores (see Appendix C) and albuterol/salbutamol MDI in their ediary. 
Revised text: 
The patient will continue using the ediary/electronic flow meter throughout the remainder of Part 1 and 
asked to measure their lung function (FEV1) in the morning prior to administering COPD medication at 
approximately the same time each day.  Patients should not perform FEV1 measurements on the home 
device prior to day 1, visit 3 (both day 21 and day 22) and visit 4 (both day 42 and 43).  Patients will be 
asked to record EXACT symptom scores (see Appendix C) and albuterol/salbutamol MDI in their ediary. 
Rationale for change: Clarification. 
 
 
Section 9.3.6 Retest Visits (page 70) 
Original text: 
Post-randomization: 
During Part 1, patients may retest for FEV1 if the value varies by more than ±10% from the predose FEV1 
at the screening visit (visit 1) up to 3 times.  If 3 retests have been conducted, the patient may need to be 
withdrawn at the discretion of the Investigator.  
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Revised text: 
Post-randomization: 
During Part 1, patients may retest for FEV1 if the value varies by more than ±10% from the predose FEV1 
at the screening visit (visit 1) visit 2 up to 3 times.  If 3 retests have been conducted, the patient may need 
to be withdrawn at the discretion of the Investigator.  
Rationale for change: Typographical error. Patients may retest if the post-randomization FEV1 value 
varies by more than ±10% from the predose FEV1 at visit 2.  
 
 
Section 10.6 Serious Adverse Event Reporting (page 75) 
Original text 
The Lupin Medical Monitor for this study is: 
 
 
Revised text: 
The Lupin Medical Monitor for this study is: 
 
 
Rationale for change: Administrative update.  The Medical Monitor’s title and phone number have been 
updated. 
 
 
Section 11.5.4 Primary Variable (page 81) 
Original text: 
A mixed model analysis consisting of fixed effects of treatment, visit, and sequence, and the random 
effect of patient will be carried out. 
Revised text: 
A repeated measures crossover model consisting of effects of treatment, period, and sequence will be 
carried out. 
Rationale for change: Clarification of the statistical model to be used to allow unstructured covariance. 
 
 
Section 11.5.7.1 Adverse events (page 81) 
Original text: 
In Part 1, the blinded, single dose crossover part of the study, AEs will be tabulated by the following 
periods: 
• 
pre-randomization 
• 
on or within 24 hours after a study treatment day  
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• 
during washout 
• 
during follow-up (more than 24 hours after the last treatment day) 
Adverse events (AEs) occurring on or within 24 hours after a study treatment day will be assigned to the 
relevant study treatment  
Revised text: 
In Part 1, the blinded, single dose crossover part of the study, AEs will be tabulated by the following 
periods: 
• 
pre-randomization 
• 
on or within 24 hours after a study treatment day double-blind treatment period 
• 
during washout 
• 
during follow-up (more than 24 hours after the last treatment day) 
Adverse events (AEs) occurring on or within 24 hours after a study treatment day will be assigned to 
the relevant study treatment. 
Adverse events (AEs) that occur before randomization for patients who are screen/randomization 
failures will be listed.  Those patients will not be part of the safety population. 
Adverse events (AEs) occurring after a study treatment during the treatment day and the day 
immediate after the treatment will be assigned to the relevant study treatment group.  
Adverse events (AEs) that occur before randomization will be summarized separately and will be listed.  
Rationale for change: Adverse events (AEs) occurring on the day of treatment and the day immediately 
after treatment will be summarized by treatment instead of washout.  Adverse events (AEs) will be 
summarized for all patients prior to randomization. 
 
 
Section 11.5.7.3 Physical Examination (page 82) 
Original text: 
For Part 1, physical examination findings at screening (visit 1) and visit 4 or ET will be summarized for 
any clinically significant findings. Significant changes from screening (visit 1) and the end of the double-
blind period will be summarized.  Changes from screening (visit 1) to the end of the double-blind period 
will be presented in 3 by 3 shift tables, where the responses are normal, abnormal but clinically 
non-significant, or abnormal and clinically significant.  Each examination area, eg, skin, abdominal, will 
have a separate table. 
Revised text: 
For Part 1, physical examination findings at screening (visit 1) and visit 4 or ET will be summarized for 
any clinically significant findings. Significant changes from screening (visit 1) and the end of the double-
blind period will be summarized.  Changes from screening (visit 1) to the end of the double-blind period 
will be presented in 3 by 3 shift tables, where the responses are normal, abnormal but clinically 
non-significant, or abnormal and clinically significant.  Each examination area, eg, skin, abdominal, will 
have a separate table.  Some patients may require 2 physical examinations before treatment starts.  If 
they do, the first one is the prescreening value and the one at visit 1 is the screening value.  Pre-
screening results will be listed only. 
Rationale for change: Clarification.  If 2 physical exams are conducted prior to double-blind treatment 
due to required medication washout, the first one will be considered prescreening with results listed, and 
the one conducted at visit 1 will be used in data analyses. 
 
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Section 11.5.7.4 HEENT, Chest Examination, and Electrocardiograms (ECG) (pages 82-83) 
Original text: 
For Part 1, during the double-blind period, abbreviated physical examination findings (HEENT and chest 
examinations) and ECG results will be summarized for any clinically significant findings and significant 
changes from screening.   
For Part 2 of the study (open label extension), findings will be summarized for any clinically significant 
findings and significant changes from screening. 
Note that the screening data for these variables is captured during the full physical examination at 
screening (visit 1). 
HEENT and chest examination findings will be summarized by five 3 by 3 shift tables where the shift is 
from screening (visit 1) to each of the 5 visits during treatment, 3 visits in Part 1 and 2 visits in Part 2. 
Revised text: 
For Part 1, during the double-blind period, abbreviated physical examination findings (HEENT and chest 
examinations) and ECG results will be summarized for any clinically significant findings and significant 
changes from screening visit 2.   
For Part 2 of the study (open label extension), findings will be summarized for any clinically significant 
findings and significant changes from screening visit 2. 
Note that the screening data for these variables is captured during the full physical examination at 
screening (visit 1). 
HEENT and chest examination findings will be summarized by five 3 by 3 shift tables where the shift is 
from screening (visit 1) visit 2 to each of the 5 4 visits during treatment, 3 2 visits in Part 1 and 2 visits in 
Part 2. 
Rationale for change: Typographical error. HEENT examinations commence at visit 2; therefore, visit 2 
will be the baseline for this assessment with a total of 4 post randomization assessments, 2 in Part 1 and 2 
in Part 2. 
 
 
Section 11.5.7.5 COPD Exacerbations (page 83) 
Original text: 
A listing of COPD exacerbations that occurred will be provided separately for Part 1 and Part 2 of the 
study. 
Revised text: 
A listing of COPD exacerbations that occurred will be provided separately for Part 1 and Part 2 of the 
study. 
COPD exacerbations will be summarized and/or listed separately for Part 1 and Part 2 of the study. 
Rationale for change: Clarification.  Part 1 of the study is randomized double-blind while Part 2 of the 
study is unrandomized and open-label so it would not be appropriate to combine them. 
 
 
Section 11.5.8 Safety Spirometry (page 83) 
Original text: 
For Part 1, FEV1 will be measured once daily: prior to dosing in the morning at approximately the same 
time each day. 
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Revised text: 
For Part 1 (commencing at the time of signing the ICF), FEV1 will be measured once daily: prior to 
dosing in the morning at approximately the same time each day. 
Rationale for change: Clarification.  Diary collection begins at the time of signing of ICF to assess the 
safety of patients during the screening period and throughout the study.  
 
 
Section 11.5.10 Albuterol/Salbutamol Usage (page 83) 
Added text: 
Albuterol/Salbutamol usage will be summarized and/or listed separately for Part 1 and Part 2 of the 
study. 
In addition, urine/serum pregnancy test, urine drug screen, clinical laboratory, drug accountability, 
smoking restriction, DPI training, and In-Check training data will also be listed. 
Rationale for change: Clarification.  Part 1 of the study is randomized double-blind while Part 2 of the 
study is unrandomized and open-label so it would not be appropriate to combine them. 
 
 
Section 11.5.11.1 Ruggedness of LUPINHALER during In-Patient Use (pages 83 -84) 
Original text: 
Patients will be instructed to report any problems that they experience with their LUPINHALER during 
the open-label extension.  The number and percentage of patients who reported at least one issue with the 
LUPINHALER will be provided.  
Additionally, a listing of the individual issues will be provided.  The listing will describe the issue in the 
detail provided by the patient. These will also be summarized according to the following categories: 
• 
lack of efficacy 
• 
mechanical problems 
• 
problems with the device after it was dropped 
• 
other 
Revised text: 
Patients will be instructed to report any problems that they experience with their LUPINHALER during 
the open-label extension.  The number and percentage of patients who reported at least one issue with the 
LUPINHALER will be provided.  
Additionally, a listing of the individual issues will be provided.  The listing will describe the issue in the 
detail provided by the patient. These will also be summarized according to the following categories: 
• 
lack of efficacy 
• 
mechanical problems 
• 
problems with the device after it was dropped 
• 
other 
• 
misuse episodes (eg, impact [problems with the device after it was dropped], moisture [fell in 
water, submersed], other) 
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• 
issues identified (eg, mechanical problems, COPD worsening/seems ineffective, other) 
Rationale for change: Clarification.  Ruggedness of the LUPINHALER will be summarized into 2 main 
categories with additional subclassification. 
 
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Original Text: 
Appendix A: Study Medication Instructions for Use 
Patient Instructions for Investigational Product Administration of the Dry Powder Inhalers 
Two dry powder inhalers will be used in this study (see Figure A1 and Figure A2):  
For the run-in period, 1 inhaler (Figure A2) will be used to administer 2 inhalations from 
1 capsule of study medication (Lupin 18 mcg tiotropium bromide or placebo) once daily for 
14 +2 days. 
For Part 1 of the study, 2 inhalers (Figure A1 and Figure A2) will be used to administer a 
single-dose of study medication (18 mcg tiotropium bromide or placebo) at each treatment 
period (visits 2, 3, and 4).  A single-dose consists of 1 capsule per inhaler administered as 
2 inhalations per capsule.  Each capsule will be placed into the inhalers by unblinded study 
personnel as per the randomization schedule. 
For Part 2 of the study, 1 inhaler (Figure A2) will be used to administer 2 inhalations from 
1 capsule of study medication (Lupin 18 mcg tiotropium bromide) once daily for 72 +3 days. 
Placebo training inhalers will also be provided for training purposes during Part 1 of the study.   
YOUR STUDY INHALERS  
Figure A1 represents INHALER 1 and Figure A2 represents INHALER 2.  These inhalers are for 
oral inhalation only.  Both INHALERS will be over-labeled with the appropriate kit/inhaler 
number. 
 
 
 
 
 
 
 
Figure A1 
Figure A2 
INHALER 1 
 
 
 
 
 INHALER 2 
 
Each INHALER comes with capsules in blister packaging.  Use the INHALER provided with the 
designated capsule(s). 
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The parts of each INHALER include: 
(See Figure B1 for INHALER 1 and Figure B2 for INHALER 2) 
1. Dust cap (lid)  
2. Mouthpiece 
3. Mouthpiece ridge 
4. Base 
5. Green piercing button 
6. Center chamber 
7. Air intake vents 
Figure B1 
 
 
    Figure B2 
 
 
Each tiotropium capsule is packaged in a blister (See Figure C).  
 
 
 
 
Figure C 
 
Each tiotropium capsule contains only a small amount of powder (See Figure D). 
Do not open the tiotropium capsule or it may not work. 
 
 
 
 
 
 
Figure D  
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FOR PATIENTS PARTICIPATING IN PART 1 
 
TAKING YOUR DOSE OF STUDY MEDICATION REQUIRES 4 MAIN STEPS. 
Note: Some of these steps will be performed by unblinded study personnel prior to you receiving 
the INHALER. 
STEP 1. OPENING YOUR INHALER: 
After unblinded study personnel has removed your INHALER from the pouch: 
• Unblinded study personnel will open the dust cap (lid) by pressing the green piercing 
button (See Figure E1 for INHALER 1 and Figure E2 for INHALER 2). 
 
 
 
 
 
 
 
 
 
Figure E1 
 
 
   Figure E2 
 
• Unblinded study personnel will pull the dust cap (lid) upwards away from the base to 
expose the mouthpiece (See Figure F1 for INHALER 1 and Figure F2 for INHALER 2). 
 
 
 
 
 
 
 
 
Figure F1 
    Figure F2 
• Unblinded study personnel will open the mouthpiece by pulling the mouthpiece ridge up 
and away from the base so center chamber is showing (See Figure G1 for INHALER 1 
and Figure G2 for INHALER 2). 
 
 
 
 
 
 
 
Figure G1    
 
 
Figure G2 
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STEP 2. INSERTING THE CAPSULE INTO YOUR INHALER: 
Unblinded study personnel will separate the blisters from the blister card by tearing along the 
perforated line (See Figure H). 
 
 
 
 
 
 
 
Figure H 
 
Unblinded study personnel will remove the capsule from the blister: 
• Do not cut the foil or use sharp instruments to take out the capsule from the blister. 
• Bend one of the blister corners with an arrow and separate the aluminum foil layers. 
• Peel back the printed foil until you see the whole capsule (See Figure J). 
• If you have opened more than 1 blister to the air, the extra capsule should not be used. 
 
 
 
 
 
 
 
 
 
Figure J 
 
 
• Unblinded study personnel will place the capsule in the center chamber of your 
INHALER (See Figure K1 for INHALER 1 and Figure K2 for INHALER 2). 
 
 
 
 
 
 
 
 
 
Figure K1 
 
 
    Figure K2 
 
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• Unblinded study personnel will close the mouthpiece firmly against the base until he/she 
hears a click.  Unblinded study personnel will leave the dust cap (lid) open  
(See Figure L1 for INHALER 1 and Figure L2 for INHALER 2). 
 
 
 
 
 
 
 
 
 
Figure L1 
 
 
    Figure L2 
 
• Unblinded study personnel will apply an opaque label/tape to cover the chamber window 
to prevent identification of the capsules. 
 
STEP 3. PIERCING THE CAPSULE: 
• Unblinded study personnel will hold your INHALER with the mouthpiece pointed up  
(See Figure M1 for INHALER 1 and Figure M2 for INHALER 2). 
   
 
 
 
 
 
 
 
Figure M1 
 
 
   Figure M2 
    
 
• Unblinded study personnel will press the green piercing button once until it is flat (flush) 
against the base, then release.  This is how to make holes in the capsule so that you get 
study medication when you breathe in. 
• Do not press the green button more than one time. 
• Do not shake the INHALER. 
• The piercing of the capsule may produce small pieces of the capsule.  Some of these 
small pieces may pass through the screen of the INHALER into the mouth or throat when 
you breathe in your medicine.  This is normal.  The small pieces of the capsule should not 
harm you. 
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STEP 4. TAKING YOUR DOSE OF STUDY MEDICATION: 
Unblinded study personnel will hand you the INHALER in a horizontal position.  Keep the 
INHALER in the horizontal position. 
 
Breathe out completely in 1 breath, emptying your lungs of any air  
(See Figure N). 
 
Important: Do not breathe into your INHALER. 
 
 
 
 
 
 
 
 
 
 
Figure N 
 
 
With your next breath, take your study medication: 
• Hold your head in an upright position while you are looking straight ahead  
(See Figure P1 for INHALER 1 and Figure P2 for INHALER 2). 
• Raise your INHALER to your mouth in a horizontal position.  Do not block the air intake 
vents. 
• Close your lips tightly around the mouthpiece. 
• Breathe in deeply until your lungs are full.  You should hear or feel the capsule 
vibrate (rattle) (See Figure P1 for INHALER 1 and Figure P2 for INHALER 2). 
• Hold your breath for a few seconds and, at the same time, take your INHALER out of 
your mouth. 
• Breathe normally again. 
 
 
 
 
 
 
 
Figure P1 
 
 
   Figure P2  
The rattle tells you that you breathed in correctly.  If you do not hear or feel a rattle, see the 
section, “If you do not hear or feel the capsule rattle as you breathe in your study medication.”
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To get the full amount from the capsule, you must again, breathe out completely  
(See Figure Q)  
 
 
 
 
 
 
 
 
 
Figure Q 
 
then for a second time, breathe in (See Figure R1 for INHALER 1 and Figure R2 for 
INHALER 2) from the same capsule. 
Important: Do not press the green piercing button again.  Do not breathe into your INHALER. 
Remember: To get your full amount from the capsule, you must breathe in 2 times from the same 
capsule.  Make sure you breathe out completely each time before you breathe in from your 
INHALER. 
 
 
 
 
 
 
 
 
 
 
Figure R1 
 
 
   Figure R2 
 
After completing 2 inhalations from your 1st INHALER, hand the INHALER to unblinded study 
personnel.  Unblinded study personnel will collect the INHALER, visually verify the capsules 
are empty (no powder contents remaining), and close the INHALER. 
 
Repeat Step 4 with the 2nd INHALER to take your 2nd capsule.  
 
Every attempt should be made to administer the powder contents from each of the 
2 capsules (2 inhalations/capsule for a total of 4 inhalations) within 2 minutes. 
 
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IF YOU DO NOT HEAR OR FEEL THE CAPSULE AS YOU BREATHE IN YOUR STUDY 
MEDICATION: 
Do not press the green piercing button again. 
Unblinded study personnel will hold your INHALER with the mouthpiece pointed up and tap 
your INHALER gently on a table (See Figure S1 for INHALER 1 and Figure S2 for INHALER 
2). 
 
 
 
 
 
 
 
 
Figure S1 
 
 
   Figure S2 
Unblinded study personnel will check to see that the mouthpiece is completely closed.  Breathe 
out completely before deeply breathing in again with the mouthpiece in your mouth  
(See Figure R1 for INHALER 1 and Figure R2 for INHALER 2). 
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FOR PATIENTS PARTICIPATING IN TRAINING/RUN-IN/PART 2 
 
TAKING YOUR DOSE OF STUDY MEDICATION REQUIRES 4 MAIN STEPS. 
 
STEP 1. OPENING YOUR INHALER: 
After study personnel has removed your INHALER from the pouch: 
• Open the dust cap (lid) by pressing the green piercing button (See Figure E). 
 
 
 
 
 
 
 
 
Figure E 
 
• Pull the dust cap (lid) upwards away from the base to expose the mouthpiece  
(See Figure F). 
 
 
 
 
 
 
 
 
Figure F 
 
• Open the mouthpiece by pulling the mouthpiece ridge up and away from the base so 
center chamber is showing (See Figure G). 
 
 
 
 
 
 
 
Figure G 
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STEP 2. INSERTING THE CAPSULE INTO YOUR INHALER: 
Each day, separate only 1 blister from the blister card by tearing along the perforated line  
(See Figure H). 
 
 
 
 
 
 
Figure H 
 
Remove the capsule from the blister: 
• Do not cut the foil or use sharp instruments to take out the capsule from the blister. 
• Bend one of the blister corners with an arrow and separate the aluminum foil layers. 
• Peel back the printed foil until you see the whole capsule (See Figure J). 
• If you have opened more than 1 blister to the air, the extra capsule should not be used. 
 
 
 
 
 
 
 
 
 
Figure J 
 
 
• Place the capsule in the center chamber of your INHALER (See Figure K). 
 
 
 
 
 
 
 
 
 Figure K 
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• Close the mouthpiece firmly against the base until you hear a click.  Leave the dust cap 
(lid) open (See Figure L). 
 
 
 
 
 
 
 
 
  
  Figure L 
 
 
STEP 3. PIERCING THE CAPSULE: 
• Hold your INHALER with the mouthpiece pointed up (See Figure M). 
   
 
 
 
 
 
 
 
 
 
   Figure M 
    
 
• Press the green piercing button once until it is flat (flush) against the base, then release.  
This is how to make holes in the capsule so that you get study medication when you 
breathe in. 
• Do not press the green button more than one time. 
• Do not shake the INHALER. 
• The piercing of the capsule may produce small pieces of the capsule.  Some of these 
small pieces may pass through the screen of the INHALER into the mouth or throat when 
you breathe in your study medication.  This is normal.  The small pieces of the capsule 
should not harm you. 
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STEP 4. TAKING YOUR FULL DAILY DOSE OF STUDY MEDICATION 
(2 INHALATIONS FROM THE SAME CAPSULE): 
 
Breathe out completely in 1 breath, emptying your lungs of any air (See Figure N). 
 
Important: Do not breathe into your INHALER. 
 
 
 
 
 
 
 
 
 
Figure N 
 
With your next breath, take your study medication: 
• Hold your head in an upright position while you are looking straight ahead  
(See Figure P). 
• Raise your INHALER to your mouth in a horizontal position.  Do not block the air intake 
vents. 
• Close your lips tightly around the mouthpiece. 
• Breathe in deeply until your lungs are full.  You should hear or feel the capsule 
vibrate (rattle) (See Figure P). 
• Hold your breath for a few seconds and, at the same time, take your INHALER out of 
your mouth. 
• Breathe normally again. 
 
 
 
 
 
 
 
 Figure P  
 
The rattle tells you that you breathed in correctly.  If you do not hear or feel a rattle, see the 
section, “If you do not hear or feel the capsule rattle as you breathe in your study medication.” 
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To get the full amount from the capsule, you must again, breathe out completely  
(See Figure Q)  
 
 
 
 
 
 
 
 
 
 
Figure Q 
 
then for a second time, breathe in (See Figure R) from the same capsule.  
Important: Do not press the green piercing button again.  Do not breathe into your INHALER. 
Remember: To get your full amount from the capsule, you must breathe in 2 times from the same 
capsule.  Make sure you breathe out completely each time before you breathe in from your 
INHALER. 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Figure R 
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CARING FOR AND STORING YOUR INHALER: 
• After taking your daily dose, open the mouthpiece and tip out the used capsule into your 
resealable bag, without touching it. 
• Remove any capsule pieces or powder buildup by turning your INHALER upside down 
and gently, but firmly, tapping it (See Figure S).  Then, close the mouthpiece and dustcap 
for storage. 
 
 
 
 
 
  Figure S 
• Do not store your INHALER and capsules (blisters) in a damp moist place.  Always store 
capsules in the sealed blisters. 
 
IF YOU DO NOT HEAR OR FEEL THE CAPSULE AS YOU BREATHE IN YOUR STUDY 
MEDICATION: 
• Do not press the green piercing button again. 
• Hold your INHALER with the mouthpiece pointed up and tap your INHALER gently on 
a table (See Figure T). 
 
 
 
 
 
 
 
 
 
 
Figure T 
 
• Check to see that the mouthpiece is completely closed.  Breathe out completely before 
deeply breathing in again with the mouthpiece in your mouth (See Figure R). 
• If you still do not hear or feel the capsule rattle after repeating the above steps: 
o Place the capsule in the resealable bag. 
o Open the base by lifting the green piercing button and check the center chamber 
for pieces of the capsule. 
o Capsule pieces in the center chamber can cause a capsule not to rattle. 
o Turn your INHALER upside down and gently, but firmly, tap to remove the 
capsule pieces. Call your study doctor for instructions. 
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CLEANING YOUR INHALER: 
• Clean your INHALER device as needed (See Figure U). 
o It takes 24 hours to air dry your INHALER after you clean it. 
o Do not use cleaning agents or detergents. 
o Do not place your INHALER in the dishwasher for cleaning. 
 
 
 
 
 
 
 
 
Figure U 
• Cleaning Steps: 
o Open the dust cap and mouthpiece. 
o Open the base by lifting the green piercing button. 
o Look in the center chamber for capsule pieces or powder buildup.  If seen, tap out. 
o Rinse your INHALER with warm water, pressing the green piercing button a few 
times so that the center chamber and the piercing needle are under the running 
water.  Check that any powder buildup or capsule pieces are removed. 
o Dry your INHALER well by tipping the excess water out on a paper towel. 
Air-dry afterwards, leaving the dust cap, mouthpiece, and base open by fully 
spreading it out so that it dries completely. 
o Do not use a hair dryer to dry your INHALER. 
o Do not use your INHALER when it is wet.  If needed, you may clean the outside 
of the mouthpiece with a clean damp cloth. 
o Document in your diary when cleaning of the INHALER has been performed. 
 
IMPORTANT INFORMATION ABOUT USING YOUR INHALER: 
11. Do not swallow capsules. 
12. Capsules should only be used with the INHALER and inhaled through your mouth (oral 
inhalation). 
13. Do not use your INHALER to take any other medicine. 
14. Do not store capsules in the INHALER. 
15. Store capsules in the sealed blister package at room temperature between 68°F to 77°F 
(20°C to 25°C). 
16. Keep capsules away from heat and cold (do not freeze). 
17. Store capsules in a dry place.  Do not use any unused capsules that have been open to air. 
18. Ask your study doctor if you have any questions about storing your capsules. 
19. Keep the INHALER and capsules out of the reach of children. 
20. Do not let the powder from the capsule get into your eyes. 
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Revised Text: 
Appendix A: Study Medication Instructions for Use  
Patient Instructions for Investigational Product Administration of the Dry Powder Inhalers 
Two dry powder inhalers will be used in this study (see Figure A1 and Figure A2):  
For the run-in period, 1 inhaler (Figure A2) will be used to administer 2 inhalations from 
1 capsule of study medication (Lupin 18 mcg tiotropium bromide or placebo) once daily for 
14 +2 days. 
For Part 1 of the study, 2 inhalers (Figure A1 and Figure A2) will be used to administer a 
single-dose of study medication (18 mcg tiotropium bromide or placebo) at each treatment 
period (visits 2, 3, and 4).  A single-dose consists of 1 capsule per inhaler administered as 
2 inhalations per capsule.  Each capsule will be placed into the inhalers by unblinded study 
personnel as per the randomization schedule. 
For Part 2 of the study, 1 inhaler (Figure A2) will be used to administer 2 inhalations from 
1 capsule of study medication (Lupin 18 mcg tiotropium bromide) once daily for 72 +3 days. 
Placebo training inhalers will also be provided for training purposes during Part 1 of the study.   
YOUR STUDY INHALERS  
Figure A1 represents HANDIHALER INHALER 1 and Figure A2 represents LUPINHALER 
INHALER 2.  These inhalers are for oral inhalation only.  Both INHALERS will be over-labeled 
with the appropriate kit/inhaler number. 
 
 
 
 
 
 
 
Figure A1 
Figure A2 
HANDIHALER INHALER 1 
 
 
LUPINHALER INHALER 2 
 
Each INHALER comes with capsules in blister packaging.  Use the INHALER provided with the 
designated capsule(s). 
 
 
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The parts of each INHALER include: 
(See Figure B1 for HANDIHALER INHALER 1 and Figure B2 for LUPINHALER INHALER 
2) 
1. Dust cap (lid)  
2. Mouthpiece 
3. Mouthpiece ridge 
4. Base 
5. Green piercing button 
6. Center chamber 
7. Air intake vents 
Figure B1 
 
 
    Figure B2 
 
 
Each tiotropium capsule is packaged in a blister (See Figure C).  
 
 
 
 
Figure C 
 
Each tiotropium capsule contains only a small amount of powder (See Figure D). 
Do not open the tiotropium capsule or it may not work. 
 
 
 
 
 
 
Figure D  
 
 
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FOR PATIENTS PARTICIPATING IN PART 1 DOUBLE-BLIND 
 
TAKING YOUR DOSE OF STUDY MEDICATION REQUIRES 4 MAIN STEPS. 
Note: Some of these steps will be performed by unblinded study personnel prior to you (the 
patient) receiving the INHALER. 
STEP 1. OPENING YOUR INHALER: 
Only unblinded study personnel should open the kits and prepare the INHALERS for the Part 
1 double-blind treatment.  Opening of the kit and preparation of the INHALERS should be 
done in a blinded study medication location away from the view of blinded study personnel 
and you. 
After unblinded study personnel has removed your INHALER from the pouch: 
• Unblinded study personnel will open the dust cap (lid) by pressing the green piercing 
button (See Figure E1 for HANDIHALER INHALER 1 and Figure E2 for 
LUPINHALER INHALER 2). 
 
 
 
 
 
 
 
        Figure E1  
 
   Figure E2 
• Unblinded study personnel will pull the dust cap (lid) upwards away from the base to 
expose the mouthpiece (See Figure F1 for HANDIHALER INHALER 1 and Figure F2 
for LUPINHALER INHALER 2). 
 
 
 
 
 
 
 
 
        Figure F1 
    Figure F2 
• Unblinded study personnel will open the mouthpiece by pulling the mouthpiece ridge up 
and away from the base so center chamber is showing (See Figure G1 for 
HANDIHALER INHALER 1 and Figure G2 for LUPINHALE
 
 
 
 
 
 
 
 
 
 
 
 
 
       Figure G1     
 
     Figure G2
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STEP 2. INSERTING THE CAPSULE INTO YOUR INHALER: 
Unblinded study personnel will separate the blisters from the blister card by tearing along the 
perforated line (See Figure H). 
 
 
 
 
 
 
 
Figure H 
 
Unblinded study personnel will remove the capsule from the blister: 
• Do not cut the foil or use sharp instruments to take out the capsule from the blister. 
• Bend one of the blister corners with an arrow and separate the aluminum foil layers. 
• Peel back the printed foil until you see the whole capsule (See Figure J). 
• If you have opened more than 1 blister to the air, the extra capsule should not be used. 
 
 
 
 
 
 
 
 
 
Figure J 
 
 
• Unblinded study personnel will place the capsule in the center chamber of your 
INHALER (See Figure K1 for HANDIHALER INHALER 1 and Figure K2 for 
LUPINHALER INHALER 2). 
 
 
 
 
 
 
 
 
 
Figure K1 
 
 
    Figure K2 
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• Unblinded study personnel will close the mouthpiece firmly against the base until he/she 
hears a click.  Unblinded study personnel will leave the dust cap (lid) open  
(See Figure L1 for HANDIHALER INHALER 1 and Figure L2 for LUPINHALER 
INHALER 2). 
 
 
 
 
 
 
 
 
 
Figure L1 
 
 
    Figure L2 
• Unblinded study personnel will apply an opaque label/tape to cover the chamber 
window to prevent identification of the capsules.  
STEP 3A. PIERCING THE CAPSULE: 
• Unblinded study personnel will hold your INHALER with the mouthpiece pointed up  
(See Figure M1 for HANDIHALER INHALER 1 and Figure M2 for LUPINHALER 
INHALER 2). 
   
 
 
 
 
 
 
Figure M1 
 
 
   Figure M2 
    
• Unblinded study personnel will press the green piercing button once until it is flat (flush) 
against the base, then release.  This is how to make holes in the capsule so that you get 
study medication when you breathe in. 
• Do not press the green button more than one time. 
• Do not shake the INHALER. 
• The piercing of the capsule may produce small pieces of the capsule.  Some of these 
small pieces may pass through the screen of the INHALER into the mouth or throat when 
you breathe in your medicine.  This is normal.  The small pieces of the capsule should not 
harm you. 
STEP 3B. APPLYING TAPE TO MASK THE CHAMBER WINDOW 
• 
After piercing the capsule, unblinded study personnel will apply an opaque label/tape 
to cover the chamber window to prevent identification of the capsules, numbering the 
inhaler dosing order based on even/odd calendar days as described in the pharmacy 
manual. 
• 
Unblinded study personnel will bring the INHALERS to the patient dosing location 
leaving the inhaler kit carton, capsule blisters in the blinded study medication location. 
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STEP 4. TAKING YOUR DOSE OF STUDY MEDICATION: 
UnBlinded study personnel will hand you the INHALER in a horizontal position.  Keep the 
INHALER in the horizontal position. 
 
Breathe out completely in 1 breath, emptying your lungs of any air  
(See Figure N). 
 
Important: Do not breathe into your INHALER. 
 
 
 
 
 
 
 
 
 
 
Figure N 
 
With your next breath, take your study medication: 
• Hold your head in an upright position while you are looking straight ahead  
(See Figure P1 for HANDIHALER INHALER 1 and Figure P2 for LUPINHALER 
INHALER 2). 
• Raise your INHALER to your mouth in a horizontal position.  Do not block the air intake 
vents. 
• Close your lips tightly around the mouthpiece. 
• Breathe in deeply until your lungs are full.  You should hear or feel the capsule 
vibrate (rattle) (See Figure P1 for HANDIHALER INHALER 1 and Figure P2 for 
LUPINHALER INHALER 2). 
• Hold your breath for a few seconds and, at the same time, take your INHALER out of 
your mouth. 
• Breathe normally again. 
 
 
 
 
 
 
Figure P1 
 
 
   Figure P2  
The rattle tells you that you breathed in correctly.  If you do not hear or feel a rattle, see the 
section, “If you do not hear or feel the capsule rattle as you breathe in your study medication.” 
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To get the full amount from the capsule, you must again, breathe out completely  
(See Figure Q)  
 
 
 
 
 
 
 
 
 
Figure Q 
 
then for a second time, breathe in (See Figure R1 for HANDIHALER INHALER 1 and 
Figure R2 for LUPINHALER INHALER 2) from the same capsule. 
Important: Do not press the green piercing button again.  Do not breathe into your INHALER. 
Remember: To get your full amount from the capsule, you must breathe in 2 times from the same 
capsule.  Make sure you breathe out completely each time before you breathe in from your 
INHALER. 
 
 
 
 
 
 
 
 
 
 
Figure R1 
 
 
   Figure R2 
 
After completing 2 inhalations from your 1st INHALER, hand the INHALER to unblinded study 
personnel.  UnBlinded study personnel will collect the INHALER, visually verify the capsules 
are empty (no powder contents remaining), and close the INHALER. 
 
Repeat Step 4 with the 2nd INHALER to take your 2nd capsule.  
 
Every attempt should be made to administer the powder contents from each of the 
2 capsules (2 inhalations/capsule for a total of 4 inhalations) within 2 minutes. 
 
After you have dosed with both INHALERS, unblinded study personnel will return the 
INHALERS to the blinded study medication location and deposit each used INHALER 
containing the used capsule along with unused capsule blisters into the pouch and carton. 
 
 
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IF YOU DO NOT HEAR OR FEEL THE CAPSULE AS YOU BREATHE IN YOUR STUDY 
MEDICATION: 
Do not press the green piercing button again. 
UnBlinded study personnel will hold your INHALER with the mouthpiece pointed up and tap 
your INHALER gently on a table (See Figure S1 for HANDIHALER INHALER 1 and Figure 
S2 for LUPINHALER INHALER 2). 
 
 
 
 
 
 
 
 
Figure S1 
 
 
   Figure S2 
UnBlinded study personnel will check to see that the mouthpiece is completely closed.  Breathe 
out completely before deeply breathing in again with the mouthpiece in your mouth  
(See Figure R1 for HANDIHALER INHALER 1 and Figure R2 for LUPINHALER INHALER 
2). 
 
 
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FOR PATIENTS PARTICIPATING IN TRAINING/RUN-IN/PART 2 
 
TAKING YOUR DOSE OF STUDY MEDICATION REQUIRES 4 MAIN STEPS. 
 
STEP 1. OPENING YOUR INHALER: 
After study personnel has removed your INHALER from the pouch: 
• Open the dust cap (lid) by pressing the green piercing button (See Figure E). 
 
 
 
 
 
 
 
 
Figure E 
 
• Pull the dust cap (lid) upwards away from the base to expose the mouthpiece  
(See Figure F). 
 
 
 
 
 
 
 
 
Figure F 
 
• Open the mouthpiece by pulling the mouthpiece ridge up and away from the base so 
center chamber is showing (See Figure G). 
 
 
 
 
 
 
 
Figure G 
 
 
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STEP 2. INSERTING THE CAPSULE INTO YOUR INHALER: 
Each day, separate only 1 blister from the blister card by tearing along the perforated line  
(See Figure H). 
 
 
 
 
 
 
Figure H 
 
Remove the capsule from the blister: 
• Do not cut the foil or use sharp instruments to take out the capsule from the blister. 
• Bend one of the blister corners with an arrow and separate the aluminum foil layers. 
• Peel back the printed foil until you see the whole capsule (See Figure J). 
• If you have opened more than 1 blister to the air, the extra capsule should not be used. 
 
 
 
 
 
 
 
 
 
Figure J 
 
 
• Place the capsule in the center chamber of your INHALER (See Figure K). 
 
 
 
 
 
 
 
 
 Figure K 
 
 
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• Close the mouthpiece firmly against the base until you hear a click.  Leave the dust cap 
(lid) open (See Figure L). 
 
 
 
 
 
 
 
 
  
  Figure L 
 
 
STEP 3. PIERCING THE CAPSULE: 
• Hold your INHALER with the mouthpiece pointed up (See Figure M). 
   
 
 
 
 
 
 
 
 
 
   Figure M 
    
 
• Press the green piercing button once until it is flat (flush) against the base, then release.  
This is how to make holes in the capsule so that you get study medication when you 
breathe in. 
• Do not press the green button more than one time. 
• Do not shake the INHALER. 
• The piercing of the capsule may produce small pieces of the capsule.  Some of these 
small pieces may pass through the screen of the INHALER into the mouth or throat when 
you breathe in your study medication.  This is normal.  The small pieces of the capsule 
should not harm you. 
 
 
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STEP 4. TAKING YOUR FULL DAILY DOSE OF STUDY MEDICATION 
(2 INHALATIONS FROM THE SAME CAPSULE): 
 
Breathe out completely in 1 breath, emptying your lungs of any air (See Figure N). 
 
Important: Do not breathe into your INHALER. 
 
 
 
 
 
 
 
 
 
Figure N 
 
With your next breath, take your study medication: 
• Hold your head in an upright position while you are looking straight ahead  
(See Figure P). 
• Raise your INHALER to your mouth in a horizontal position.  Do not block the air intake 
vents. 
• Close your lips tightly around the mouthpiece. 
• Breathe in deeply until your lungs are full.  You should hear or feel the capsule 
vibrate (rattle) (See Figure P). 
• Hold your breath for a few seconds and, at the same time, take your INHALER out of 
your mouth. 
• Breathe normally again. 
 
 
 
 
 
 
 
 Figure P  
 
The rattle tells you that you breathed in correctly.  If you do not hear or feel a rattle, see the 
section, “If you do not hear or feel the capsule rattle as you breathe in your study medication.” 
 
 
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To get the full amount from the capsule, you must again, breathe out completely  
(See Figure Q)  
 
 
 
 
 
 
 
 
 
 
Figure Q 
 
then for a second time, breathe in (See Figure R) from the same capsule.  
Important: Do not press the green piercing button again.  Do not breathe into your INHALER. 
Remember: To get your full amount from the capsule, you must breathe in 2 times from the same 
capsule.  Make sure you breathe out completely each time before you breathe in from your 
INHALER. 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Figure R 
 
 
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CARING FOR AND STORING YOUR INHALER: 
• After taking your daily dose, open the mouthpiece and tip out the used capsule into your 
resealable bag trash can, without touching it. 
• Remove any capsule pieces or powder buildup by turning your INHALER upside down 
and gently, but firmly, tapping it (See Figure S).  Then, close the mouthpiece and dustcap 
for storage. 
 
 
 
 
 
  Figure S 
• Do not store your INHALER and capsules (blisters) in a damp moist place.  Always store 
capsules in the sealed blisters. 
 
IF YOU DO NOT HEAR OR FEEL THE CAPSULE AS YOU BREATHE IN YOUR STUDY 
MEDICATION: 
• Do not press the green piercing button again. 
• Hold your INHALER with the mouthpiece pointed up and tap your INHALER gently on 
a table (See Figure T). 
 
 
 
 
 
 
 
 
 
 
Figure T 
 
• Check to see that the mouthpiece is completely closed.  Breathe out completely before 
deeply breathing in again with the mouthpiece in your mouth (See Figure R). 
• If you still do not hear or feel the capsule rattle after repeating the above steps: 
o Place the capsule in the resealable bag. Throw away the used capsule. 
o Open the base by lifting the green piercing button and check the center chamber 
for pieces of the capsule. 
o Capsule pieces in the center chamber can cause a capsule not to rattle. 
o Turn your INHALER upside down and gently, but firmly, tap to remove the 
capsule pieces. Call your study doctor for instructions. 
 
 
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CONFIDENTIAL 
CLEANING YOUR INHALER: 
• Clean your INHALER device as needed (See Figure U). 
o It takes 24 hours to air dry your INHALER after you clean it. 
o Do not use cleaning agents or detergents. 
o Do not place your INHALER in the dishwasher for cleaning. 
 
 
 
 
 
 
 
 
Figure U 
• Cleaning Steps: 
o Open the dust cap and mouthpiece. 
o Open the base by lifting the green piercing button. 
o Look in the center chamber for capsule pieces or powder buildup.  If seen, tap out. 
o Rinse your INHALER with warm water, pressing the green piercing button a few 
times so that the center chamber and the piercing needle are under the running 
water.  Check that any powder buildup or capsule pieces are removed. 
o Dry your INHALER well by tipping the excess water out on a paper towel. 
Air-dry afterwards, leaving the dust cap, mouthpiece, and base open by fully 
spreading it out so that it dries completely. 
o Do not use a hair dryer to dry your INHALER. 
o Do not use your INHALER when it is wet.  If needed, you may clean the outside 
of the mouthpiece with a clean damp cloth. 
o Document in your diary when cleaning of the INHALER has been performed. 
 
IMPORTANT INFORMATION ABOUT USING YOUR INHALER: 
21. Do not swallow capsules. 
22. Capsules should only be used with the INHALER and inhaled through your mouth (oral 
inhalation). 
23. Do not use your INHALER to take any other medicine. 
24. Do not store capsules in the INHALER. 
25. Store capsules in the sealed blister package at room temperature between 68°F to 77°F 
(20°C to 25°C). 
26. Keep capsules away from heat and cold (do not freeze). 
27. Store capsules in a dry place.  Do not use any unused capsules that have been open to air. 
28. Ask your study doctor if you have any questions about storing your capsules. 
29. Keep the INHALER and capsules out of the reach of children. 
30. Do not let the powder from the capsule get into your eyes. 
168


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Page 169 of 174 
Version: Amendment 1 (11-May-2017) 
 
________________________________________________________________________________________________________ 
Lupin Inc.  
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
Original Text: 
Appendix B: Inhalation Training with In-Check DIAL 
The In-Check DIAL is an inhalation airflow meter that can help educate and assess patients who 
use inhaler devices.  It simulates the internal resistance of several common inhaler devices, and 
measures inspiratory flow.  Inspiratory flow rate measurements will be obtained at screening and 
visits 2, 3, and 4 using the In-Check DIAL device and will be recorded in the eCRF.  
How to use the In-Check DIAL 
1.  Reset the In-Check DIAL.  The cursor should be reset to zero through a “tap and turn” 
maneuver which releases a seated magnet from the top of the DIAL and pushes the cursor 
back. The DIAL should then be turned upside down to reseat the magnet so as not to get in 
the way of an accurate measurement. 
 
2.    Align the scale with the inhaler device.  With the triangular pointer on top of the scale, align 
the “dial” portion of the device for use with HANDIHALER adapter by setting the device to 
“free flow” (wavy flag icon) - an audible "click" should be heard.   
 
 
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Version: Amendment 1 (11-May-2017) 
 
________________________________________________________________________________________________________ 
Lupin Inc.  
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
3.   Attach a clean mouthpiece.  Attach the HANDIHALER resistance adapter (blue transparent 
cylinder provided separately in a sealed plastic bag) to mimic SPIRIVA HANDIHALER 
resistance.  Insert a disposable one-way valved inspiratory mouthpiece into the wider end of 
the blue transparent adapter. 
 
 
4.   Ask the patient to exhale slowly and fully. 
 
 
 
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Version: Amendment 1 (11-May-2017) 
 
________________________________________________________________________________________________________ 
Lupin Inc.  
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
5.   Seal lips around the mouthpiece. According to the inhaler setting (wavy flow icon and 
HANDIHALER resistance adapter), instruct the patient to inhale deeply.  
 
6.   Record the inspiratory flow from the position of the red cursor against the scale.  Reset, and 
repeat until 3 successful inspiratory flow rates (≥40 L/min) are achieved.  Record the three 
(3) inspiratory flow rates on the patient’s source and eCRF.  
 
171


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Page 172 of 174 
Version: Amendment 1 (11-May-2017) 
 
________________________________________________________________________________________________________ 
Lupin Inc.  
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
Revised Text: 
Appendix B: Inhalation Training with In-Check DIAL 
The In-Check DIAL is an inhalation airflow meter that can help educate and assess patients who 
use inhaler devices.  It simulates the internal resistance of several common inhaler devices, and 
measures inspiratory flow.  Inspiratory flow rate measurements will be obtained at screening and 
visits 2, 3, and 4 using the In-Check DIAL device and will be recorded in the eCRF.  
How to use the In-Check DIAL 
1.  Reset the In-Check DIAL.  The cursor should be reset to zero through a “tap and turn” 
maneuver which releases a seated magnet from the top of the DIAL and pushes the cursor 
back. The DIAL should then be turned upside down to reseat the magnet so as not to get in 
the way of an accurate measurement. 
 
 
2.   Align the scale with the inhaler device.  With the triangular pointer on top of the scale, align 
the “dial” portion of the device for use with HANDIHALER adapter by setting the device to 
“free flow” (wavy flag icon) no resistance circle (pMDI) icon - an audible "click" should be 
heard.   
 
172


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Page 173 of 174 
Version: Amendment 1 (11-May-2017) 
 
________________________________________________________________________________________________________ 
Lupin Inc.  
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
3.  Attach a clean mouthpiece.  Attach the HANDIHALER resistance adapter (blue transparent 
cylinder provided separately in a sealed plastic bag) to mimic SPIRIVA HANDIHALER 
resistance.  Insert a disposable one-way valved inspiratory mouthpiece into the wider end of 
the blue transparent adapter. 
 
 
4.   Ask the patient to exhale slowly and fully. 
 
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Lupin Inc.  
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
5. Seal lips around the mouthpiece. According to the inhaler setting (wavy flow icon no 
resistance circle [pMDI] icon and HANDIHALER resistance adapter), instruct the patient to 
inhale deeply.  
 
6.   Record the inspiratory flow from the position of the red cursor against the scale.  Reset, and 
repeat until 3 successful inspiratory flow rates (≥40 L/min) are achieved.  Record the three 
(3) inspiratory flow rates on the patient’s source and eCRF.  
 
 
174

SAP_000.pdf: 
Sponlor. Lupin Inc. 
ProCoGol no: TB-OPI-301 
1.0 Appro 'C.'s 
Spoaor: Lupla lac. 
Repraeotativel Title: 
Slpat11re !Date: 
Representative/ Title: 
Signatare !Date: 
PRA 
Project 
Maugermtte: 
Sipature /Date: 
8101tadlticiao I Title 
(Owner): 
Sigaature /Date: 
 
- 
Lupin Inc. 
TB-DPI-301 
LPBTB30 1-TB30 I X 
11-May-2017 
Amendment I 
,. . 
. - la:: 
St8tilticll N PWt 
Veilon oate:F"IMI 01Feb2018 
A Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Crosover, 
Multicenter Clinical Study to Assess the Efficacy and Safety of Once Daily 
Administration of Lupin Tiotropiurn Bromide Inhalation Powder Compared to 
SPIRIV A® HANDIHALER® and Placebo in Patients with COPD including a 
12-Week Open-Label Extension to Assess Inhaler Robustnes 
14-Mar-201 7 
SAP2 Final/ 08Feb20 18 
velopment Inhalation, Complex Generics, and Brands 
/ 
 
 
(Original aut/ror; XID MD I Semor BIOIaiUiciOI) 
 OR-	18 
P.1 of 52 
Strictly Confidential. C 2004-2015,
 All rights reserved. 
Page 1 of 49


Statistical Analysis Plan
Version Date:Final 08Feb2018
Sponsor: Lupin Inc.
Protocol no: TB-DPI-301
Page 2 of 49
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Table of Contents
Approvals.............................................................................................................................................................................................1
Table of Contents..............................................................................................................................................................................2
Purpose.................................................................................................................................................................................................4
Scope......................................................................................................................................................................................................4
Introduction........................................................................................................................................................................................4
Study Objectives ...............................................................................................................................................................................4
Study Design.......................................................................................................................................................................................5
7.1 Sample Size Considerations................................................................................................................................................. 17
7.2 Randomization .......................................................................................................................................................................... 18
Study Variables............................................................................................................................................................................... 18
8.1 Primary Efficacy Variable...................................................................................................................................................... 18
8.2 Safety Variables......................................................................................................................................................................... 18
8.3 Other Variables ........................................................................................................................................................................... 19
Definitions........................................................................................................................................................................................ 19
9.1 Baseline and Change from Baseline.................................................................................................................................. 19
9.2 Baseline-adjusted FEV1 AUC0-24h......................................................................................................................................... 19
9.3 Treatment, Washout and Follow-up................................................................................................................................. 20
9.4 Double-blind Period vs. Open-label Period ................................................................................................................... 20
9.5 Treatment Emergent Adverse Event (TEAE)................................................................................................................ 21
9.6 Serious Adverse Event (SAE)............................................................................................................................................... 21
9.7 Spirometry (Part 1 Only)....................................................................................................................................................... 21
9.8 Spirometry (Part 1 and 2)..................................................................................................................................................... 23
9.9 COPD Exacerbations (Part 1 and Part 2)........................................................................................................................ 23
9.10 COPD Symptom Scores (Part 1 and Part 2)................................................................................................................. 23
9.11 Methods for Handling Dropouts and Missing Data.................................................................................................. 24
Analysis Population................................................................................................................................................................... 25
10.1 Intention-to-Treat ................................................................................................................................................................. 25
10.2 Per Protocol.............................................................................................................................................................................. 25
10.3 Safety........................................................................................................................................................................................... 26
10.4 Part 2 of the Study................................................................................................................................................................. 26
10.5 All Subjects ............................................................................................................................................................................... 26
10.6 All Randomized Subjects .................................................................................................................................................... 26
Interim Analysis.......................................................................................................................................................................... 26
11.1 Objective of the Interim Analysis.................................................................................................................................... 26
11.2 Endpoint for the Interim Analysis .................................................................................................................................. 26
11.3 Interim Analysis Population.............................................................................................................................................. 26
11.4 Sample Size Re-calculation for the Interim Analysis .............................................................................................. 27
11.4.1 Intra-patient CV Estimation...................................................................................................................................... 27
11.4.2 Sample Size Re-calculation........................................................................................................................................ 28
11.5 Results of the Interim Analysis........................................................................................................................................ 29
Data Review.................................................................................................................................................................................. 29
12.1 Data Handling and Transfer.............................................................................................................................................. 29
12.2 Data Screening........................................................................................................................................................................ 30
Statistical Methods..................................................................................................................................................................... 30


Statistical Analysis Plan
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Protocol no: TB-DPI-301
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13.1 Subject Disposition................................................................................................................................................................ 30
13.2 Protocol Deviations............................................................................................................................................................... 30
13.3 Treatments............................................................................................................................................................................... 31
13.3.1 Extent of Study Drug Exposure................................................................................................................................ 31
13.3.2 Prior and Concomitant Medications...................................................................................................................... 31
13.4 Demographic and Baseline Characteristics ................................................................................................................ 32
13.5 Medical History....................................................................................................................................................................... 32
13.6 Efficacy Analyses.................................................................................................................................................................... 32
13.6.1 Primary Variable............................................................................................................................................................ 32
13.6.2 Statistical Analysis for the Primary Variable..................................................................................................... 32
13.6.3 Subgroup Analyses ....................................................................................................................................................... 35
13.6.4 Multiplicity....................................................................................................................................................................... 35
13.6.5 Pooling of Sites............................................................................................................................................................... 35
13.7 Safety Analyses....................................................................................................................................................................... 35
13.7.1 Adverse Events............................................................................................................................................................... 36
13.7.2 Laboratory Data............................................................................................................................................................. 37
13.7.3 Vital Signs......................................................................................................................................................................... 37
13.7.4 Physical Examinations ................................................................................................................................................ 37
13.7.5 HEENT, Chest Examination, and Electrocardiograms (ECG) ...................................................................... 37
13.7.6 COPD Exacerbations..................................................................................................................................................... 38
13.7.7 Safety Spirometry.......................................................................................................................................................... 38
13.7.8 EXACT/ER-S Scores...................................................................................................................................................... 38
13.7.9 Albuterol/Salbutamol Usage .................................................................................................................................... 38
13.7.10 Urine/Serum Pregnancy Test................................................................................................................................ 38
13.7.11 Urine Drug Screen ...................................................................................................................................................... 38
13.7.12 Inhaler Robustness (Part 1 and Part 2)............................................................................................................. 39
Validation....................................................................................................................................................................................... 39
References..................................................................................................................................................................................... 39
Appendix 1 Glossary of Abbreviations......................................................................................................................................... 40
Appendix 2: EXACT DAILY DIARY ................................................................................................................................................. 42
Appendix 3: Results from the Interim Analysis ....................................................................................................................... 45


Statistical Analysis Plan
Version Date:Final 08Feb2018
Sponsor: Lupin Inc.
Protocol no: TB-DPI-301
Page 4 of 49
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Purpose
The statistical analysis plan (SAP) describes the statistical methods to be used during the reporting and 
analyses of data collected under Lupin Inc. Protocol TB-DPI-301.
Scope
This plan is a living document that will be created during the trial start-up.  Statistical Analysis Plan
(SAP) 1 will be drafted within three months of the final case report form (CRF), and maintained 
throughout the lifecycle of the trial.  The Statistical Analysis Plan 2 will be finalized prior to database 
lock. SAP 1 and SAP 2 will require sign off from the Project Manager and the sponsor.  
The Statistical Analysis Plan outlines the following:

Study objectives

Study design

Variables analyzed and analysis sets

Applicable study definitions

Interim Analysis

Statistical methods regarding subject disposition, important protocol deviations, study drug 
exposure, prior and concomitant medications, demographic and baseline characteristics, medical 
history, efficacy analysis, adverse events handling, and other safety data examinations 
The Table, Listing and Figure Shells will be provided in a separate document. 
Introduction
This SAP describes the statistical methods to be used during the reporting and analyses of data collected 
under Lupin Inc. Protocol TB-DPI-301. 
This SAP should be read in conjunction with the study protocol and CRF. This version of the plan has 
been developed using the protocol Amendment version 1 dated 11May2017 and CRF dated 14Mar2017. 
Any further changes to the protocol or CRF may necessitate updates to the SAP.
The SAP is to be developed in two stages. The purpose is to “finalize” a SAP so that PRA can start 
programming earlier in the process. Versions of the SAP up to initial sponsor approval will be known as 
SAP1. Changes following approval of SAP1 will be tracked in the SAP Change Log and a final version 
of the SAP, known as SAP2, will be issued for sponsor approval prior to database lock.
Study Objectives
Primary Objective 
The primary objective of this study is to show clinical Bioequivalence (BE) in the efficacy of the Lupin 
Tiotropium Bromide Inhalation Powder, 18 mcg administered as a single dose versus SPIRIVA 


Statistical Analysis Plan
Version Date:Final 08Feb2018
Sponsor: Lupin Inc.
Protocol no: TB-DPI-301
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HANDIHALER, 18 mcg based on the baseline-adjusted forced expiratory volume in the first second 
(FEV1) area under the curve from time zero to 24 hours postdose (AUC0-24h) on day 1. 
Secondary Objectives
The secondary objectives of this study are to evaluate the safety and tolerability of the Lupin Tiotropium 
Bromide Inhalation Powder and SPIRIVA HANDIHALER following single doses of 18 mcg in patients 
40 years of age and older with COPD. 
Other Objectives 
For a subset of the Lupin tiotropium DPIs (LUPINHALER™) used during the open-label extension 
(Part 2) the following objectives will be assessed: 

ruggedness of the LUPINHALER during 72 days of in-patient use 

in vitro performance post 72 days of in-patient use 
Study Design
This is a Phase 3 Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Crossover, 
Multicenter Clinical Study to Assess the Efficacy and Safety of Once Daily Administration of Lupin 
Tiotropium Bromide Inhalation Powder Compared to SPIRIVA® HANDIHALER® and Placebo in 
Patients with COPD including a 12-Week Open-Label Extension to assess Inhaler Robustness. The 
study is planned to be conducted at approximately 40 investigational centers in the United States of 
America (USA). Additional centers in the USA may be added as needed. 
This clinical study includes two parts. The duration of patient participation for Part 1 is approximately 
14 weeks and for patients participating in both Part 1 and Part 2, the duration of patient participation is 
approximately 26 weeks.
Part 1 (14 weeks)
Part 1 is a randomized, double-blind, double-dummy, placebo-controlled, 3-period, single-dose 
crossover study that will evaluate the clinical BE of single-dose treatment of Lupin Tiotropium Bromide 
Inhalation Powder, 18 mcg and SPIRIVA HANDIHALER, 18 mcg in patients 40 years of age and older 
with established COPD. 
Part 1 of the study consists of a screening period up to 30 days, followed by a single-blind placebo run-
in period of 14 (+2) days and 3 single-dose, double-blind treatment periods (visits 2-4) each separated 
by a 21-day (+3 days) washout period. Each double-blind treatment period begins with administration of 
the study medication at the investigational center, followed by lung function assessments collected over 
a 24-hour period. For patients ending participation in the study after completing Part 1 and not enrolling 
into the open-label extension (Part 2), a follow-up visit via phone contact will be conducted 7 days 
(±3 days) after the completion of treatment period 3 (visit 4). 


Statistical Analysis Plan
Version Date:Final 08Feb2018
Sponsor: Lupin Inc.
Protocol no: TB-DPI-301
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Screening period: up to 30 days
The screening period allows for adequate washout of the COPD therapies including long-acting 
anti-muscarinic agent (LAMA), long-acting beta agonist (LABA), or inhaled corticosteroid (ICS)/LABA 
therapy, along with other prohibited medications per protocol. If a patient is washing out of ICS 
(monotherapy) or ICS/LABA combination therapy as stated above, an additional 3 day window is 
permitted to complete the assessments for the screening visit (visit 1).
If the patients were formerly taking LAMA, LABA, or ICS/LABA therapy, the medications will need to 
be discontinued and may be replaced at the discretion of the Investigator with the short-acting anti-
muscarinic agent (SAMA) medication, ipratropium bromide, for use during the course of the study. 
Patients who have not taken LAMA, LABA or ICS/LABA combination products within the time period 
specified above, or who are not on medications that are restricted according to the protocol criteria, and 
who have met the selection criteria (e.g., reversibility and baseline safety measures) at the screening visit 
(visit 1) will begin the 14 (+2) day single-blind placebo run-in period.
All patients enrolled in the screening/run-in periods will be supplied with the following: 

eDiary/electronic flow meter to measure lung function for monitoring disease stability during the 
screening and run-in periods

short-acting bronchodilator (SABA), ie, albuterol/salbutamol metered dose inhaler 
(MDI) 90 mcg ex-actuator or equivalent, for use during the course of the study
Single-blind placebo run-in period: 14 (+2) days 
Patients enrolled in the run-in period will also be supplied with a placebo Lupin Tiotropium Bromide 
Inhalation Powder (placebo LUPINHALER) for once daily administration (2 inhalations from one 
capsule) in the morning throughout the single-blind run-in period. 
Patients will be required to measure FEV1 prior to dosing in the morning at approximately the same time 
each day. The FEV1 results and usage of study medication/albuterol/salbutamol MDI will be monitored 
and recorded in the eDiary. Patients will also complete the Exacerbations of Chronic Pulmonary Disease 
Tool (EXACT®) Patient Reported Outcome (PRO) within the eDiary, once daily, each evening before 
bedtime during the screening and run-in periods. 
Three single-dose, double-blind treatment periods (visits 2-4) each separated by a 21-day (+3 days) 
washout period 
Patients will present at the investigational center for visit 2 on day 0 between 0600 and 1000 having 
withheld the prohibited/restricted medications for the prescribed protocol-defined period and without 
conducting lung function measurements on the electronic flow meter (home device). Patients will record 
albuterol/salbutamol MDI usage in their diaries on the mornings prior to this visit. Patients meeting all 
of the randomization criteria will be randomly assigned to 1 of the following 6 treatment sequences in a 
double-dummy manner using a Williams design Latin Square as described in Table 1: 


Statistical Analysis Plan
Version Date:Final 08Feb2018
Sponsor: Lupin Inc.
Protocol no: TB-DPI-301
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Table 1  Randomization Design
Treatment 
sequence 
Treatment period 
1 
Treatment period 
2 
Treatment period 
3 
A (TRP) 
Lupin Tiotropium 
Bromide 
Inhalation Powder 
18 mcg 
SPIRIVA 
HANDIHALER 
18 mcg 
Placebo 
B (RPT) 
SPIRIVA 
HANDIHALER 
18 mcg 
Placebo 
Lupin Tiotropium 
Bromide 
Inhalation Powder 
18 mcg 
C (PTR) 
Placebo 
Lupin Tiotropium 
Bromide 
Inhalation Powder 
18 mcg 
SPIRIVA 
HANDIHALER 
18 mcg 
D (PRT) 
Placebo 
SPIRIVA 
HANDIHALER 
18 mcg 
Lupin Tiotropium 
Bromide 
Inhalation Powder 
18 mcg 
E (TPR) 
Lupin Tiotropium 
Bromide 
Inhalation 
Powder18 mcg 
Placebo 
SPIRIVA 
HANDIHALER 
18 mcg 
F (RTP) 
SPIRIVA 
HANDIHALER 
18 mcg 
Lupin Tiotropium 
Bromide 
Inhalation Powder 
18 mcg 
Placebo 
In order to maintain the patient blind, a specified member of the investigational center (i.e., unblinded 
administrator) will load and dispense the study medication to the patient and instruct the patients to take 
2 full inhalations from each of 2 inhalers. The unblinded administrator will also apply an opaque 
covering to the chamber windows prior to patient administration to obstruct capsule identification in 
each inhaler. 
Patients will undertake 2 baseline FEV1 measurements at 0 hours (-30 and -15 minutes before study 
medication administration) followed by serial FEV1 measurements at 5 and 30 minutes postdose, and at 
1, 2, 4, 6, 8, 10, 12, 23, and 24 hours postdose. The 23 and 24 hour FEV1 measurements will be taken on 
the 2nd day of the visit (day 1) in the morning at the investigational center. Prior to and for the duration 
of the FEV1 measurements at the investigational center visits (day 0 and day 1), patients should refrain 
from using albuterol/salbutamol MDI and other prohibited medication; patients should not smoke for at 
least 1 hour prior to lung function assessments during the visit; and patients should adhere to the dietary 
restrictions as per protocol. 


Statistical Analysis Plan
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Protocol no: TB-DPI-301
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After completion of all assessments at visit 2, the patients will enter a 21-day (+3 days) washout phase 
where the patients may continue to use albuterol/salbutamol MDI and other medications permitted per 
protocol (eg, SAMA). Patients will continue to measure lung function for monitoring disease stability 
during the double-blind treatment period. On days of non-investigational center visits, patients will be 
required to measure FEV1 once daily prior to dosing in the morning at approximately the same time each 
day. The FEV1 will be recorded in the eDiary/electronic flow meter. Patients will also complete the 
EXACT once daily, each evening before bedtime within the eDiary. On days of investigational center 
visits, patients will perform the FEV1 measurements and administer the study medication at the 
investigational center, and the EXACT will be collected at home in the evening before bedtime. Usage 
of albuterol/salbutamol MDI will also be recorded in the eDiary. 
Prior to visit 3 (days 21 and 22) and visit 4 (days 42 and 43) patients should observe the same smoking, 
dietary and medication restrictions as visit 2. Patients will record albuterol/salbutamol MDI usage in 
their diaries on the mornings prior to these visits; however, no FEV1 measurements will be performed in 
the morning using the electronic flow meter (home device). Patients should present at the investigational 
center so that the start of lung function testing will be within ±1 hour from the lung function testing at 
visit 1. Patients will then undertake 2 baseline FEV1 measurements at 0 hours (-30 and -15 minutes 
before study medication administration), followed by serial FEV1 measurements at 5 and 30 minutes 
post-dose, and at 1, 2, 4, 6, 8, 10, 12, 23, and 24 hours post-dose. After completion of all assessments at 
visit 3 (days 21 and 22), the patient will enter a 21-day (+3 days) washout phase where the patient may 
continue to use albuterol/salbutamol MDI and other medications permitted per protocol (eg, SAMA). 
Follow-up period: 7 days (±3 days)
Patients who successfully complete the 3 single-dose treatments in Part 1 and who are not enrolled into 
the open-label extension (Part 2) will be contacted via phone 7 days (±3 days) after the visit for a final 
safety check and then formally discharged from the study.
Part 2 (12 weeks)
Part 2 is a 12-week open-label extension of Part 1, which will enroll a subset of patients (approximately 
120 patients) at select investigational centers who successfully completed Part 1 of the study and 
continue to meet the continuation criteria, to assess robustness of the LUPINHALER over 72 days of 
treatment. 
The open-label extension (Part 2) will consist of 7 visits (visit 5 through visit 10, and follow-up), and 
will begin on the last day of visit 4 (Part 1). Visits 6 and 8 will be conducted via telephone contact. The 
final safety follow-up for those patients participating in Part 2 will be conducted via telephone 7 days 
(±3 days) after the last active treatment of the open-label extension (ie, visit 10). 
Patients participating in the open-label extension will begin study activities on the same day as the final 
visit in the double-blind treatment period (visit 4), which will be considered the first day of the open-
label extension (visit 5). Patients will be issued a 90-day supply of the Tiotropium Bromide Inhalation 


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Sponsor: Lupin Inc.
Protocol no: TB-DPI-301
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Powder, 18 mcg for once-daily administration (to be taken at home each morning) during a 72-day 
treatment phase. Treatment with the Lupin Tiotropium Bromide Inhalation Powder will begin on visit 5 
after all FEV1 assessments and study activities were completed for Part 1. Patients will be permitted to 
resume other non-study medications and albuterol/salbutamol MDI as permitted per protocol. LAMA 
medications (mono and combination therapies), other than the study medication, are prohibited in Part 2 
of the study. Patients will assess functionality of the LUPINHALER daily and record this data in the 
eDiary.
Patients will measure lung function to monitor disease stability via the eDiary/electronic flow meter 
during the open-label extension. Patients will be required to measure FEV1 twice daily: upon awakening 
in the morning immediately prior to dosing with the study medication and at 2 (+2) hours after study 
medication administration. The FEV1 results and albuterol/salbutamol MDI/study medication usage will 
be monitored and recorded in the eDiary/electronic flow meter. Patients will also complete the EXACT 
once daily, each evening before bedtime within the eDiary. 
At visit 6 and visit 8, patients will be contacted via telephone by investigational center personnel to 
monitor AEs and any issues regarding the inhaler function. The patients will return to the investigational 
center on visit 7 and visit 9 for an overall assessment of safety and tolerability, to verify inhaler 
technique, and to assess any inhaler issues/malfunctions. On visit 10, patients will return for a final 
treatment visit, in which vital signs will be assessed, inhaler issues/malfunctions assessed, and the 
eDiary/electronic flow meter, albuterol/salbutamol MDI, and study medication collected and stored 
appropriately. The patient should be contacted via phone 7 ±3 days after the final treatment visit (visit 
10) for a final safety check and to be formally discharged from the study. 
Safety will be monitored throughout Part 1 and Part 2 of the study by vital signs measurements, 
albuterol/salbutamol MDI and concomitant medication usage, physical examinations, head, ears, eyes, 
nose, throat (HEENT)/chest examinations, spirometry (FEV1 ) measurements, electrocardiography 
(ECGs), ER-S: COPD scores (derived from the EXACT), COPD exacerbations, and AEs. During the 
screening and run-in periods, safety will be assessed via FEV1 measurements, ER-S: COPD scores, and 
monitoring of AEs and COPD exacerbations.
The schedule of events for this study is provided in Table 2 Schedule of Events.


Statistical Analysis Plan
Version Date:Final 08Feb2018
Sponsor: Lupin Inc.
Protocol no: TB-DPI-301
Page 10 of 49
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.  All rights reserved.
Table 2 Schedule of Events
Screening 
period
Single-
blind 
run-in 
period
Part 1
Double-blind treatment period
Part 2
Open-label extension
Study visit
Visit 1
NA
TP1
(Visit 2)
TP2
(Visit 3)
TP3
(Visit 4)
F/U1
Visit 
5
Visit 
6
Visit 
7
Visit 
8
Visit 
9
Visit 
10
F/U2
ET3
Study days4
-44 to -145
14-16
day 
period 
before 
day 0
0
1
21
(+3)
22
42
(+3)
43
50
(±3)
436
57
(±2)
71
(±2)
85
(±2)
99
(±2)
115
(+3)
122
(±3)
NA
Clinic visit7
X
X
X
X
X
X
X
Tele-
phone 
only
X
Tele-
phone 
only
X
Tele-
phone 
only
X
X
Tele-
phone 
only
X
Informed consent
X
Assign patient via IRT
X
Assess inclusion/ 
exclusion criteria
X
Demography
X
Physical examination
X8
X
X
X
Height and weight
X
HEENT and chest 
examination
X
X
X
X
X
Medical history 
including prior 
concomitant 
medications
X
12-lead ECG
X
X
X
X
X
X
X
Clinical laboratory 
tests (hematology, 
biochemistry, and 
urinalysis)
X
Serum pregnancy test 
(female patients of
X
X9
X9
X


Statistical Analysis Plan
Version Date:Final 08Feb2018
Sponsor: Lupin Inc.
Protocol no: TB-DPI-301
Page 11 of 49
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.  All rights reserved.
Screening 
period
Single-
blind 
run-in 
period
Part 1
Double-blind treatment period
Part 2
Open-label extension
Study visit
Visit 1
NA
TP1
(Visit 2)
TP2
(Visit 3)
TP3
(Visit 4)
F/U1
Visit 
5
Visit 
6
Visit 
7
Visit 
8
Visit 
9
Visit 
10
F/U2
ET3
Study days4
-44 to -145
14-16
day 
period 
before 
day 0
0
1
21
(+3)
22
42
(+3)
43
50
(±3)
436
57
(±2)
71
(±2)
85
(±2)
99
(±2)
115
(+3)
122
(±3)
NA
Clinic visit7
X
X
X
X
X
X
X
Tele-
phone 
only
X
Tele-
phone 
only
X
Tele-
phone 
only
X
X
Tele-
phone 
only
X
childbearing potential 
only)
Urine pregnancy test 
(female patients of 
childbearing potential 
only)
X
Urine drug screen
X
Vital signs 
measurements10
X
X11
X
X11
X
X11
X
X
X
X
X
Demonstrate study 
medication inhalation 
technique
X
X
X
X
X
X
X
Demonstrate 
albuterol/salbutamol 
MDI inhalation 
technique
X
X
X
X
X
X
X
Dispense single-blind 
run-in medication
X12
Assess inspiratory flow 
rate via In-Check 
DIAL device
X
X
X
X
Ipratropium 
reversibility13
X


Statistical Analysis Plan
Version Date:Final 08Feb2018
Sponsor: Lupin Inc.
Protocol no: TB-DPI-301
Page 12 of 49
Strictly Confidential.  © 2004-2015, 
.  All rights reserved.
Screening 
period
Single-
blind 
run-in 
period
Part 1
Double-blind treatment period
Part 2
Open-label extension
Study visit
Visit 1
NA
TP1
(Visit 2)
TP2
(Visit 3)
TP3
(Visit 4)
F/U1
Visit 
5
Visit 
6
Visit 
7
Visit 
8
Visit 
9
Visit 
10
F/U2
ET3
Study days4
-44 to -145
14-16
day 
period 
before 
day 0
0
1
21
(+3)
22
42
(+3)
43
50
(±3)
436
57
(±2)
71
(±2)
85
(±2)
99
(±2)
115
(+3)
122
(±3)
NA
Clinic visit7
X
X
X
X
X
X
X
Tele-
phone 
only
X
Tele-
phone 
only
X
Tele-
phone 
only
X
X
Tele-
phone 
only
X
Study qualifying FEV1
X
Determine FEV1
baseline/stability limits
X14
X15
Administer
single-blind run-in 
medication
X
Collect single-blind 
run-in medication
X
X
Review randomization 
criteria
X
Randomization via 
IRT
X
Review continuation 
criteria
X
X
X
X
X
X
X
Administer study 
medication at clinic
X
X
X
X
Enroll in open-label 
extension via IRT16
X
Predose and serial 
FEV1 measurements17
X
X
X
X
X
X
Dispense eDiary/ 
electronic flow meter
X18
X
Review eDiary/ 
electronic flow meter 
instructions
X
X
X
X
X


Statistical Analysis Plan
Version Date:Final 08Feb2018
Sponsor: Lupin Inc.
Protocol no: TB-DPI-301
Page 13 of 49
Strictly Confidential.  © 2004-2015, 
.  All rights reserved.
Screening 
period
Single-
blind 
run-in 
period
Part 1
Double-blind treatment period
Part 2
Open-label extension
Study visit
Visit 1
NA
TP1
(Visit 2)
TP2
(Visit 3)
TP3
(Visit 4)
F/U1
Visit 
5
Visit 
6
Visit 
7
Visit 
8
Visit 
9
Visit 
10
F/U2
ET3
Study days4
-44 to -145
14-16
day 
period 
before 
day 0
0
1
21
(+3)
22
42
(+3)
43
50
(±3)
436
57
(±2)
71
(±2)
85
(±2)
99
(±2)
115
(+3)
122
(±3)
NA
Clinic visit7
X
X
X
X
X
X
X
Tele-
phone 
only
X
Tele-
phone 
only
X
Tele-
phone 
only
X
X
Tele-
phone 
only
X
Dispense 
albuterol/salbutamol 
MDI, as applicable
X19
X
X
X
X
X
X
X
Dispense/collect 
placebo trainer
X
X
X
X
Dispense study 
medication20
X
X
X
X
Assess eDiary data
X
X
X
X
X
X
X
X
X
X
X
Collect eDiary/
electronic flow meter, as 
applicable
X
X
X
X
X
Check for issues with 
study inhalers
X
X
X
X
X
X
X
X
X
X
X21
Collect COPD 
exacerbation data
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record concomitant 
medication/therapies
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Collect study 
medication
X
X
X
X
X
Collect 
albuterol/salbutamol 
MDI, as applicable
X
X
X
X
X
X
X
X
X
Schedule next visit
X
X
X
X
X
X
X
X
X
X


Statistical Analysis Plan
Version Date:Final 08Feb2018
Sponsor: Lupin Inc.
Protocol no: TB-DPI-301
Page 14 of 49
Strictly Confidential.  © 2004-2015, 
.  All rights reserved.
Screening 
period
Single-
blind 
run-in 
period
Part 1
Double-blind treatment period
Part 2
Open-label extension
Study visit
Visit 1
NA
TP1
(Visit 2)
TP2
(Visit 3)
TP3
(Visit 4)
F/U1
Visit 
5
Visit 
6
Visit 
7
Visit 
8
Visit 
9
Visit 
10
F/U2
ET3
Study days4
-44 to -145
14-16
day 
period 
before 
day 0
0
1
21
(+3)
22
42
(+3)
43
50
(±3)
436
57
(±2)
71
(±2)
85
(±2)
99
(±2)
115
(+3)
122
(±3)
NA
Clinic visit7
X
X
X
X
X
X
X
Tele-
phone 
only
X
Tele-
phone 
only
X
Tele-
phone 
only
X
X
Tele-
phone 
only
X
Discuss COPD 
treatment options
X
X
X
X
X
X
Discharge patient via 
IRT
X
X
X
Home-based FEV1 
measurements
Record morning pre-dose in eDiary/electronic flow meter22
Record morning pre-dose and 2 hours post-dose
in eDiary/electronic flow meter
Assess EXACT 
symptom scores
Record once daily in the evening before bedtime via eDiary
Record once daily in evening before bedtime via 
eDiary
Albuterol/salbutamol 
MDI medication use
Record daily in eDiary
Record daily in eDiary
1)
For patients participating in Part 1 only, a follow-up visit will occur via phone contact by investigational center personnel 7 days (±3 days) after completing 
visit 4.
2)
This follow-up visit will only be required for patients participating in Part 2 of the study, and will occur via phone contact by investigational center personnel 7 
±3days after the final treatment visit (visit10).
3)
Regardless if patient is participating in Part 1 or Part 2, the assessments listed for ET will be performed for any patient who is withdrawn prematurely from the
study.
4)
As there is only the potential to extend visit intervals with permitted visit windows, the terminology of study days will not necessarily represent the exact day 
of the visit.
5)
The screening visit (visit 1) may take place over several days beginning on day -44 to -14 dependent on the patient’s washout. If a patient is washing out of 
ICS (monotherapy) or ICS/LABA combination therapy, an additional 3 days is permitted to complete the assessments for the screening visit (visit 1). All 
results, with the exception of the clinical laboratory assessments, must be available and evaluated prior to commencing the run-in period.  The clinical 
laboratory results must be available and evaluated prior to randomization.  The procedures for the screening visit (visit 1), with the exception of signing of the 
ICF, performing a pre-washout physical examination, and dispensing/completing the ediary, cannot occur until appropriate medication washouts have been 


Statistical Analysis Plan
Version Date:Final 08Feb2018
Sponsor: Lupin Inc.
Protocol no: TB-DPI-301
Page 15 of 49
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.  All rights reserved.
completed in accordance with the protocol.  Once the washout requirements have been met, the screening visit (visit 1) should immediately precede the start of 
the run-in period.  If a patient does not require washout, and the patient passes all entry criteria at the screening visit (visit 1), the patient will be eligible to 
enter the run-in period on the same day as the screening visit (visit 1).  The patient must successfully complete the visit 1 procedures/assessments prior to 
entering the run-in period.
6)
After completion of visit 4 (days 42 and 43), patients will either be discharged from the study after completing all double-blind study assessments at visit 4 or a 
subset of patients (approximately 120 patients) will be eligible for enrollment into a 12-week open-label extension, which will begin on the same day as the 
final visit in the double blind treatmentperiod.
7)
All visits for Part 1 should be scheduled in the mornings between 0600 and 1000 and spirometry testing should begin at ±1 hour of the start of visit 1 testing
time.
8)
If washout of baseline therapy is needed, then 2 physical examinations are required: one before a patient commences the washout period and one after the 
washout period ends, prior to enrolling into the run-inperiod.
9)
The visit 4 end of study serum pregnancy test will be performed for women of childbearing potential who are only participating in Part 1 of the study. For 
women of childbearing potential who are participating in both Part 1 and Part 2, the end of study serum pregnancy test will be performed at visit 10.
10) Vital signs measurements include blood pressure, heart rate, respiration rate, and temperature.
11) Vital signs will be collected within 60 minutes of measuring the predose FEV1 on days 0, 21, and 42.
12) Single blind run-in must be dispensed 14 to 16 days prior to randomization. Patients will administer the single-blind placebo LUPINHALER one daily in the 
morning for 14 (+2) days after completing theFEV1 measurements.
13) Patient has demonstrated ≥15% reversibility of FEV1 within 30 or 60 minutes following 68 mcg of ipratropium bromide inhalation (pMDI). If required, spacers 
are permitted for use during reversibility testing for ipratropium bromide administration. Patients who do not demonstrate a positive improvement of at least 
15% in FEV1 measured at 30 or 60 minutes (±5 minutes) post inhalation will not be eligible to participate in the study. However, based on Investigator 
judgment, patients will be allowed to retest once no sooner than 24 hours and no later than 2 weeks after initial failure to meet the reversibility criteria. 
Reversibility values of 14.50-14.99 will be rounded to 15.
14) A stability limit will be established at the screening visit (visit 1) to determine alert criteria for worsening COPD during the screening and run-in periods, and
will be calculated by selecting the best pre-bronchodilator qualifying FEV1 measurement at the screening visit using the onsite spirometer x 80%.
15) Two stability limits (at home and investigational center) will be re-established at the randomization visit (visit 2) for use during the double-blind and open-
label treatment periods. The at home limit will be calculated by taking the mean of the best predose FEV1 measurements on the last 3 days before 
randomization on the electronic flow meter (home device) x 80%, and the investigational center limit will be the mean FEV1 of the predose pre-bronchodilator
qualifying FEV1 measurements (-30 and -15 minutes) using the onsite spirometer × 80%.
16) A subset of patients (approximately 120 patients) at select investigational centers who successfully completed Part 1 will be eligible for enrollment into the 
open-label extension (Part 2).
17) Pre-dose FEV1 will be measured at 30 and 15 minutes before administration of study medication.  Serial FEV1 spirometry measured at 0 hours (within 30 and 
15 minutes prior to study medication administration [equivalent to the pre-dose FEV1 ]), and at 5 and 30 minutes post-dose, and at 1, 2, 4, 6, 8, 10, 12, 23, and 
24 hours post-dose. The following windows are permitted: +5 minutes for predose measurements (-30 and -5 minutes) and 5 minute postdose measurement; ±5 
minutes for 0.5-6 hours, and ±15 minutes for 8-24 hours.
18) Diary collection begins at the time of signing the ICF until the conclusion of the run-in period, and then continues throughout Part 1 and Part 2, per the 


Statistical Analysis Plan
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Protocol no: TB-DPI-301
Page 16 of 49
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randomization scheme.
19) Dispensation of the albuterol/salbutamol MDI is not required during the screening period if the patient is taking this medication as part of their current COPD 
therapy. Once the patient is enrolled in the run-in period, dispensation/administration of the study albuterol/salbutamol MDI is required and the patient will 
discontinue the use oftheir own albuterol/salbutamol MDI.
20) Administration of study medication at the investigational center will occur in the presence of the unblinded and blinded staff members.
21) For patients participating in Part 2.
22) Home based FEV1 measurements will not be performed on the mornings of visit 2 (both day 0 and day 1), visit 3 (both day 21 and day 22), and visit 4 
(both day 42 and day 43).


Statistical Analysis Plan
Version Date: Final 08Feb2018
Sponsor: Lupin Inc.
Protocol no: TB-DPI-301
Page 17 of 49
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7.1 Sample Size Considerations
The sample size estimation was determined based on demonstrating equivalence between the 
Test (T) product (Lupin Tiotropium Bromide Inhalation Powder) and the Reference (R) 
product (SPIRIVA HANDIHALER) for the primary endpoint change from baseline in FEV1
AUC0-24 on the treatment day, and to demonstrate that both the Test (T) and Reference (R) 
products are superior to the placebo. Bioequivalence (BE) will be demonstrated if the 90% 
confidence interval (CI) on the T to R ratio for the endpoint is contained within the interval 
(0.80, 1.25). Superiority will be demonstrated by showing that each active treatment’s 
response for the endpoint is greater than, and statistically different from (p<0.05, two-sided), 
that of the placebo (P). For the equivalence evaluation, the results in the PP analysis set will 
be considered definitive and for the superiority evaluations, those in the Intent-to-Treat (ITT) 
population will be considered definitive. 
A review of the literature did not yield any estimates of within-patient variability of baseline-
adjusted FEV1 AUC0-24 from a crossover study using a similar patient population with similar 
objectives. From a review of studies on clinicaltrials.gov, there were a number of estimates 
available of between-patient variability for baseline-adjusted FEV1 AUC0-24. From the 
12 studies reviewed, the mean coefficient of variation (CV) for the variable was 121%. 
Within-patient variability is generally much less than between-patient variability. As a 
starting point for the sample size estimation it was assumed that the within-patient variability 
would be about 50% of the between-patient variability, or a CV of 60%. 
The goal of the study is to complete 180 patients per protocol. With a sample size in each of 
the 6 sequence groups of 30, for a total sample size of 180, a crossover design will have 90% 
power to reject both the null hypothesis that the ratio of the test mean to the standard mean is 
below 0.80 and the null hypothesis that the ratio of test mean to the standard mean is above 
1.25 (ie, that the test and standard are not equivalent), in favor of the alternative hypothesis 
that the means of the 2 treatments are equivalent, assuming that the expected ratio of means 
is 1.00, the between-patient CV is 1.21, the intra-patient CV is 0.60. In order to allow for a 
potential 30% premature withdrawal rate or loss from the PP population due to protocol 
deviations, 240 patients will be randomized in total, 40 to each of the 6 treatment sequences. 
As no estimates of within-patient variability were available in the public domain, a blinded 
interim analysis will be conducted in order to assess the within-patient variability. The 
blinded interim analysis will be done to ascertain if an increase in sample size is necessary 
maintain 90% power to complete the study with a 90% CI for the relative bioavailability of 
the Test (T) to the Reference (R) product inside of the pre-specified interval 0.80-1.25. The 
blinded interim analysis will be discussed in Section 11.0. 


Statistical Analysis Plan
Version Date: Final 08Feb2018
Sponsor: Lupin Inc.
Protocol no: TB-DPI-301
Page 18 of 49
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7.2 Randomization
Patients will be randomly assigned to the treatment sequences by means of a computer 
generated randomization list after confirmation of all eligibility criteria. The randomization 
list and study medication will be assigned via interactive response technology (IRT). Y-
Prime Inc. will be responsible for generating the randomization schedule.
The randomization scheme utilized in TB-DPI-301 will be central. A total of 240 patients
will be randomized in a ratio of 1:1:1:1:1:1 to the 6 treatment sequences based on a Williams 
design Latin square in the cross-over design shown in Table 1. 
Additionally, on each study day, as this is a double-dummy study, the order of administration 
of the LUPINHALER and HANDIHALER will be assigned based on even/odd calendar days.
On odd calendar days (eg, 1, 3, 5, 29, 31), the LUPINHALER will be dosed first.  On even 
calendar days (eg, 2, 4, 6, 28, 30), the HANDIHALER will be dosed first. 
A subset of approximately 120 patients (at select investigational centers) will be enrolled into 
the open-label phase of the study (Part 2). These patients will not be randomized and all 
patients in Part 2 will receive Lupin Tiotropium Bromide Inhalation Powder.
Study Variables 
8.1 Primary Efficacy Variable
The primary variable is the baseline-adjusted FEV1 AUC0-24h on the single-dose treatment 
days. Baseline is defined as the average of the FEV1 values recorded at approximately 
30 minutes and 15 minutes before dosing with study medication. 
8.2 Safety Variables
Safety will be assessed throughout Part 1 and Part 2 of the study by monitoring the following: 

adverse events (AEs) 

SABA (albuterol/salbutamol MDI) and concomitant medication use 

vital signs measurements 

physical examinations 

head, ears, eyes, nose, and throat (HEENT) and chest examinations 

COPD exacerbations 

12-lead electrocardiograms (ECGs)

Laboratory (screening only)

ER-S: COPD Scores

Safety Spirometry


Statistical Analysis Plan
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Protocol no: TB-DPI-301
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8.3 Other Variables 
For a subset of the LUPINHALERs used during the open-label extension (Part 2), the 
following endpoints will be assessed: 

ruggedness of the LUPINHALER during 72 days of in-patient use: 
-
percent (%) of overall inhalers with reported problems or malfunctions; 
comprised of misuse episodes (eg, impact and moisture) and issues identified (eg, 
mechanical problems and COPD worsening/seems ineffective) during 72 days of 
in-patient use 

in vitro performance of 100 inhalers post 72 days of in-patient use 
The data resulting from the in vitro evaluation of the pharmaceutical performance will 
be presented in a separate report.
Definitions
9.1 Baseline and Change from Baseline
Baseline is defined as the last observation prior to dosing. Generally, baseline in Part 2 of the 
study will be the same as baseline in Part 1 of the study unless otherwise specified. For the 
primary variable (FEV1 AUC0-24h), baseline is defined as the average of the FEV1 values 
recorded at approximately 30 minutes and 15 minutes before dosing with study medication.
Change from baseline = post-baseline value – baseline value. 
9.2 Baseline-adjusted FEV1 AUC0-24h 
The baseline-adjusted FEV1 AUC0-24h is defined as the baseline-adjusted area under the curve 
for forced expiratory volume in 1 second from time zero to 24 hours postdose using the 
trapezoidal rule based on actual time of measurement. 
The baseline FEV1 will be the average of the 2 predose FEV1 measurements (30 minutes and 
15 minutes pre-dose) at the clinic visit.  If one of the predose FEV1 measurements is missing, 
or excluded due to poor quality spirometry effort, the other non-missing measurement will be 
used as baseline. If both predose FEV1 measurements are missing or excluded, baseline will 
be treated as missing. 
Baseline-adjusted FEV1 will be calculated as postdose FEV1 after subtracting the baseline 
FEV1 value. 
The general area under the concentration-time effect curve (AUC) formula by the trapezoidal
rule is given below:
)
(
2
1
i =1
1





i
i
n
i
i
t
t
c
c
AUC(0 – tn)


Statistical Analysis Plan
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Sponsor: Lupin Inc.
Protocol no: TB-DPI-301
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where tn is the maximum time, n is the number of time points, and ci is the change in FEV1
from baseline at time ti. For AUC calculations t0 will be the start time of dose administration
(t0=0), and c0 will be 0. AUC calculations will utilize the actual time of spirometry 
measurements.
Note- the area under the curve that is the primary variable is the area between the baseline 
value (straight red line and the curve). It is NOT measured from the x-axis.
9.3 Treatment, Washout and Follow-up
For summary purposes, treatment will be defined as days of dosing and days immediately
after dosing, eg, day 0, 1, 21(+3), 22, 42(+3) and 43; washout will be days between 
treatments; follow-up is defined as 7 ±3days after visit 4 for Part 1, for patients who did not 
enter into the open-label Part 2 extension. 
For Part 2, treatment is defined as first dosing date in Part 2 until the end of study or early 
termination (ET) for Part 2; follow-up is defined as 7 ±3days after visit 10.
9.4 Double-blind Period vs. Open-label Period
The double-blind period is defined as Part 1 of the study, from randomization to visit 4 or 
early termination before visit 4. For those who do not participate in Part 2 of the study (open-
label), it also includes the follow-up period, which is 7 ±3days after visit 4.
Open-label period is defined as Part 2 of the study, from enrollment in Part 2 (open-label) to 
the end of Part 2 study or ET from Part 2. It also includes the follow-up period, which is
7 ±3days after visit 10.


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Sponsor: Lupin Inc.
Protocol no: TB-DPI-301
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9.5 Treatment Emergent Adverse Event (TEAE)
AEs will be summarized separately for TEAEs and Non-TEAEs.
Non-TEAEs are AEs observed after signing ICF until the initiation of the dose of the first 
experimental treatment.
A TEAE is defined as an event with an onset date/time on or after the initiation of the dose of 
the first experimental treatment after randomization or an event that is present at the initiation 
of the study medication and that subsequently increases in severity or frequency. AEs with a 
missing onset date and a stop date on or after 1st Dose Date or with a missing stop date, will 
be summarized as TEAEs.
9.6 Serious Adverse Event (SAE)
An SAE is defined as an AE that results in any of the following: 

death 

life-threatening

requires hospitalization or prolongs existing hospitalization 

results in persistent or significant disability or incapacity 

results in a congenital abnormality or birth defect 

an important medical event which requires medical intervention to prevent any of the 
above outcomes 
9.7 Spirometry (Part 1 Only)
FEV1
The spirometry endpoint data will be captured using standardized equipment supplied by a 
central spirometry vendor - ERT.
All visits to the investigational center for Part 1 must be scheduled in the mornings between 
0600 and 1000 and spirometry testing should begin at ±1 hour of the start of visit 1 study 
qualifying spirometry testing time. Predose FEV1 measurements will be recorded at 0 hours 
(-30 and -15 minutes before administration of study medication) at the investigational center 
at visits 1 through 4; serial FEV1 measurements will be recorded postdose at 5 and 30 
minutes, and at 1, 2, 4, 6, 8, 10, 12, 23, and 24 hours. 
The following windows are permitted: +5 minutes for predose measurements (-30 
and -15 minutes) and 5 minute postdose measurement; ±5 minutes for 0.5-6 hours, and ±15 
minutes for 8-24 hours.
Reversibility Testing 
For reversibility testing, patients will receive 68 mcg of ipratropium bromide inhalation 
pMDI as 4 actuations of 17 mcg/actuation (ex-mouthpiece); given at approximately 


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30 second intervals. If required, spacers are permitted for use during reversibility testing for 
ipratropium bromide administration. All actuations are to be completed within 3 minutes of 
the 1st actuation. The ATS/ERS criteria will be followed for spirometry measures. Patients 
who do not demonstrate a positive improvement of at least 15% in FEV1 measured at 30 or 
60 minutes (±5 minutes) post inhalation will not be eligible to participate in the study (except 
as permitted per the retest specified below). Reversibility values of 14.50-14.99 will be 
rounded to 15. Refer to the spirometry manual for additional information related to 
reversibility testing. Patients failing to meet the reversibility requirement will be permitted to 
retest once, based on Investigator judgment (for only those patients who would normally 
achieve this level of reversibility) no sooner than 24 hours and no later than 2 weeks after the 
initial failure.
FEV1 Stability Limits 
FEV1 stability limits will be calculated for each patient at the screening visit (visit 1) using 
the onsite spirometer and the randomization visit (visit 2), using both the home device and 
onsite spirometer. 
Screening Visit: 
The stability limit established at the screening visit will be used to determine alert criteria for 
worsening COPD during the screening and run-in periods. The FEV1 stability limit at the 
screening visit will be calculated as follows: 
Best pre-bronchodilator qualifying FEV1 measurement at the screening visit (visit 1)
using the onsite spirometer × 80%. 
Randomization Visit:
Two stability limits will be re-established at the randomization visit (visit 2) for use during 
the double-blind and open-label treatment periods using the following equations: 

Investigational Center Stability Limits (for use with onsite spirometer at the 
double-blind visits only): mean FEV1 of the predose pre-bronchodilator qualifying 
FEV1 measurements (-30 and -15 min) using the onsite spirometer × 80%

At Home Stability Limits (for use with the electronic flow meter [home device]): 
mean of the best predose FEV1 measurements on the last 3 days before randomization 
on the home device × 80%
If a patient falls below any of the above FEV1 stability limits, an alert will be triggered to the 
patient and investigational center personnel.
Note: If the reschedule icon on the site spirometer is chosen for the screening visit (visit 1) or 
visit 2, and therefore, visit 1 or visit 2 is performed again, the FEV1 stability limit will be 
updated accordingly.  If V1_RETEST on the site spirometer is performed, the stability limit 
will not be updated.


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9.8 Spirometry (Part 1 and 2) 
Patients enrolled in Part 1 and Part 2 of the study will be issued with an eDiary/electronic 
flow meter to assess their lung function (FEV1). FEV1 collection begins at the time of signing 
the ICF, and then continues throughout Part 1 and Part 2, per the randomization scheme.
For Part 1, FEV1 will be measured once daily: prior to dosing in the morning (if applicable) 
at approximately the same time each day. On days of the investigational center visits, 
spirometry will be performed using the equipment at the investigational center. 
For Part 2, FEV1 will be measured twice daily at home: upon awakening in the morning 
immediately prior to dosing with study medication and at 2 (+2) hours after study medication 
administration. Three (3) FEV1 measures should be taken at each time point; the highest 
effort will be used.
9.9 COPD Exacerbations (Part 1 and Part 2) 
A COPD exacerbation is defined as worsening of symptoms of COPD for at least 
2 consecutive days and classified as mild when patients do not require treatment with 
systemic corticosteroids and/or antibiotics; moderate when treatment with systemic 
corticosteroids and/or antibiotics are required; or severe when hospitalization or visit to the 
emergency care/acute care unit is required. A separate exacerbation is considered when an 
interval of clinical improvement of at least 7 days is observed. 
Any moderate or severe COPD exacerbation occurring during Part 1 will result in withdrawal.
COPD exacerbations will be documented separately from AEs on a COPD exacerbation log 
in the electronic case report form (eCRF), unless the exacerbation meets the definition of an 
SAE. In this instance, the exacerbation will be recorded on both the AE and COPD 
exacerbation pages of the eCRF. 
Collection of COPD exacerbations will begin at the time of consent and will continue 
through the final visits in Part 1 and Part 2 of the study. COPD exacerbations will be 
captured via patient interview during the onsite or telephone visits.
9.10 COPD Symptom Scores (Part 1 and Part 2)
During Part 1 (commencing at the time of consent) and Part 2 of the study, patients will 
assess and record their COPD symptoms scores once daily in the evening before bedtime 
using the EXACT. 
The EXACT is a 14-item daily diary designed to provide a direct measure of patient-reported 
symptoms of COPD exacerbation. The EXACT Total score is computed across the 14 items 
and has a theoretical range of 0 to 100, with higher values indicating a more severe condition. 
The total score is used in the determination of exacerbation frequency, severity, and duration 
of exacerbation. 


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All 14 items of the EXACT are to be completed by the patient each evening prior to bedtime, 
reflecting back on their experiences “today.”
The ER-S: COPD is a derivative instrument of the EXACT designed to address the need for 
standardized daily diary to assess respiratory symptoms in patients with COPD.
The ER-S: COPD is comprised of 11 respiratory symptom items contained in the 14-item 
EXACT. A daily Total score (RS-Total score) representing respiratory symptom severity, 
overall and 3 subscale scores (RS-Breathlessness, RS-Cough and Sputum, and RS-Chest 
Symptoms) can be computed from the E-RS. The daily RS-Total score is computed by 
summing the raw score assigned to each of the 11 items and has a theoretical range of 0 to 40, 
with higher values indicating more severe respiratory symptoms. The same simple 
summation procedure is used for obtaining the 3 daily domain scores of the E-RS: RS-
Breathlessness is the sum of items 7, 8, 9, 10, and 11 (score range 0-17); RS-Cough and 
Sputum is the sum of items 2, 3, 4 (score range 0-11); and RS-Chest Symptoms is the sum of 
items 1, 5, 6 (score range 0-12).
The ER-S: COPD (derived from the EXACT score) will be used to assess disease stability 
throughout the study. A baseline score will be obtained from the first available evening 
session after the signing the ICF for use during the screening and run-in periods and from the 
latest available evening session before the randomization visit (visit 2) for use during the 
double-blind and open-label treatment periods. If at any time, there is increase in the ERS-
COPD daily RS-Total score of ≥2 from baseline, the eDiary will alert the patient to notify the 
investigational center personnel to discuss the patient’s current health status. The Investigator 
will need to determine if the patient is able to continue participating in the study as per the
withdrawal criteria. 
9.11 Methods for Handling Dropouts and Missing Data
Missing efficacy data will be handled in the following ways:
For missing serial spirometry measurements:
Missing data methods will be used provided that at least 9 of the 11 post-dose serial 
spirometry measurements are available.  Linear interpolation between the 2 adjacent FEV1
measurements will be used to estimate missing spirometry measurements occurring between 
2 available measurements. The exception to this would be the unlikely event of missing 
measurements that occur near the peak of the FEV1 -time curve, expected to occur between 
30 min to 2 hours post dose. In these cases the average percentage change from the preceding 
value for patients receiving the same treatment will be used. This makes use of the response 
of other patients to the same treatment. For analysis, the percentage will be expressed in 
terms of an FEV1 value. 
For missing measurements at the end of the time profile (i.e., no available FEV1 value after a 
point in time): 

For values at the end of the profile that were missing because rescue medication was 
taken, the minimum observed FEV1 value on that test day, including the predose


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value, will be used as the estimate. This is similar to assuming that there would be no 
increase from baseline after the point that rescue medication was required. 

For values at the end of the profile that were missing for reasons unrelated to the 
patient’s response to treatment, the average percentage change from the preceding 
values for patients receiving the same treatment will be used. This makes use of the 
response of other patients to the same treatment. For analysis, the percentage will be 
expressed in terms of an FEV1 value. 

For values at the end of the profile that were missing for unknown reasons, the 
observed minimum FEV1 value on the day of testing, including the pre-dose value, 
will be used as an estimate. This conservatively assumes that there would be no 
increase from baseline after the point that the data were missing. 
Two additional sensitivity analyses will be performed, where the missing data rules for the 
tail end of the profile will be based on the following: (a) the AUC calculation will be based 
on the time interval up to the last non-missing time point, and will then be standardized by 
dividing by the length of time for which FEV 1 measurements were included (ie. the AUC 
will be a weighted average), and (b) the baseline value will be substituted for the missing 
values.
If a patient contributes data to at least 2 of the crossover legs, data from that patient will be 
included in the analysis as the patient will have provided data for one of the treatment 
comparisons. If a patient completes only 1 leg of the crossov er, data from the patient will be 
listed but will not be included in summary statistics or the analysis. There is no reasonable 
basis for imputing data for a completely missing leg of the crossover.
Analysis Population
10.1 Intention-to-Treat
The ITT analysis population will adhere as closely as practically possible to the intention -to-
treat (ITT) ideal, and will be based on data from all patients who were randomized, took at 
least one dose of study medication and contributed sufficient data for at least one ef ficacy 
endpoint to be calculated. The ITT analysis population will be the primary analysis 
population used for the demonstration of the superiority of the active treatments to placebo. 
In this population, treatment will be assigned based upon the treatment to which patients 
were randomized regardless of which treatment they actually received.
10.2 Per Protocol
The Per Protocol (PP) analysis population will be the primary analysis population used for 
the determination of BE between the Test and Reference products.  The PP analysis 
population will exclude patients from the ITT population who have major protocol deviations 
in Part 1 of the study on either the Test treatment day or the Reference treatment day. 
Patients may have a major protocol deviation on the Placebo treatment day and still be 


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included in the Per Protocol population that will be used to asses BE although data from the 
Placebo day will be excluded from the analysis.
All patients with a major protocol deviation will be identified before the study blind is 
broken, and the removal of a patient from a treatment period will be documented within the 
clinical trial management system’s protocol deviation file. In addition, individual FEV1 
values from a patient may be removed from their 24-hour serial curve, including the 
2 predose measurements, if they were the result of poor quality spirometry efforts.  In those 
cases, the value will be set to missing and missing value rules applied as described in Section 
9.11.
10.3 Safety
The safety analysis population will include all patients who receive at least one dose of any 
one of the randomized investigational products and for whom data have been collected after 
randomization.
10.4 Part 2 of the Study
All patients who begin treatment during the open-label portion of the study.
10.5 All Subjects
All patients who sign consent form for the study.
10.6 All Randomized Subjects
All patients who are randomized in the study.
Interim Analysis
11.1 Objective of the Interim Analysis
A blinded interim look at the data will be made in order to check the assumption about intra-
patient variability made when estimating sample size with the possibility of increasing 
sample size, if necessary, to maintain 90% power. The interim look is planned when 150 of 
the planned 240 randomized patients have completed Part 1 of the study. Issues impacting 
the choice of a final sample size will include the estimate of intra-patient variability and the 
estimate of the ratio of the means demonstrated in the pivotal PK study. The interim analysis 
will be conducted by PRA Health Sciences.
11.2 Endpoint for the Interim Analysis
The endpoint for the interim analysis is the baseline-adjusted FEV1 AUC0-24h on the single-
dose treatment days.
11.3 Interim Analysis Population
The PP population will be used for the interim analysis.  Patients who have major protocol 
deviations will be excluded from the interim analysis population.


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11.4 Sample Size Re-calculation for the Interim Analysis
The original sample size estimate is based on an assumed intra-patient variability to which 
sample size estimates are very sensitive. From a review of studies on clinicaltrials.gov, there 
were a number of estimates available of between-patient variability for baseline-adjusted 
FEV1 AUC0-24. From the 12 studies reviewed, the mean CV for the variable was 121%. 
Within-patient variability is generally much less than between-patient variability. As a 
starting point for the sample size estimation it was assumed that the within-patient variability
would be about 50% of the between-patient variability, or a CV of 60%. A blinded interim 
review of the data is planned to assess if this reduction is obtained. The missing data 
methods outlined in section 9.11 will be applied for the interim analysis, with the following 
exceptions: (1) no imputation would be performed during peak times, and (2) missing data at 
the tail-end of the spirometry profile would use Last Observation Carried Forward (LOCF) 
methods.
11.4.1 Intra-patient CV Estimation
In order to perform the interim sample size re-estimation (by nQuery7), the between-subject 
CV and the intra-subject CV need to be estimated using the interim data:

Between-subject CV (CVB)= σB / μR

Intra-subject CV (CVI)= σI / μR
Where σB is between-subject variance, σI is intra-subject variance and μR is the Least Square 
Mean (LSMean) of the reference (SPIRIVA) treatment.  
To get estimates for σB, σI and μR, a mixed model can be used with a fixed effect for period 
and a random effect for patient using the PP population.  The typical crossover model fixed 
effects for treatment and sequence are not included because the treatment codes are to remain 
blinded.
The SAS procedure to be used is:
proc mixed data=interim; 
   
   class usubjid period;
   
   model Baseline-adjusted FEV1 AUC0-24h = period/ solution;
   
   random usubjid;
            run;
where 

usubjid = patient

period = treatment period


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In the SAS output, the covariance (COV) estimate of σB will be called “Usubjid” and σI will 
be called “Residual”. Normally we estimate μR as the LSMean for the reference (SPIRIVA) 
treatment, however, since this is a blinded estimation, we could instead use the estimate of 
CVB from the Protocol as: μR = σB / 1.21. Then, we use that estimate of μR to estimate CVI
= σI / μR.
One downside of this approach is that it includes placebo which will almost surely inflate the 
intra-subject variance (and hence CVI). The effect could be dramatic if the two active 
treatments are efficacious (i.e., much different from placebo). It should not affect between-
subject variance.
To address this concern, 2 methods will be used to estimate the intra-subject variability and 
CV:

Use the subject’s AUC values from all 3 treatments to estimate the intra-subject CV. 
This method will provide a liberal (i.e., likely too large) sample size estimate since 
the placebo data will increase the intra-subject CV.

Only use the data from the two “closest” AUC values from each subject’s data to 
estimate the intra-subject CV. This approach mimics the inclusion of only the two 
active treatments in the sample size re-estimation (i.e., akin to excluding placebo).
This method will produce a conservative (ie, likely too small) sample size estimate.
A decision on the sample size re-estimation will be made based on the results from the above 
2 methods.
11.4.2 Sample Size Re-calculation
Once intra-patient CV is identified, sample size re-calculation will be performed using 
nQuery 7.0 with the following parameters:

Power = 90%

Expected ratio = 0.88 to 1.12

Lower equivalence limit = 0.8

Upper equivalence limit = 1.25

Test significance level alpha (one-sided) = 0.05

CV between subjects = 1.21 (assumption from the protocol)

CV within subjects = new number calculated from the above mentioned 
model based on the actual interim data
The results of the 2 new sample size estimates (one based on data from all treatments and the 
other based on the 2 “closest” data values) will be available after using the above parameters. 
The estimate of the ratio of the means demonstrated in the pivotal PK study will help inform
which expected ratio will be used in the final sample size chosen.


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11.5 Results of the Interim Analysis
The final interim analysis report was dated 01Sep2017, and is attached in Appendix 3.
A total of 122 (of the 150) patients had 3 treatment periods with evaluable AUC data, and 
these data were included in the “closest” AUC analysis. Based on the results, the intra-patient 
CV was 0.3642 and the between-patient CV was 1.210.  The table below summarizes the 
crossover design of two one-sided tests (TOST) for difference or ratio of means:
Closest AUC (N=122)
Protocol
Low ratio
Ratio=1
High ratio
  Test significance levels, α (one-sided)
0.050
0.050
0.050
0.050
      Lower equivalence limit for µT / µR, DL
0.800
0.800
0.800
0.800
      Upper equivalence limit for µT / µR, DU
1.250
1.250
1.250
1.250
  Expected ratio, µT / µR
1.000
0.880
1.000
1.120
  Coefficient of variation between subjects, CVB
1.210
1.210
1.210
1.210
  Coefficient of variation, intrasubject, CVi
0.600
0.3642
0.3642
0.3642
  Power ( % )
90
90
90
90
  n total
178
372
78
220
Results obtained from nQuery Advisor® 7.0
Based on the results, sample size estimates range from:
a total of 372 across the six treatment sequences if the expected ratio of test to 
reference is 0.88 
a total of 220 patients across the six treatment sequences if the expected ratio of test 
to reference is 1.12
Assuming an expected ratio of means of 0.90 based on results from the pivotal PK study, an 
estimated 238 per-protocol patients would be needed to demonstrate equivalence between the 
test and reference products.  Therefore, the Sponsor plans to randomize a total of 
approximately 378 patients (instead of 240 patients specified in the protocol with 
Amendment 1, dated 11May2017), to allow for a potential 30% withdrawal rate or loss from 
the per-protocol population due to protocol deviations.   
Data Review
Final data for analysis should always be cleaned prior to receipt by Clinical Programming. 
The purpose of this section is to indicate the history of the data and the process used to 
ensure that the data are acceptable for statistical analysis prior to database lock.
12.1 Data Handling and Transfer
PRA prepares and delivers electronic media to each site of their respective subjects’ eCRFs 
and a complete set of subject eCRFs are delivered to each site and Lupin Inc.
The data in the following table will be provided by third-party vendors:
Data Type
Vendor
Central Lab
Eurofins


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Central Spirometry
ERT
ECG
ERT
eDiary
ERT
Randomization
YPrime
All of the study data will be provided in SAS® dataset format (SAS version 9.4 or later) and 
converted to Study Data Tabulation Model (SDTM) version 1.4 using the Study Data 
Tabulation Model Implementation Guide (SDTMIG) Version 3.1.4.  
12.2 Data Screening
Review of 2 pre-freeze TFL dry runs allow for further data screening prior to lock. The pre-
freeze TFL will be discussed with the sponsor in a data review meeting to identify any final 
data issues and seek corrections prior to database lock. The PRA biostatistician and the 
sponsor must approve database lock.
Statistical Methods
The statistical analyses will be reported using summary tables, figures, and data listings.  The 
summary tables will be presented separately for Part 1 and Part 2 of the study. All analyses 
will use SAS version 9.4 or higher.
Continuous variables will be summarized using the number of observations (n), mean, 
standard deviation (std), median, minimum, and maximum values.  
Unless otherwise noted, categorical variables will be summarized by counts and percentages 
of patients in corresponding categories.  Percentages will be rounded to one decimal place 
except for 100%, which will be displayed without any decimal places, and zero counts, for 
which the percentage will be displayed as zero percent.   
Raw data obtained from eCRFs and transferred from third-part vendors and derived data will 
be included in data listings.  
13.1 Subject Disposition
The number and percentage of patients with informed consent, screened, screen failure, 
randomization failure, randomized/enrolled, and analysis population will be presented, 
together with the number and percentage of patients who withdraw from the study 
prematurely and are excluded from a particular analysis population, and a breakdown of the 
corresponding reasons.  
A tabulation of the number and percentage of patients randomized/enrolled at each center 
will also be presented.
13.2 Protocol Deviations
The study team and the sponsor will conduct on-going reviews of the deviation data 
throughout the study. The PP population must be identified prior to database lock.


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Protocol deviation data will be categorized into one of the following categories:

01-Inclusion/Exclusion/Randomization Criteria

02-Continuation Criteria

03-Spirometry Evaluation

04-Study Procedures

05-Study Drug

06-Out of Window Visits

07-Informed Consent

08-Prohibited / Restricted Medications

09-Other

10-Diary

11-ICH/GCP
Each deviation will be further classified as major/minor as defined in the protocol deviation 
guidelines.  A summary of the number of patients with major deviations will be presented by 
category and treatment for Part 1 and Part 2 of the study separately.  All protocol deviation 
data will be listed.
13.3 Treatments
13.3.1 Extent of Study Drug Exposure
Summary statistics for study drug exposure for Part 1 include:

Patients exposed to one or more treatments (1, 2 or 3)

Patients exposed to a 
specific treatment
(Lupin 
Tiotropium, 
SPIRIVA 
HANDIHALER or Placebo)
Summary statistics for study drug exposure for Part 2 include:

Days of exposure
13.3.2 Prior and Concomitant Medications
A prior medication is defined as any medication started and stopped prior to the first 
randomized dose.
A concomitant medication is defined as any medication taken on or after the first randomized 
dose regardless of start day.
All medications will be coded using the WHO Drug Dictionary (version of September 2016), 
and Anatomical Therapeutic Chemical (ATC) classification system.
Prior and concomitant medications will be summarized by ATC classification for Part 1 and 
only concomitant medications will be summarized for Part 2.  All prior and concomitant 
medications will be listed.


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13.4 Demographic and Baseline Characteristics
Patient demographic and baseline characteristics will be summarized by treatment for the 
safety population, ITT population, PP population, and Part 2 of the study respectively and 
will include summary statistics for sex, age, age group (40 to <65, 65 to <75, ≥ 75), race, 
ethnicity, baseline height (cm), baseline weight (kg) and tobacco usage.
13.5 Medical History
Medical history will be summarized for Part 1 only. All medical history will be listed. 
13.6 Efficacy Analyses
13.6.1 Primary Variable
The primary variable is the baseline-adjusted FEV1 AUC0 -24h on the single-dose treatment 
days. Baseline is defined as the average of the FEV1 values recorded at approximately 
30 minutes and 15 minutes before dosing with study medication. 
This crossover study will follow a Williams design with 6 treatment sequences balanced for 
first order carryover effects (see Table 1).
A repeated measures crossover model consisting of effects of treatment, period, and sequence 
will be carried out.
The SAS code for the model is as follows:
       proc mixed data= final; 
         class usubjid period treatment sequence;
         model Baseline-adjusted FEV1 AUC0-24h = treatment period sequence / 
solution ddfm=SAT;
         repeated period /type = un subject = usubjid;
   
  lsmeans treatment / alpha=0.05 cl diff;  
       run;
where 

usubjid = patient

period = treatment period

sequence = treatment sequence
13.6.2 Statistical Analysis for the Primary Variable
13.6.2.1 Establishing Superiority of Test (T) and Reference (R) to Placebo
The hypotheses planned to be tested for the Superiority analysis are:
           H01: μT = μP  vs. H11: μT ≠μP and
           H02: μR = μP  vs. H12: μR ≠μP


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where μT = mean of baseline adjust FEV1 AUC0-24 for the Test Group and
           μR= mean of baseline adjust FEV1 AUC0-24 for the Reference Group and
           μP= mean of baseline adjust FEV1 AUC0-24 for the Placebo Group
Study sensitivity will be demonstrated if the Reference (R) product is shown to be 
statistically superior to Placebo (P) (p <0.05 [two-tailed]). Efficacy of the Test product will 
be demonstrated if the Test (T) product is shown to be statistically superior to Placebo (P) (p 
<0.05 [two-tailed]). For these comparisons, the repeated measures model described in 
Section 13.6.1 will be applied to the ITT population.
13.6.2.2 Establishing Bioequivalence between Test (T) and Reference (R) products
The hypotheses planned to be tested for the BE analysis are:
             H0: μT / μR ≤ 0.8 or μT / μR ≥ 1.25
             H1: 0.8 < μT / μR < 1.25
where μT = mean of the baseline adjusted FEV1 AUC0-24 for Test Group, and
           μR= mean of the baseline adjusted FEV1 AUC0-24 for Reference Group
The analysis of the primary endpoint for BE will be the repeated measures analysis
(described in the section 13.6.1) performed on the PP Analysis Set which will include all 
patients in the ITT population except those who had major protocol deviations. 
The extension of Fieller’s theorem to a 3-way crossover will be used as the primary method 
to assess the bioequivalence of the Test (T) and Reference (R) products.  An analysis that 
applies Fieller’s theorem only to the data of the Test (T) and Reference (R) products (i.e. 
ignoring data from the placebo treatment) will also be performed as a secondary method of 
analysis.
We use Fieller’s theorem to create a 100(1-2α)% CI for θ= μT / μR. The CI (θ1 , θ2) will 
include all values of θ for which the above null hypotheses are rejected.
Fieller’s theorem considers the quantity G= YT – θ*YR, in which YT and YR are unbiased 
estimates of μT and μR. Note that E(G)=0. We want to find all values of the parameter θ that 
do not reject H0: G=0 versus H1: G≠0.
To do this computationally, we fit the crossover model to obtain the estimated means YT and 
YR (i.e., the estimated LSMeans). For this study, there are 6 treatment sequences with 3 
periods, which gives the following LSMeans for μT and μR, respectively:
LSmean (Test) = μ + τT + 1/3(π1 + π2+ π3) + 1/6*(δ1+δ2+δ3+δ4+δ5+δ6)           (1)
LSmean (Reference) = μ + τR + 1/3(π1 + π2+ π3) + 1/6*(δ1+δ2+δ3+δ4+δ5+δ6),           (2)


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where μ is the intercept, the τ’s are the treatment effects, the π’s are the period effects, and 
the δ’s are the sequence effects from the mixed model. The placebo data are included in the 
analysis but the placebo treatment effect, τP, is not needed in the bioequivalence assessment.
Writing G with equations (1) and (2):
G =  (τT – θ* τR) + (1 – θ) [μ + 1/3(π1 +π2+ π3) + 1/6(δ1 +...+ δ6)],    (3)
We use various values of θ to test H0: G=0, and the 100(1-2α)% C.I. (θ1, θ2) is defined as 
largest/smallest values which do not reject the two α-level tests for H0 above (Note: This is 
equivalent to a two one-sided tests procedure). The construction of the estimate statements 
in PROC MIXED will be based on equation (3), and will include data for all sequences, 
treatments and periods (i.e., placebo data will not be deleted).  A sample SAS code for this 
mixed model is shown below, where the estimate statements are used to obtain the 90% 
confidence limits:
proc mixed data=<<dataset>>;
class usubjid treatment period sequence;
model auc0_24 = treatment period sequence / DDFM=SAT solution;   
repeated period /type = un subject = usubjid;   
*** Sample estimate statements ***;  
estimate ' 0.720' intercept  0.280 treatment  0  -0.72  1
                  
period 0.0933 0.0933 0.0933
sequence 0.0467 0.0467 0.0467 0.0467 0.0467 0.0467 /alpha=0.05 upper;
estimate ' 0.721' intercept  0.279 treatment  0 -0.721  1
period  0.093  0.093  0.093
sequence 0.0465 0.0465 0.0465 0.0465 0.0465 0.0465 /alpha=0.05 upper;
estimate ' 0.722' intercept  0.278 treatment  0 -0.722  1
period 0.0927 0.0927 0.0927
sequence 0.0463 0.0463 0.0463 0.0463 0.0463 0.0463/alpha=0.05 upper;
... 
estimate ' 1.369' intercept -0.369 treatment  0 -1.369  1
period -0.123 -0.123 -0.123
sequence -0.061 -0.061 -0.061 -0.061 -0.061 -0.061/alpha=0.05 lower;
estimate ' 1.370' intercept -0.370 treatment  0  -1.37  1
period -0.123 -0.123 -0.123
sequence -0.062 -0.062 -0.062 -0.062 -0.062 -0.062/alpha=0.05 lower;
*** end of sample estimate statements ***;  
lsmeans treatment / alpha=0.05 cl diff cov;   
run;
The Satterthwaite (DDFM=SAT) option provides the usual within-subject error degrees of 
freedom (DF) in the case of no missing data, and provides an adjustment to the error DF in 
the case of missing data.  In either case, the error degrees of freedom will be quite large given 
the sample size of this trial so that the test statistic will have a near normal distribution.
Bioequivalence (BE) will be declared if the estimated 90% CI, (θ1, θ2) is entirely contained 
within the required BE limits of 0.80 to 1.25.
In addition to the 3-treatment effect model above, a separate analysis will be done using a 2-
treatment approach, where Placebo (P) will be removed from the data.  The construction of 


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the 90% C.I. (θ1, θ2) will use the same approach as defined above, with only the 2 active 
treatments needed in the estimate statement.
The above approach is equivalent to a closed form solution created by Fieller’s theorem 
which only requires the Test (T) and Reference (R) LSMean estimates and their 
variances/covariances, and the critical value of the test statistic (T-test or Z-test).
13.6.2.3 Time to Maximum Bronchodilator Response
The time to maximum bronchodilator response (tmax) is defined as the time post-dosing of the 
maximum FEV1 value for a patient.  This will be summarized using descriptive statistics by 
treatment and sequence.
13.6.3 Subgroup Analyses
No subgroup analyses are planned for this study.
13.6.4 Multiplicity
In this clinical trial, the comparisons of interest are: 
1. The superiority comparison between Lupin Tiotropium Bromide Inhalation 
Powder, 18 mcg (T) and Placebo (P) 
2. The superiority comparison between SPIRIVA HANDIHALER, 18 mcg (R) and 
Placebo (P) 
3. The bioequivalence comparison between Lupin Tiotropium Bromide Inhalation 
Powder, 18 mcg (T) and SPIRIVA HANDIHALER, 18 mcg (R) 
As all 3 of these comparisons must be successfully achieved in order to demonstrate BE, no 
adjustment for multiplicity is required. The order of testing will be according to the list above.
13.6.5 Pooling of Sites
Pooling of sites is not planned for this study.
13.7 Safety Analyses
Safety analyses will be summarized by treatment for the safety population as defined in
Section 10.3 for Part 1 and Part 2 separately. Summary statistics (number of subjects, mean, 
standard deviation, median, minimum, and maximum) will be included for continuous 
variables. Summarizations of categorical variables will be presented in tabular form (number 
of subjects and percentages). Safety of drug regimen will be assessed for adverse events, 
serious adverse events (SAEs), COPD exacerbations, vital signs, physical examinations, 
HEENT and chest examinations, ECG recordings, SABA (albuterol/salbutamol MDI) and 
concomitant medication use. 
Listings of all safety measurements will be provided.


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13.7.1 Adverse Events
The adverse event (AE) data will be summarized separately for Part 1 and Part 2 of the study
by treatment and total.
Summaries of treatment-emergent adverse events (TEAEs), including the number and 
percentage of events reported, the number and percentage of patients reporting at least one 
AE, at least one severe AE, at least one treatment-related AE, at least one SAE, at least one 
treatment-related SAE, at least one non-SAE, at least one AE leading to withdrawal, and at 
least one AE resulting in death will be presented by treatment. Treatment-emergent adverse 
events are those which first occur or increase in severity or relationship to study drug after 
the first dose of study drug after randomization. 
A breakdown of the number and percentage of patients reporting each adverse event, 
categorized by System Organ Class (SOC) and Preferred Term (PT) according to MedDRA 
20.0, will be presented by treatment. Note that counting will be by patient not event and 
patients are only counted once within each SOC or PT.
A further tabulation of these data, categorized by relationship to study drug, will be presented. 
Relationship to study drug is categorized as Related/Not Related as recorded on the CRF.
A summary of events reported, categorized by severity (Mild, Moderate and Severe), will 
also be provided. Patients with multiple events within a particular body system or preferred 
term will be counted under the category of their most severe event within that SOC or PT.
A summary of SAEs, AEs leading to discontinuation and AEs leading to death will be 
provided by treatment, study part and total, grouped by SOC and PT.
Adverse events (AEs) that occur before randomization will be summarized separately and 
will be listed. Those patients will not be part of the safety population. 
All adverse events (including non-treatment-emergent events) recorded on the CRF will be 
listed.
13.7.1.1 AE Summary for Part 1 of the Study
In Part 1, the blinded, single dose crossover part of the study, AEs will be tabulated by the 
following periods: 
•
The double-blinded study treatment period (Lupin Tiotropium Inhalation 
Powder, SPIRIVA HANDIHALER and Placebo)
•
during washout 
•
during follow-up 
Adverse events (AEs) occurring after a study treatment during a treatment day and the day 
immediately after the treatment will be assigned to the relevant study treatment group. AEs 
occurring between the treatment days will be assigned to the washout period.
13.7.1.2 AE Summary for Part 2 of the Study
Adverse events (AEs) will be tabulated separately for Part 2 of the study by the following periods: 


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•
The open-label study treatment period, which starts after the first dose of Part 2
•
During follow-up 
13.7.2 Laboratory Data
Standard clinical laboratory tests
including hematology, chemistry, urinalysis and 
immunochemistry (serum pregnancy) will be performed as indicated in Table 2 Schedule of 
Eventsusing a central laboratory as indicated in the study procedures manual.
All laboratory data (including re-tests) provided by the central laboratory will be listed.
13.7.3 Vital Signs
Vital signs, including blood pressure, heart rate, respiratory rate and body temperature, will 
be collected at the screening visit (visit 1) and all subsequent investigational center visits. 
Descriptive statistics for vital signs at screening and at treatment visits (visits 2 through 4 or 
ET for Part 1 and visits 7, 9, and 10 or ET for Part 2) will be provided. 
For Part 1, the double-blind period, summary statistics will be provided by treatment. 
Summary statistics will be provided separately for Part 2, the open label extension. 
13.7.4 Physical Examinations
For Part 1, physical examination findings at screening (visit 1) and visit 4 or ET will be 
summarized for any clinically significant findings. Significant changes from screening 
(visit 1) to the end of the double-blind period will be summarized. Changes from screening 
(visit 1) to the end of the double-blind period will be presented in 3 by 3 shift tables, where 
the responses are normal, abnormal but clinically non-significant, or abnormal and clinically 
significant. Each examination area, eg, skin, abdominal, will have a separate table. Some 
patients may require 2 PEs before treatment starts. If they do, the first one is the 
prescreening value and the one at visit 1 is the screening value. Prescreening results will be
listed only.
For Part 2 of the study (open-label extension), findings at visit 10 or ET will be summarized 
for any clinically significant findings and significant changes from screening (visit 1) to the 
end of the open-label extension using the 3 by 3 shift tables described above.
13.7.5 HEENT, Chest Examination, and Electrocardiograms (ECG) 
For Part 1, during the double-blind period, abbreviated physical examination findings 
(HEENT and chest examinations) will be summarized for any clinically significant findings 
and significant changes from Visit 2.  ECG results will be summarized by visit, and changes 
in overall clinical interpretation will be summarized.
For Part 2 of the study (open label extension), findings will be summarized for any clinically 
significant findings and significant changes from Visit 2. 


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HEENT and chest examination findings will be summarized by four 3 by 3 shift tables where 
the shift is from visit 2 to each of the 4 visits during treatment, 2 visits in Part 1 and 2 visits 
in Part 2.
Electrocardiography (ECG) findings will be summarized by four 3 by 3 shift tables where the 
shift is from screening (visit 1) to each of the 4 visits during treatment, 2 visits in Part 1 and 2
visits in Part 2.
13.7.6 COPD Exacerbations
COPD exacerbations will be summarized and/or listed separately for Part 1 and Part 2 of the 
study.
13.7.7 Safety Spirometry
Patients will be issued an eDiary/electronic flow meter to measure FEV1 for monitoring 
disease stability. 
For Part 1, FEV1 will be measured once daily: prior to dosing in the morning at 
approximately the same time each day. 
For Part 2, FEV1 will be measured twice daily at home: upon awakening in the morning 
immediately prior to dosing with study medication and at 2 (+2) hours after study medication 
administration. 
Values for each patient will be listed.
13.7.8 EXACT/ER-S Scores
EXACT scores will be recorded in the patient’s eDiary once daily each evening before 
bedtime. Values of the ER-S COPD for each patient will be listed.
13.7.9 Albuterol/Salbutamol Usage
Albuterol/Salbutamol usage will be summarized and/or listed by treatment and study period.
13.7.10 Urine/Serum Pregnancy Test
Urine/Serum pregnancy test results will be listed.
13.7.11 Urine Drug Screen
Urine drug screen results will be listed.
In addition, drug accountability, smoking restriction, DPI training and In-Check training will 
also be listed. 


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13.7.12 Inhaler Robustness (Part 1 and Part 2)
13.7.12.1 Ruggedness of LUPINHALER during In-Patient Use
Patients will be instructed to report any problems that they experience with their 
LUPINHALER during the open-label extension. The number and percentage of patients who 
reported at least one issue with the LUPINHALER will be provided separately for Part 1 and 
Part 2. 
Additionally, a summary of the individual issues will be provided. The summary will 
describe the issue in the detail provided by the patient. These will also be summarized 
according to the following categories: 

Misuse (impact, moisture, other) and

Issues identified (hard to open cover/mouthpiece, hard to insert capsule, hard to 
pierce capsule, capsule not rattling with inhalation, hard to remove capsule, hard to 
close mouthpiece/cover, COPD worsening/seems ineffective, other)
13.7.12.2 In Vitro Pharmaceutical Performance
In vitro pharmaceutical performance of 100 inhalers post 72 days of in-patient use will be 
assessed. The data resulting from the in vitro evaluation of the pharmaceutical performance 
will be presented in a separate report.
Validation
PRA's goal is to ensure that each TFL delivery is submitted to the highest level of quality. 
Our quality control procedures will be documented separately in the study specific quality 
control plan. 
References
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the 
diagnosis, management, and prevention of COPD. Updated 2016. http://www.goldcopd.org 
Barr RG, Bourbeau J, Camargo CA, Ram FS. Inhaled tiotropium for stable chronic 
obstructive pulmonary disease. Cochrane database of systematic reviews 2005:CD002876 
Cheyne L, Irvin-Sellers MJ, White J. Tiotropium versus ipratropium bromide for chronic 
obstructive pulmonary disease. Cochrane Database Syst Rev 2013 Sep 16;9:CD00955
Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 
2030. PLoS Med 2006;3:e442 
Van den Boom G, van Schayck CP, van Mollen MP, et al. Active detection of chronic 
obstructive pulmonary disease and asthma in the general population. Results and economic 
consequences of the DIMCA program. Am J Respir Crit Care Med 1998;158:1730-8.


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Protocol no: TB-DPI-301
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Appendix 1 Glossary of Abbreviations
Glossary of Abbreviations:
Abbreviation
Definition
AE
Adverse Event
ATC
Anatomic Therapeutic Classification
AUC0-24
Area Under The Curve From Time Zero To 24 Hours 
Post-dose
BE
Bioequivalence
BMI
Body Mass Index
CI
Confidence Interval 
CV
Coefficient Of Variation 
COPD
Chronic Obstructive Pulmonary Disease
CRF
Case Report Form
DPI
Dry Powder Inhaler
ECG
Electrocardiogram
ER-S
Evaluating Respiratory Symptoms
ET
End Of Treatment
EXACT
Exacerbations Of Chronic Pulmonary Disease Tool
FEV1 
Forced Expiratory Volume In The First Second
GCP
Good Clinical Practice
HEENT
Head, Ears, Eyes, Nose, And Throat
ICH
International Conference On Harmonization
ICS
Inhaled Corticosteroid
ID
Identification
IRT
Interactive Response Technology 
ITT
Intention-To-Treat
LABA
Long-Acting Beta Agonist
LAMA
Long-Acting Anti-Muscarinic Agent
MDI
Metered Dose Inhaler 
MedDRA
Medical Dictionary For Regulatory Activities
P
Placebo
PDV
Protocol Deviation
PK
Pharmacokinetic
PP
Per Protocol


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PRO
Patient Reported Outcome 
PT
Preferred Term
R
Reference
SABA
Short-Acting Bronchodilator 
SAMA
Short-Acting Anti-Muscarinic Agent
SAP
Statistical Analysis Plan
SAE
Serious Adverse Event
SDTM
Study Data Tabulation Model 
SDTMIG
Study Data Tabulation Model Implementation Guide
SI
International System 
SOC
System Organ Class 
T
Test
TEAE
Treatment Emergent Adverse Event 
WHO
World Health Organization


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Appendix 2: EXACT DAILY DIARY
Instructions: Please complete your diary every evening, just before you go to bed. As you 
answer the following questions, please select the option that best describes your 
experience.
The eDiary will be programmed to display your ER-S: COPD daily respiratory symptoms 
(RS) Total score. A baseline score will be obtained from the first available evening 
session after the screening visit (visit 1) for use during the screening an d run-in periods 
and from the latest available evening session before the randomization visit (visit 2) for 
use during the double-blind and open-label treatment periods.  If at any time, there is 
increase in the daily RS Total score of ≥2 from baseline, the eDiary will alert you to notify 
investigational center personnel to discuss your current health status.
1. Did your chest feel congested
today?
Not at all
Slightly
Moderately
Severely
Extremely
2. How often did you cough today?
Not at all
Rarely
Occasionally
Frequently
Almost constantly
3. How much mucus (phlegm) did
you bring up when coughing today?
None at all
A little
Some
A great deal
A very great deal
4. How difficult was it to bring up
mucus (phlegm) today?
Not at all
Slightly
Moderately
Quite a bit
Extremely
5. Did you have chest discomfort
today?
Not at all
Slight
Moderate
Severe
Extreme
6. Did your chest feel tight today?
Not at all


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Slightly
Moderately
Severely
Extremely
7. Were you breathless today?
Not at all
Slightly
Moderately
Severely
Extremely
8. Describe how breathless you
were today:
Unaware of breathlessness
Breathless during strenuous activity
Breathless during light activity
Breathless when washing or dressing
Present when resting
9. Were you short of breath today
when performing your usual
personal care activities like washing
or dressing?
Not at all
Slightly
Moderately
Severely
Extremely
Too breathless to do these
10. Were you short of breath today
when performing your usual indoor
activities like cleaning or household
work?
Not at all
Slightly
Moderately
Severely
Extremely
Too breathless to do these
11. Were you short of breath today
when performing your usual
activities outside the home such as
yard work or errands?
Not at all
Slightly
Moderately
Severely
Extremely
Too breathless to do these
12. Were you tired or weak today?
Not at all
Slightly
Moderately
Severely


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Extremely
13. Last night, was your sleep
disturbed?
Not at all
Slightly
Moderately
Severely
Extremely
14. How scared or worried were you
about your lung problems today?
Not at all
Slightly
Moderately
Severely
Extremely
Copyright
EXACT© 2013, Evidera, Inc. All rights reserved. 
EXACT version 1.1-English (universal) 9/9/2009
*The EXACT instrument and scoring program are owned by Evidera. The questions
listed above may be displayed in another format as per the formal licensing agreement
with the eDiary vendor.