Clinical trial NCT03256695
Conditions: Chronic Obstructive Pulmonary Disease
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Start date: 2017-09-28; Completion date: 2018-04-17
Enrollment: 405 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 3B, 12-week, multicenter, open-label study to evaluate the relationship between as-needed usage of albuterol eMDPI and Clinical Exacerbation-Chronic Obstructive Pulmonary Disease (CE-COPD) in adult participants at least 40 years of age with exacerbation-prone COPD.

Detailed description:

Arms: arm 1: Participants will receive 90 micrograms (mcg) of albuterol sulfate (ABS) via eMDPI (sitting on the upper part of the device for the purposes of detecting and storing usage information), 1 to 2 inhalations every 4 hours, as needed for 12 weeks. ABS eMDPI is a rescue/reliever agent that includes an eModule on top of the approved PROAIR RESPICLICK® inhaler. Participants will be allowed to continue use of other COPD and non-COPD medications as advised by their physician without changes unless deemed necessary by their physician.
Interventions: intervention 1: Albuterol sulfate (ABS)
Intervention descriptions: intervention 1: ABS will be administered via eMDPI as per the dose and schedule specified in the arm.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
Clinical Study Protocol with Amendment 03 
 
 
A 12-Week, Open-Label Study to Evaluate the Relationship Between Use of Albuterol 
eMDPI, an Inhaled Short-Acting Beta Agonist “Rescue” Agent with an eModule, and 
Exacerbations in Patients (40 Years of Age or Older) with Chronic Obstructive Pulmonary 
Disease 
 
Study Number ABS-COPD-30065 
 
NCT03256695 
 
Protocol with Amendment 03 Approval Date: 26 June 2017  
 


 
Uncontrolled Study–COPD 
Clinical Study Protocol with Amendment 03 
Study ABS-COPD-30065 
1 
 
 
Clinical Study Protocol with Amendment 03 
Study Number ABS-COPD-30065 
A 12-Week, Open-Label Study to Evaluate the Relationship Between Use of Albuterol 
eMDPI, an Inhaled Short-Acting Beta Agonist “Rescue” Agent with an eModule, and 
Exacerbations in Patients (40 Years of Age or Older) with Chronic Obstructive Pulmonary 
Disease 
(Phase 3B) 
IND Number: 104532; NDA Number: N/A;  BLA Number: N/A;  EudraCT Number: N/A 
EMA Decision Number of Pediatric Investigation Plan: Not applicable 
Article 45 or 46 of 1901/2006 does not apply 
Protocol Approval Date: 24 August 2016 
Protocol with Amendment 01 Approval Date: 29 September 2016 
Protocol with Amendment 02 Approval Date: 21 March 2017 
Protocol with Amendment 03 Approval Date: 26 June 2017 
Sponsor 
Teva Branded Pharmaceutical 
Products R&D, Inc. 
41 Moores Road 
Frazer, Pennsylvania 19355 
United States of America 
 
Information regarding clinical laboratories and other departments and institutions is 
found in Appendix A. 
 
Confidentiality Statement 
This clinical study will be conducted in accordance with current Good Clinical Practice (GCP) as directed 
by the provisions of the International Council for Harmonisation (ICH); United States (US) Code of 
Federal Regulations (CFR), and European Union (EU) Directives (as applicable in the region of the 
study); national country legislation; and the sponsor’s Standard Operating Procedures (SOPs). 
 
This document contains confidential and proprietary information (including confidential commercial 
information pursuant to 21CFR§20.61) and is a confidential communication of Teva Branded 
Pharmaceutical Products R&D, Inc. The recipient agrees that no information contained herein may be 
published or disclosed without written approval from the sponsor. 
© 2017 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved. 


 
Uncontrolled Study–COPD 
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2 
AMENDMENT HISTORY 
The protocol for study ABS-COPD-30065 (original protocol dated 24 August 2016) has been 
amended and reissued as follows: 
Amendment 01 
29 September 2016 
no patients enrolled to date 
Amendment 02 
21 March 2017 
no patients enrolled to date 
Amendment 03 
26 June 2017 
no patients enrolled to date 
The Summary of Changes to the Protocol includes corresponding reason/justification for each 
change and is provided in Section 16.  


 
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Clinical Study Protocol with Amendment 03 
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3 
INVESTIGATOR AGREEMENT 
Original Protocol Dated 24 August 2016 
Clinical Study Protocol with Amendment 03, Dated 26 June 2017 
IND Number: 104532; NDA Number: N/A; BLA Number: N/A; EudraCT Number: N/A 
EMA Decision Number of Pediatric Investigation Plan: Not applicable  
Article 45 or 46 of 1901/2006 does not apply 
 
A 12-Week, Open-Label Study to Evaluate the Relationship Between Use of Albuterol 
eMDPI, an Inhaled Short-Acting Beta Agonist “Rescue” Agent with an eModule, and 
Exacerbations in Patients (40 Years of Age or Older) with Chronic Obstructive Pulmonary 
Disease 
 
Principal Investigator: __________________________________________ 
Title: _________________________________________________ 
Address of Investigational Center: __________________________________ 
 
__________________________________ 
 
__________________________________ 
Tel: ______________ 
I have read the protocol with Amendment 03 and agree that it contains all necessary details for 
carrying out this study. I am qualified by education, experience, and training to conduct this 
clinical research study. The signature below constitutes approval of this protocol and 
attachments, and provides assurance that this study will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and according to 
national or local legal and regulatory requirements and applicable regulations and guidelines. 
I will make available the protocol and all information on the investigational medicinal product 
(IMP) that were furnished to me by the sponsor to all physicians and other study personnel 
responsible to me who participate in this study and will discuss this material with them to ensure 
that they are fully informed regarding the IMP and the conduct of the study. I agree to keep 
records on all patient information, IMPs shipment and return forms, and all other information 
collected during the study, in accordance with national and local Good Clinical Practice (GCP) 
regulations. 
Principal Investigator 
 
Signature 
Date 


 
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SPONSOR PROTOCOL APPROVAL 
 


 
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5 
CLINICAL STUDY PROTOCOL SYNOPSIS 
Study ABS-COPD-30065 
Title of Study: A 12-Week, Open-Label Study to Evaluate the Relationship Between Use of 
Albuterol eMDPI, an Inhaled Short-Acting Beta Agonist “Rescue” Agent with an eModule, and 
Exacerbations in Patients (40 Years of Age or Older) with Chronic Obstructive Pulmonary 
Disease 
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. 
Investigational New Drug (IND) Number: 104532; 
New Drug Application (NDA) 
Number: Not applicable;  
Biological License Application (BLA) Number: Not applicable;
 
EudraCT Number: Not applicable 
EMA Decision Number of Pediatric Investigation Plan: Not applicable;  
Article 45 or 46 
of 1901/2006 does not apply. 
Name of Test Investigational Medicinal Product (IMP): Albuterol sulfate (ABS) multidose 
dry powder inhaler with an eModule (eMDPI) 
EudraVigilance (EV) code for the IMP, if applicable: Not applicable 
Type of the Study: Phase 3B 
Indication: Exacerbation-prone chronic obstructive pulmonary disease (COPD) 
Is This Study Conducted to Investigate the New Use of an Approved, Marketed Product? 
No 
Number of Investigational Centers Planned: Approximately 40 
Countries Planned: United States 
Planned Study Period: Approximately 9 months 
Number of Patients Planned (Total): Approximately 500 patients will be screened to achieve 
400 enrolled patients. A subset of patients (n=100) who agree to participate at specific 
investigational centers will wear an accelerometer on the wrist to measure sleep disruption index 
(SDI). A second subset of patients (n=100) who agree to participate at specific investigational 
centers will wear an accelerometer on the ankle to measure total daily steps (TDS).  
Study Population: The cohort will consist of patients 40 years of age or older with moderate or 
severe clinical exacerbation of COPD (CE-COPD; defined in Section 6.1.1 of the protocol) in the 
past 12 months.  
Objectives and Endpoints 
The objectives of this study are to explore the pattern and amount of albuterol use (as captured in 
the ABS eMDPI), alone or in combination with other study data, preceding a moderate or severe 
CE-COPD (as diagnosed by the investigators per the protocol). The hypothesis is that albuterol 
use will increase several days prior to a moderate or severe CE-COPD and can serve as a marker 
of COPD deterioration. 
The endpoints of the trial are the primary outcome measure (ie, CE-COPD) and the primary 
outcome predictor (ie, albuterol use) alone or in combination with secondary predictors (ie, other 


 
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6 
study data). These predictors of CE-COPD will be modeled to determine which patterns best 
predict the subsequent development of CE-COPD. 
For albuterol use, parameters of interest will include (1) the total number of inhalations in the 
days preceding the peak of a CE-COPD, (2) the number of days prior to the peak of a CE-COPD 
when albuterol use increased, and (3) the number of albuterol uses in the 24 hours preceding a 
CE-COPD. Therefore, endpoints are not designated as either primary or secondary.  
In addition to albuterol use, inspiratory flow values (maximal inhalational flow [MIF], 
inhalational volume, inhalation duration, and time to MIF), SDI, TDS, and baseline information 
regarding disease state and demographics will be studied. These data will be analyzed using both 
a univariate and multivariate approach, to determine which patterns best predict the subsequent 
development of a CE-COPD. Inspiratory flow values are obtained from the eMDPI, SDI is 
obtained for a subset of patients who agree to participate at specific investigational centers 
(n=100) from an accelerometer worn on the wrist, and TDS is obtained for a subset of patients 
who agree to participate at specific investigational centers (n=100) from an accelerometer worn 
on the ankle. Baseline disease state and demographic information will be obtained at screening. 
An additional objective for this study is to evaluate the safety of ABS eMDPI use in patients 
with exacerbation-prone COPD. 
The safety endpoints for this study include the following: 
• adverse event data  
• physical examinations 
General Design: This is a 12-week, multicenter, open-label study to evaluate the relationship 
between as-needed usage of ABS eMDPI and CE-COPD in adult patients at least 40 years of age 
with exacerbation-prone COPD. ABS eMDPI is a rescue/reliever agent that includes an eModule 
on top of the approved PROAIR® RESPICLICK inhaler. The on-board electronics and power 
source are fully integrated into the inhaler and are designed to operate for the life of the inhaler 
without intervention. The electronic module records timestamped, pre-defined events such as cap 
open and inhalation parameters. The inclusion of the eModule has been shown to have no impact 
on the dose delivery compared with the approved product without the eModule. 
The study will consist of a screening period of up to 2 weeks and a 12-week intervention period. 
After providing written informed consent, patients will complete a screening visit (visit 1) to 
determine eligibility for the study. Patients will provide medical history (including prior 
medications), complete a physical examination, pregnancy test, if applicable, and review COPD 
exacerbation history. Eligible patients will return to the investigational center within 2 weeks for 
the baseline visit (visit 2). Those meeting entry criteria will be trained on the use of the eMDPI 
device and, upon demonstrated competency, will receive ABS eMDPI devices for use as rescue 
bronchodilators during the study. The screening visit and baseline visit may be combined. 
Patients must use ABS eMDPI as their only rescue agent for the duration of their participation in 
this study and will be advised to place any current rescue pills, inhalers, or nebulizers, including 
short-acting beta2 agonists (SABA), short-acting muscarinic antagonists (SAMAs), or 
SABA/SAMA combination, into storage. Patients may continue the use of other COPD and 
non-COPD medications as advised by their physician without changes unless a change is deemed 


 
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necessary by their physician. Patients will be managed according to routine clinical practice by 
their treating physician with no specific study-related instructions provided other than those on 
the proper use of ABS eMDPI. 
Patients will be contacted by phone on a monthly basis for the collection of information about 
COPD exacerbations and treatments, concomitant medications, and adverse events. A review of 
the instructions for the use of ABS eMDPI and the procedure for replacement and return of 
ABS eMDPI will also occur during the monthly call. 
Patients will receive initial eMDPI devices at visit 2 based on anticipated usage pattern. In the 
event that additional eMDPI devices are needed, patients will be required to visit the 
investigational center to receive them. Patients will be instructed to return all inhalers to the 
investigational center at the last study visit or earlier, including at the early termination visit, as 
well as at any other point if there is a problem with the inhaler. At the last study visit or early 
termination, patients will be queried for adverse events, concomitant medications, and COPD 
exacerbations; a physical examination will be completed; and the patient will subsequently be 
discharged from the trial. 
Two subsets of patients who agree to participate at specific investigational centers and to wear an 
accelerometer either on the ankle to measure TDS (n=100) or on the wrist to measure SDI 
(n=100) will be instructed on the proper use of these devices at the baseline visit (visit 2). The 
devices will be worn throughout the 12-week intervention period and will be returned to the 
investigational center at the final visit or upon early termination. 
Brief Summary of Study Design for the Trial Registry: 
This is a 12-week, multicenter, open-label study to evaluate the relationship between ABS 
eMDPI and CE-COPD in adult patients at least 40 years of age with exacerbation-prone COPD. 
The ABS eMDPI dose will be 90 mcg, 1 to 2 inhalations every 4 hours as needed, but patient 
dosing will not be limited to this dosing regimen. The purpose of this study is to evaluate the 
relationship between albuterol dosing and CE-COPD. 
Method of Randomization and Blinding: This is a nonrandomized study. All patients will use 
the one Test IMP, the ABS eMDPI. Blinding is not applicable. 
Investigational Medicinal Products: Dose, Pharmaceutical Form, Route of Administration, 
and Administration Rate 
Test IMP: The ABS eMDPI dose will be 90 mcg, 1 to 2 inhalations every 4 hours as needed. 
Reference IMP: Not applicable 
Placebo IMP: Not applicable 
Duration of Patient Participation and Maximal Exposure to IMP: The total duration of 
patient participation in the study is planned to be up to 14 weeks (a screening period of up to 
2 weeks and a 12-week intervention period). 
Study Duration: Approximately 9 months 
End of Study: End of study is defined as the last visit of the last patient. 
Plans for Treatment or Care After the Patient Has Ended Participation in the Study: No 
treatment is planned by the sponsor after the end of the study. Patients should be treated with 
standard of care after withdrawal from or termination of the study, as appropriate. 


 
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Inclusion Criteria: Patients may be enrolled in the study only if they meet all of the following 
criteria:  
a. The patient is male or female, 40 years of age or older, with a physician diagnosis of 
COPD. The diagnosis should include a history of forced expiratory volume in 
1 second (FEV1)/forced vital capacity <70% predicted and FEV1 <80% predicted 
documented in the patient’s chart. 
b. The patient is currently using a SABA reliever plus at least one of the following: 
long-acting beta agonist (LABA), an inhaled corticosteroid (ICS)/LABA, a 
long-acting muscarinic antagonist (LAMA), or a LABA/LAMA. 
c. The patient has had at least 1 episode of moderate or severe CE-COPD (as described 
in Section 6.1.1 of the protocol) over the past 12 months before screening. 
d. The patient must be able to demonstrate appropriate use of albuterol from the 
ABS eMDPI. 
e. The patient is able to provide written informed consent. 
f. The patient must be willing and able to comply with study requirements as specified 
in the protocol, including the use of a wearable accelerometer for the subset of 
patients who consent to use of the device. 
g. The patient is willing to discontinue all other rescue or maintenance SABA or 
short-acting anti-muscarinic agents and replace them with the study-provided ABS 
eMDPI for the duration of the trial. 
h. Women of childbearing potential (not surgically sterile or ≥2 years postmenopausal) 
must have exclusively same-sex partners or use a highly effective or acceptable 
method of birth control and must agree to continue the use of this method for the 
duration of the study and for 30 days after discontinuation of the IMP. Highly 
effective methods of birth control are defined as those, alone or in combination, that 
result in a low failure rate (ie, <1% per year) when used consistently and correctly. 
Highly effective methods of birth control in this study include combined (estrogen- 
and progestogen-containing) or progestogen-only hormonal contraception associated 
with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing 
system, bilateral tubal occlusion, vasectomized partner, and sexual abstinence. 
Acceptable birth control methods that result in a failure rate of more than 1% per year 
include: progestogen-only oral hormonal contraception, for which the inhibition of 
ovulation is not the primary mode of action; male or female condom with or without 
spermicide; and cap, diaphragm, or sponge with spermicide. The combination of male 
condom with either cap, diaphragm, or sponge with spermicide (double barrier 
methods) are also considered acceptable, but not highly effective, methods of birth 
control. 
Exclusion Criteria: Patients will not be enrolled in this study if they meet any of the following 
criteria: 
a. The patient has any clinically significant medical condition (treated or untreated) that, 
in the opinion of the investigator, would interfere with participation in the study. 


 
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b. The patient has any other confounding underlying lung disorder other than COPD. 
c. The patient has used an investigational drug within 5 half-lives of it being 
discontinued, or within 1 month of visit 2, whichever is longer.  
d. The patient is a pregnant or lactating woman, or plans to become pregnant during the 
study. Note: Any woman becoming pregnant during the study will be withdrawn from 
the study. 
e. The patient is either an employee or an immediate relative of an employee of the 
investigational center. 
f. The patient is known to be allergic to albuterol or any of the excipients in the IMP or 
rescue medication formulation (ie, lactose [milk protein]). Dietary lactose intolerance 
does not exclude the patient from inclusion in the study or as per the investigator’s 
medical discretion.  
g. The patient has a history of drug or alcohol abuse within 2 years prior to the screening 
visit. 
h. The patient has a history of positive testing for human immunodeficiency virus 
types 1 and 2, hepatitis B, hepatitis C, and tuberculosis. Note: A history of a positive 
tuberculosis skin test without active tuberculosis may be acceptable only if the patient 
has received an accepted prophylactic treatment regimen and has no clinical evidence 
of active disease. Patients with a history of hepatitis C who have undergone treatment 
and achieved a sustained virologic response may be eligible if they meet all other 
selection criteria and receive medical monitor approval. 
i. The patient has symptomatic congestive heart failure. 
j. A member of the patient’s household is participating in the study at the same time. 
Statistical Considerations:  
Sample Size Rationale: Assuming an expected dropout rate of 10%, it is recommended that 
400 patients be enrolled, so that 360 evaluable patients complete the study. This rationale is 
based on a review of relevant literature, as follows. 
Based on previous studies of an exacerbation-prone COPD cohort (Dransfield et al 2013, 
Vogelmeier et al 2011, Wedzicha et al 2013, Wedzicha et al 2016), it is expected that 91 (range, 
73 to 110) CE-COPD events will occur over the 12-week evaluation period in this study based 
on reported CE-COPD exacerbation rates of 1.05 and 1.14 events per year. Furthermore, it is 
expected that 14% (14) of total exacerbations will be severe. 
This sample size (ie, n=400 patients, 73 to 110 CE-COPD events) is considered adequate for the 
fulfillment of the study objectives to evaluate the relationship of albuterol use, inspiratory flow, 
SDI, and TDS data associated with a subsequent CE-COPD event. Per a previous study (Jenkins 
et al 2013), a statistically significant relationship was established between daily SABA usage and 
subsequent CE-COPD. 
In the present study, approximately 73 to 110 CE-COPD events are desired because the model’s 
fitting of the current study involves the analysis of multiple predictors as described in more detail 


 
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below. Because the largest model considered has 7 covariates, it is desirable to have at least 
70 events. The probability to observe at least 70 CE-COPD events is higher than 0.99. 
Risk models published in the literature have typically included between 4 and 6 covariates/risk 
factors (Bateman et al 2015, Greenberg et al 2012, Quezada et al 2016) to examine the 
relationship between possible risk factors and a disease. When there is more than 1 covariate 
(risk factor) in the model, multiple logistic regression may be used to estimate the relationship of 
a specific covariate of interest (ie, albuterol use) to a primary outcome (ie, CE-COPD), adjusting 
for the other/remaining covariates (risk factors). In this case, the required sample size to estimate 
such a relationship is greater than that for univariate logistic regression.  
The number of events per variable has been suggested as a criterion for the size of a data set 
(Harrell et al 1984, Laupacis et al 1997, Peduzzi et al 1996). The rule of thumb when building 
logistic regression models is 1 predictor variable for every 10 events (Peduzzi et al 1996, 
Vittinghoff and McCulloch 2007). Therefore, this sample size would be adequate for predicting 
the primary outcome (CE-COPD) using multiple logistic regression, including the covariate of 
primary interest (ie, albuterol use) and the remaining multiple predictors (inspiratory flow values, 
SDI, and TDS) as potential risk factors for CE-COPD in the model for this patient population. 
Analysis of Endpoints: The relationship between albuterol usage and CE-COPD will be 
analyzed as follows, without controlling for multiplicity. 
The multiple device-use-measures will be used as predictors of CE-COPD in the following 
stepwise selection logistic regression models to select significant predictors in a forward manner: 
1. albuterol usage 
2. albuterol usage + inspiratory flow values 
3. albuterol usage + SDI 
4. albuterol usage + TDS 
5. albuterol usage + inspiratory flow values + SDI 
6. albuterol usage + inspiratory flow values + TDS 
The selection of covariates will be performed at the 0.2 level. 
Baseline disease state and demographic variables collected at study enrollment will also be 
considered as predictors. Because the device-use-measures will be collected continuously over 
time, these measures could be used to derive many potential predictors of risk. For example, with 
respect to albuterol use, a patient using the inhaler 3 times in the span of a 2-day or 3-day period 
could be a strong predictor of a CE-COPD, but a better marker for risk might be 10 times in the 
span of a week. There are no prior robust data to inform these decisions; 1 possible benefit of 
this work will be to examine the relationship between multiple functional forms for the 
device-use-measures to determine which forms have predictive power. 
Furthermore, the effect of including interaction terms in the model (ie, testing the assumption of 
additivity of predictors on the log odds scale) will also be studied. Pair-wise interactions will be 
assessed at the 0.01 significance level to avoid weak interaction signals that would potentially 
not translate when applying the risk score to new cohorts. Goodness-of-fit tests may be applied 
to make sure that the finally selected model fits the data closely. The C-statistic, as described by 


 
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Hosmer et al will be used to compare the goodness of fit of various logistic regression models in 
terms of how well the predictor(s) discriminate between patients with and without CE-COPD. 
Efficacy Analysis: Efficacy will not be assessed in this study. 
Sensitivity Analysis: Sensitivity will not be assessed in this study. 
Multiple Comparisons and Multiplicity: Not applicable 
Analysis of Tertiary/Exploratory/Other Endpoints: Not applicable  
Safety Analyses: Safety data will be collected over the 12-week intervention period and will be 
descriptively summarized using appropriate summary statistics for the safety analysis set. 
Tolerability Analysis: Tolerability is not specifically defined. 
Pharmacokinetic Analysis: Not applicable 
Pharmacodynamic Analysis: Not applicable 
Pharmacokinetic/Pharmacodynamic Analysis: Not applicable  
Biomarker Analysis: Not applicable 
Immunogenicity Analysis: Not applicable 
Ancillary Studies Analysis: Not applicable 
Planned Interim Analysis: Not applicable 


 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
AMENDMENT HISTORY .............................................................................................................2 
INVESTIGATOR AGREEMENT...................................................................................................3 
SPONSOR PROTOCOL APPROVAL ...........................................................................................4 
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................5 
LIST OF ABBREVIATIONS ........................................................................................................17 
1. 
INTRODUCTION AND BACKGROUND INFORMATION ..................................19 
1.1. 
Introduction .................................................................................................................19 
1.2. 
Findings from Nonclinical and Clinical Studies .........................................................20 
1.2.1. 
Nonclinical Studies .....................................................................................................20 
1.2.2. 
Clinical Studies ...........................................................................................................21 
1.2.2.1. 
Clinical Safety and Efficacy Studies ..........................................................................23 
1.3. 
Known and Potential Benefits and Risks to Patients ..................................................23 
1.3.1. 
Known and Potential Benefits and Risks of the Test Investigational 
Medicinal Product .......................................................................................................23 
1.3.2. 
Overall Benefit and Risk Assessment for This Study ................................................24 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................25 
2.1. 
Study Objectives and Endpoints .................................................................................25 
2.1.1. 
Justification of the Endpoints .....................................................................................25 
3. 
STUDY DESIGN .......................................................................................................27 
3.1. 
General Design ...........................................................................................................27 
3.2. 
Planned Number of Patients and Countries ................................................................28 
3.3. 
Justification for Study Design and Selection of Population .......................................28 
3.4. 
Stopping Rules for the Study ......................................................................................29 
3.5. 
Schedule of Study Procedures and Assessments ........................................................30 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................33 
4.1. 
Patient Inclusion Criteria ............................................................................................33 
4.2. 
Patient Exclusion Criteria ...........................................................................................34 
4.3. 
Withdrawal Criteria and Procedures for the Patient ...................................................34 
4.4. 
Replacement of Patients .............................................................................................35 
4.5. 
Rescreening .................................................................................................................35 
4.6. 
Screening Failure ........................................................................................................35 


 
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5. 
TREATMENTS ..........................................................................................................36 
5.1. 
Investigational Medicinal Products Used in the Study ...............................................36 
5.1.1. 
Test Investigational Medicinal Product ......................................................................36 
5.1.1.1. 
Starting Dose and Dose Levels ...................................................................................36 
5.1.1.2. 
Dose Modification and Dose Stratification ................................................................36 
5.1.2. 
Reference Investigational Medicinal Product .............................................................36 
5.1.3. 
Placebo Investigational Medicinal Product ................................................................36 
5.2. 
Preparation, Handling, Labeling, Storage, and Accountability for 
Investigational Medicinal Products ............................................................................37 
5.2.1. 
Storage and Security ...................................................................................................37 
5.2.2. 
Labeling ......................................................................................................................37 
5.2.3. 
Accountability .............................................................................................................37 
5.3. 
Justification for Investigational Medicinal Products ..................................................38 
5.3.1. 
Justification for Dose of Test Investigational Medicinal Product ..............................38 
5.4. 
Treatment After the End of the Study .........................................................................38 
5.5. 
Restrictions .................................................................................................................38 
5.6. 
Prior and Concomitant Medication or Therapy ..........................................................38 
5.7. 
Procedures for Monitoring Patient Compliance .........................................................39 
5.8. 
Randomization and Blinding ......................................................................................39 
5.9. 
Total Blood Volume ...................................................................................................39 
6. 
ASSESSMENT OF EFFICACY ................................................................................40 
6.1. 
Assessments ................................................................................................................40 
6.1.1. 
Clinical Exacerbation of Mild, Moderate, and Severe CE-COPD .............................40 
6.1.2. 
Albuterol Use ..............................................................................................................41 
6.1.3. 
Inspiratory Flow Values Upon Albuterol Dosing .......................................................41 
6.1.4. 
Accelerometry .............................................................................................................41 
7. 
ASSESSMENT OF SAFETY .....................................................................................42 
7.1. 
Adverse Events ...........................................................................................................42 
7.1.1. 
Definition of an Adverse Event ..................................................................................42 
7.1.2. 
Recording and Reporting of Adverse Events .............................................................42 
7.1.3. 
Severity of an Adverse Event .....................................................................................43 
7.1.4. 
Relationship of an Adverse Event to the Test Investigational Medicinal 
Product ........................................................................................................................43 


 
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7.1.5. 
Serious Adverse Events ..............................................................................................44 
7.1.5.1. 
Definition of a Serious Adverse Event .......................................................................44 
7.1.5.2. 
Expectedness ...............................................................................................................45 
7.1.5.3. 
Reporting a Serious Adverse Event ............................................................................45 
7.1.6. 
Protocol-Defined Adverse Events not for Expedited Reporting ................................47 
7.1.7. 
Protocol-Defined Adverse Events of Special Interest ................................................47 
7.1.8. 
Protocol Deviations Because of an Adverse Event ....................................................48 
7.2. 
Pregnancy ...................................................................................................................48 
7.3. 
Medication Error and Special Situations Related to the Investigational 
Medicinal Products .....................................................................................................48 
7.4. 
Clinical Laboratory Tests ...........................................................................................49 
7.5. 
Physical Examinations ................................................................................................49 
7.6. 
Vital Signs ..................................................................................................................49 
7.7. 
Electrocardiography ....................................................................................................50 
8. 
ASSESSMENT OF PHARMACOKINETICS/ PHARMACODYNAMICS/ 
BIOMARKERS/PHARMACOGENOMICS/ IMMUNOGENICITY/ 
ANCILLARY STUDIES ............................................................................................51 
9. 
STATISTICS ..............................................................................................................52 
9.1. 
Sample Size and Power Considerations .....................................................................52 
9.2. 
Analysis Sets ...............................................................................................................53 
9.2.1. 
Intent-to-Treat Analysis Set ........................................................................................53 
9.2.2. 
Modified Intent-to-Treat Analysis Set ........................................................................53 
9.2.3. 
Safety Analysis Set .....................................................................................................53 
9.3. 
Data Handling Conventions ........................................................................................53 
9.3.1. 
Handling Withdrawals and Missing Data ...................................................................53 
9.4. 
Study Population .........................................................................................................53 
9.4.1. 
Patient Disposition ......................................................................................................53 
9.4.2. 
Demographic and Baseline Characteristics ................................................................53 
9.5. 
Endpoint Analysis .......................................................................................................54 
9.5.1. 
Endpoints ....................................................................................................................54 
9.5.2. 
Planned Method of Analysis .......................................................................................54 
9.5.2.1. 
Endpoint Analysis .......................................................................................................54 
9.5.2.2. 
Sensitivity Analysis ....................................................................................................55 


 
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9.6. 
Multiple Comparisons and Multiplicity......................................................................55 
9.7. 
Safety Analysis ...........................................................................................................55 
9.8. 
Tolerability Analysis ..................................................................................................56 
9.9. 
Planned Interim Analysis ............................................................................................56 
9.10. 
Reporting Deviations from the Statistical Analysis Plan ...........................................56 
10. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................57 
11. 
COMPLIANCE STATEMENT ..................................................................................58 
12. 
DATA MANAGEMENT AND RECORD KEEPING ..............................................59 
13. 
FINANCING AND INSURANCE .............................................................................60 
14. 
PUBLICATION POLICY ..........................................................................................61 
15. 
REFERENCES ...........................................................................................................62 
16. 
SUMMARY OF CHANGES TO PROTOCOL .........................................................65 
16.1. 
Amendment 03 Dated 26 June 2017 ...........................................................................65 
16.2. 
Amendment 02 Dated 21 March 2017 ........................................................................79 
16.3. 
Amendment 01 Dated 29 September 2016 .................................................................86 
APPENDIX A. CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND 
INSTITUTIONS .........................................................................................................93 
APPENDIX B. STUDY PROCEDURES AND ASSESSMENTS BY VISIT ...........................94 
APPENDIX C. QUALITY CONTROL AND QUALITY ASSURANCE ................................96 
APPENDIX D. ETHICS .............................................................................................................98 
APPENDIX E. WOMEN OF CHILDBEARING POTENTIAL AND BIRTH 
CONTROL METHODS ...........................................................................................100 
APPENDIX F. LOST TO FOLLOW-UP .................................................................................103 
APPENDIX G. PRODUCT COMPLAINTS ............................................................................104 
APPENDIX H. DATA MANAGEMENT AND RECORD KEEPING ...................................106 
APPENDIX I. PUBLICATION POLICY .................................................................................109 


 
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LIST OF TABLES 
Table 1: 
Study Procedures and Assessments ............................................................................31 
Table 2: 
Investigational Medicinal Products Used in the Study ...............................................37 
Table 3: 
Systemic Glucocorticoid Treatment Equivalent to 10 mg of Prednisone...................41 
Table 4: 
The Relationship of an Adverse Event to the Test IMP .............................................44 
 


 
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LIST OF ABBREVIATIONS 
List of Abbreviations 
Abbreviation 
Term 
6MWT 
6-minute walk test 
ABS 
albuterol sulfate 
CDMS 
clinical data management system 
CE-COPD 
clinical exacerbation of COPD 
CFR 
Code of Federal Regulations (United States) 
COPD 
chronic obstructive pulmonary disease 
eCRF 
electronic case report form 
CRO 
contract research organization 
CSR 
clinical study report 
DCRI 
Duke Clinical Research Institute 
EDC 
electronic data capture 
EIB 
exercise-induced bronchospasm 
eMDPI 
multidose dry powder inhaler with an eModule 
EV 
EudraVigilance  
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
GCP 
Good Clinical Practice 
GPSP 
Global Patient Safety and Pharmacovigilance 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICS 
inhaled corticosteroid 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
LABA 
long-acting beta agonist 
LAMA 
Long-acting muscarinic antagonist 
MDI 
metered dose inhaler 
MDPI 
multidose dry powder inhaler 
MIF 
maximal inhalational flow 
mITT 
modified intent-to-treat 


 
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Abbreviation 
Term 
PP 
per protocol 
RSI 
reference safety information 
SABA 
short-acting beta2 agonist 
SAMA 
short-acting muscarinic antagonist 
SCS 
systemic corticosteroid 
SDI 
sleep disruption index 
SGRQ-AS 
St. George’s Respiratory Questionnaire Activity Score 
SmPC 
Summary of Product Characteristics 
SUSAR 
suspected unexpected serious adverse reaction 
TDS 
total daily steps 
ULN 
upper limit of normal 


 
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1. 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1. 
Introduction 
Chronic obstructive pulmonary disease (COPD) is a disease composed of the respiratory 
illnesses chronic bronchitis and emphysema and is the third leading cause of death in the United 
States (American Lung Association 2011, Miniño et al 2010). Unfortunately, COPD is often 
underdiagnosed or misdiagnosed, leading to a large population of untreated patients. At present, 
more than 12 million Americans are diagnosed with COPD; it is estimated that another 
12 million Americans have undiagnosed COPD (US Dept of HHS 2009). According to a 2012 
survey, physicians reported that 28% of their COPD patients had mild COPD, 35% had moderate 
COPD, and 38% had severe COPD. This equates to just over 3.3 to 4.5 million Americans in 
each category (American Lung Association 2011, Forest Laboratories 2012, Forest Laboratories 
2009).  
The association among symptoms, spirometric classification, and future risk of exacerbation is 
routinely evaluated and risk assigned according to Global Initiative for Chronic Obstructive 
Lung Disease categories (GOLD 2011). GOLD patient groups are as follows: A–low risk, less 
symptoms; B–low risk, more symptoms; C–high risk, less symptoms; D–high risk, more 
symptoms. 
Patients with COPD may experience periodic increases in their symptoms. An exacerbation is an 
episode characterized by worsening of symptoms, such as dyspnea, cough, and the volume and 
purulence of sputum associated with bronchospasm and frequently bronchospasm-promoting 
events such as infection and heart failure. Exacerbations may also be associated with physiologic 
deterioration (eg, a decline in forced expiratory volume in 1 second [FEV1]) and increases in 
airway and systemic inflammation, as evidenced by an increase in inflammatory markers in the 
airways (Wedzicha and Wilkinson 2006). Patients may have other symptoms such as fever or 
sore throat, indicating an infectious process (Reilly et al 2011). 
As the recommended drug for relief of acute bronchospasm, short-acting beta2 agonists (SABA), 
such as albuterol, are a mainstay of asthma management. The use of inhaled aerosol medications 
for COPD is ideal because inhalation delivers relatively low doses of the drug rapidly to the site 
of action. This preferred administration mode achieves high drug concentrations in the airways 
while minimizing systemic side effects (Dolovich et al 2005). Inhaled albuterol aerosols are the 
most commonly prescribed treatments for the relief of bronchoconstriction. PROAIR® (albuterol 
sulfate [ABS]) RESPICLICK Inhalational Powder is approved for the treatment or prevention of 
bronchospasm in patients with reversible obstructive airway disease and delivers the equivalent 
of 90 mcg of albuterol base ex-mouthpiece per actuation. More detailed prescribing information 
for this product may be found in the Investigator’s Brochure (IB). 
Although albuterol has traditionally been administered via conventional “press-and-breathe” 
metered dose inhalers (MDIs), inefficient inhaler technique (ie, inability to properly coordinate 
actuation with inspiration) is a common problem with these devices; as a consequence, delivery 
of the active drug to the airways can be compromised, potentially resulting in suboptimal clinical 
benefits (Allen et al 2003, Kamps et al 2000, Larsen et al 1994, Molimard et al 2003). To 
eliminate the necessity for coordinating actuation with inspiration, Teva has developed the 
breath-actuated inhaler PROAIR® RESPICLICK, which utilizes a formulation blend of ABS 


 
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with lactose as an excipient. Breath actuation has been found to reduce administration errors in 
comparison with conventional MDIs (Lenney et al 2000, Price et al 1999). ABS is a 
beta2-adrenergic agonist with the chemical name α1 [(tert butylamino) methyl]-4-hydroxy-m-
xylene-α,αʹ-diol sulfate (2:1) [salt]. PROAIR® RESPICLICK delivers the equivalent of 90 mcg 
of albuterol base ex-mouthpiece per actuation and has been approved in the United States since 
March of 2015.  
In this study, 90 mcg of ABS is delivered via a multidose dry powder inhaler (MDPI) with an 
eModule (eMDPI) sitting on the upper part of the device for the purposes of detecting and 
storing usage information. A more detailed description of the product is given in Section 5.1.1. 
The eMDPI stores information on the date, time, and inspiratory flow values each time a patient 
takes a dose. In addition, a subset of patients who agree to participate at specific investigational 
centers will wear an accelerometer on the wrist as a marker of sleep disruption, and a second 
subset of patients who agree to participate at specific investigational centers will wear an 
accelerometer on the ankle to quantify daily physical activity. Information from eMDPI and 
wearable devices will be used to determine if they can help predict the subsequent development 
of a clinical exacerbation of COPD (CE-COPD).  
1.2. 
Findings from Nonclinical and Clinical Studies 
In the clinical development program for PROAIR® RESPICLICK, the investigational medicinal 
product (IMP) was reported using nomenclature other than that of the then-unbranded product. 
Within this document, we update the name of the IMP to the marketed product, PROAIR® 
RESPICLICK, to promote alignment with current medical practice. 
Brief summaries of nonclinical pharmacology, pharmacokinetics, toxicology, and clinical studies 
are provided in the following sections. More detailed information is provided in the IB and the 
package insert for PROAIR® RESPICLICK. 
1.2.1. 
Nonclinical Studies 
In a 2-year study in Sprague-Dawley rats, ABS caused a dose-related increase in the incidence of 
benign leiomyomas of the mesovarium at and above dietary doses of 2 mg/kg (approximately 
15 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis). In 
another study, this effect was blocked by the co-administration of propranolol, a nonselective 
beta-adrenergic antagonist. In an 18-month study in CD-1 mice, ABS showed no evidence of 
tumorigenicity at dietary doses of up to 50 mg/kg (approximately 210 times the maximum 
recommended daily inhalation dose for adults on a mg/m2 basis). ABS was not mutagenic in the 
Ames test or a mutation test in yeast. ABS was not clastogenic in a human peripheral 
lymphocyte assay or in an AH1 strain mouse micronucleus assay. Reproduction studies in rats 
demonstrated no evidence of impaired fertility at oral doses up to 50 mg/kg (approximately 
310 times the maximum recommended daily inhalation dose for adults on a mg/m2 basis).  
Pre-clinical intravenous studies in rats with ABS have demonstrated that albuterol crosses the 
blood-brain barrier and reaches brain concentrations amounting to approximately 5% of the 
plasma concentrations. In structures outside the blood-brain barrier (pineal and pituitary glands), 
albuterol concentrations were found to be 100 times those in the whole brain. Studies in 
laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac 
arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when 


 
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beta-agonists and methylxanthines were administered concurrently. The clinical significance of 
these findings is unknown.  
1.2.2. 
Clinical Studies 
Summary of SABA Studies from the Global Initiative for COPD (GOLD): Per the GOLD 
guidelines, bronchodilator medications such as albuterol are central to symptom management in 
COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] GOLD 2016). Regular 
and as-needed use of SABA, including albuterol, improve FEV1 and symptoms in COPD 
(GOLD 2016). Generally, the inhalational route is preferred for the delivery of bronchodilators 
in COPD (GOLD 2016).  
A Prospective, Open-label Assessment of the ABS MDPI with Integrated Dose Counter in 
Asthma and COPD: The primary objective of this study was to evaluate the performance of the 
ABS MDPI with dose counter; the secondary objective was to evaluate the handling 
characteristics (eg, ruggedness) of the device. ASB MDPI (90 mcg/inhalation) was administered 
to patients ages 4 years and older with asthma or COPD as 2 inhalations/dose cycles twice daily 
for up to 50 days in an open-label study design. 
Approximately 15% of patients would complete the study in 5 weeks. The per-protocol (PP) 
population was considered primary for analysis purposes. Data identified as likely errors were 
excluded from the PP analysis. The intent-to-treat (ITT) population included all enrolled patients, 
and analyses also included data likely to involve patient-recording errors. 
A total of 345 patients with asthma or COPD with symptoms of bronchoconstriction requiring 
the use of SABA were screened for enrollment into this study; 317 patients were enrolled at 
30 centers in the United States. The safety population consisted of 316 patients due to 1 patient 
being lost to follow-up. The PP population, all of whom completed the study, consisted of 
253 patients. A total of 16 patients withdrew from the study. All enrolled patients had a diagnosis 
of asthma or COPD as required by the protocol. The mean age of the 317 patients in the ITT 
population was 51.3 years, and the age range was from 5 years to 88 years, with patients enrolled 
in 3 age groupings. The majority of patients were female (n=178, 56%), and the vast majority 
were white (n=268, 85%). Approximately half of the patients had a diagnosis of asthma (53%) 
and half had a diagnosis of COPD (47%). 
The total number of patient-reported dose cycles for the PP population (n=253) in the study was 
49454. For the ITT population (n=317), the number of dose cycles was 57471. The overall rate 
of discrepancies for the primary endpoint, dose cycle not counted, was 2.05 per 200 dose cycles 
for the PP population. This was slightly lower than the rate of 2.34 per 200 dose cycles for the 
ITT population. These accounted for less than half of all dosing discrepancies. The 
mean±standard deviation number of dose cycles not counted in the PP population was 1.1±0.37, 
with a range from 1 to 4. This was smaller than for the ITT population in which a large range 
was present, indicative of higher variation among patients included in the ITT population. 
The model-estimated mean of the absolute value of the total discrepancy size after 200 doses was 
low (2.07 for the PP and 2.31 for the ITT populations). The estimated probability of exceeding a 
total discrepancy size of 10 dose cycles per 200 dose cycles, the projected life of the inhaler, is 
very low (0.0009 and 0.003 for the PP and ITT populations, respectively).  


 
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In general, the patients with a diagnosis of COPD has a lower discrepancy rate for “dose cycle 
not count” than did the patients with asthma, but this may be related to patient characteristics 
rather than inhaler characteristics. The discrepancy rates per 200 dose cycles in the PP 
population were 1.81 and 2.30 and in the ITT population were 1.93 and 2.73 for COPD and 
asthma patients, respectively. As with the primary endpoint, the patients with a diagnosis of 
COPD had a lower discrepancy rate for dose cycle overcount (2.18 in the PP population and 2.11 
in the ITT population) than did the patients with a diagnosis of asthma (2.78 in the PP population 
and 3.10 in the ITT population). The rates for count unknown cycle and count up unknown cycle 
were much lower for patients with a diagnosis of COPD.  
Overall, of the 253 patients in the PP population, 86 (34%) preferred the trial device, 65 (26%) 
their prescribed device, and 102 (40%) had no preference. Some 70% of patients were 
(somewhat to very) likely to use the new inhaler, while 20% were unlikely to use the new 
inhaler, compared with 78% of patients who were (somewhat to very) likely to use their 
prescribed inhaler and only 13% unlikely to use their prescribed inhaler among the PP 
population. 
Each use of the inhaler was generally high, as 209 patients (83%) in the PP population were 
somewhat to very satisfied with the study inhaler, with another 21 (8%) patients expressing 
neither satisfaction nor dissatisfaction. Other measures, such as ease of use and ease of dosing, 
generally showed satisfaction in about 90% of patients. The device was considered quite rugged 
as only 3 patients reported non-counter device issues, of which 2 were confirmed independently 
by the study site. 
A total of 29 patients (8%) out of the 345 screened patients had 1 or more adverse events during 
the screening/run-in period and 85 patients (27%) out of the 316 included in the safety analysis 
set following enrollment into the study reported adverse events. There were no deaths reported in 
the study. Two patients had serious adverse events (atrial fibrillation and supraventricular 
tachycardia judged related to study drug in 1 patient, and skin eruption due to metformin in the 
second patient) while on study, and 1 patient was withdrawn due to an unrelated adverse event of 
sinusitis.  
The most frequently occurring adverse event in the enrolled patients was headache in 4 patients 
during the run-in and 8 patients on study, followed by respiratory infections and disorders. These 
consisted of sinusitis in 7 patients, cough in 6 patients, upper respiratory infection in 6 patients, 
and nasopharyngitis in 4 patients while on study. The adverse events judged related to study drug 
were those commonly associated with albuterol products in the treatment of asthma, including 
abdominal pain, feeling jittery, irritability, weight increase, tremor, nervousness, coughing, and 
sneezing. 
In conclusion, ABS MDPI with integrated dose counter is robust, and the counter functioned 
reliably and accurately in the clinical setting of twice daily dosing for up to 50 days (projected 
inhaler actuation life of 200 doses). Importantly, the discrepancy rate for “dose cycle not count” 
(undercount) for the PP population was low (2.05 per 200 dose cycles), as were the overall rate 
of discrepancies (5.11 per 200 dose cycles) and other discrepancies. The most common 
discrepancy was dose cycle overcount (2.46 per 200 dose cycles). The model-estimated mean of 
the absolute value of the total discrepancy size after 200 doses was low (2.07 for the PP 
population), and the estimated probability of exceeding a total discrepancy size of 10 dose cycles 
per 200 dose cycles is very low. ABS MDPI with integrated dose counter was well tolerated in 


 
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this study. The observed safety profile was consistent with the known safety profile of albuterol 
and was not altered by the inclusion of the integrated dose counter. 
Bronchospasm Associated with Asthma: In two 12-week, randomized, double-blind, 
placebo-controlled studies of identical design (Study 1 and Study 2), PROAIR® RESPICLICK 
was compared to a matched placebo dry powder inhaler in 153 and 163 asthmatic patients, 
respectively, 12 to 76 years of age, at a dose of 180 mcg albuterol 4 times daily. Patients were 
maintained on inhaled corticosteroid (ICS) treatment. Serial measurements of FEV1 
demonstrated that 2 inhalations of PROAIR® RESPICLICK produced significantly greater 
improvement in FEV1 area under the plasma concentration-time curve from time 0 to 6 hours 
after IMP administration over the pre-treatment value than placebo in Study 1. Results of Study 2 
were consistent with those of Study 1. In a double-blind, randomized, placebo-controlled, 
single-dose, crossover study evaluating PROAIR® RESPICLICK and PROAIR® 
hydrofluoroalkane in 71 adult and adolescent patients 12 years of age and older with persistent 
asthma, PROAIR® RESPICLICK had bronchodilator efficacy that was significantly greater than 
placebo at administered doses of 90 and 180 mcg.  
Exercise-Induced Bronchospasm: In a randomized, single-dose, crossover study in 38 adult 
and adolescent patients with exercise-induced bronchospasm (EIB), 2 inhalations of PROAIR® 
RESPICLICK taken 30 minutes before exercise prevented EIB for the hour following exercise 
(defined as the maintenance of FEV1 within 80% of postdose, pre-exercise baseline values) in 
97% (37 of 38) of patients as compared to 42% (16 of 38) of patients who received placebo. 
Patients who participated in these clinical studies were allowed to use concomitant steroid 
therapy. 
More detailed information is provided in the IB and the package insert for PROAIR® 
RESPICLICK. 
1.2.2.1. 
Clinical Safety and Efficacy Studies 
A total of 1120 patients with asthma were treated with PROAIR® RESPICLICK during the 
clinical development program. The most common adverse reactions (≥1% and >placebo) were 
back pain, pain, gastroenteritis viral, sinus headache, and urinary tract infection. In a long-term 
study of 168 patients treated with PROAIR® RESPICLICK for up to 52 weeks (including a 
12-week, double-blind period), the most commonly reported adverse events (≥5%) were upper 
respiratory infection, nasopharyngitis, sinusitis, bronchitis, cough, oropharyngeal pain, headache, 
and pyrexia. In a small cumulative-dose study, tremor, palpitations, and headache were the most 
frequently occurring (≥5%) adverse events. 
More detailed information is provided in the IB and the package insert for PROAIR® 
RESPICLICK. 
1.3. 
Known and Potential Benefits and Risks to Patients 
1.3.1. 
Known and Potential Benefits and Risks of the Test Investigational Medicinal 
Product 
This study is being undertaken to determine if a specific pattern of changes in ABS eMDPI use 
can predict a patient’s risk for subsequent development of a CE-COPD event. In addition to ABS 
eMDPI use, inhalation flow values, sleep disruption index (SDI), and total daily steps (TDS) data 


 
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will be used to determine if changes in these measures can further improve the prediction of risk 
for CE-COPD.  
ABS eMDPI is a rescue/reliever agent that includes an eModule on top of the approved 
PROAIR® RESPICLICK inhaler. The on-board electronics and power source are fully integrated 
into the inhaler and are designed to operate for the life of the inhaler without intervention. The 
electronic module records timestamped pre-defined events such as cap open and inhalation 
parameters. The inclusion of the eModule has been shown to have no impact on the dose 
delivery compared with the approved product without the eModule. Furthermore, the instructions 
for the use of ABS eMDPI are identical to that of the currently approved PROAIR® 
RESPICLICK. Therefore, it is unlikely that the inclusion of the eModule will add additional risk 
to the approved product. Information on the risks of PROAIR® RESPICLICK can be found in 
the package insert. Additional information regarding benefits and risks of ABS eMDPI to 
patients may be found in the IB. 
In summary, the benefit and risk assessment for ABS eMDPI is favorable following review of 
the outlined data. 
1.3.2. 
Overall Benefit and Risk Assessment for This Study 
This study is in patients 40 years of age or older with exacerbation-prone COPD being conducted 
for assessment of the relationship of the use of ABS eMDPI and other electronically collected 
data with a CE-COPD event. The study data will be used to inform patients, providers, and the 
design of future intervention trials to demonstrate improved clinical outcomes. It is anticipated 
that risks to patients beyond those listed in the PROAIR® RESPICLICK label are unlikely. 


 
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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives and Endpoints 
The study objectives and endpoints are as follows: 
Objective 
Endpoints 
The objectives of this study are to explore the 
pattern and amount of albuterol use (as captured in 
the ABS eMDPI), alone or in combination with 
other study data, preceding a moderate or severe 
CE-COPD (as diagnosed by the investigators per 
the protocol). The hypothesis is that albuterol use 
will increase several days prior to a moderate or 
severe CE-COPD and can serve as a marker of 
COPD deterioration. 
The endpoints of the trial are the primary outcome measure 
(ie, CE-COPD) and the primary outcome predictor (ie, 
albuterol use) alone or in combination with secondary 
predictors (ie, other study data). These predictors of 
CE-COPD will be modeled to determine which patterns 
best predict the subsequent development of CE-COPD.  
For albuterol use, parameters of interest will include (1) the 
total number of inhalations in the days preceding the peak 
of a CE-COPD, (2) the number of days prior to the peak of 
a CE-COPD when albuterol use increased, and (3) the 
number of albuterol uses in the 24 hours preceding a 
CE-COPD. Therefore, endpoints are not designated as 
either primary or secondary.  
In addition to albuterol use, inspiratory flow values (MIF, 
inhalational volume, inhalation duration, and time to MIF), 
SDI, TDS, and baseline information regarding disease state 
and demographics will be studied. These data will be 
analyzed using both a univariate and multivariate approach, 
to determine which patterns best predict the subsequent 
development of a CE-COPD. Inspiratory flow values are 
obtained from the eMDPI, SDI is obtained for a subset of 
patients who agree to participate at specific investigational 
centers (n=100) from an accelerometer worn on the wrist, 
and TDS is obtained for a subset of patients who agree to 
participate at specific investigational centers (n=100) from 
an accelerometer worn on the ankle. Baseline disease state 
and demographic information will be obtained at screening. 
Another objective for this study is to evaluate the 
safety of ABS eMDPI use in patients with 
exacerbation-prone COPD. 
The safety endpoints for this study include the following: 
• 
adverse event data 
• 
physical examinations 
ABS = albuterol sulfate; CE-COPD = clinical exacerbation of COPD; COPD = chronic obstructive pulmonary 
disease; eMDPI = multidose dry powder inhaler with an eModule; MIF = maximal inhalational flow; SDI = sleep 
disruption index; TDS = total daily steps. 
2.1.1. 
Justification of the Endpoints  
The endpoints of the trial are the primary outcome measure (ie, CE-COPD) and the primary 
outcome predictor (ie, albuterol use) alone or in combination with secondary predictors (ie, other 
study data). These predictors of CE-COPD will be modeled to determine which patterns best 
predict the subsequent development of CE-COPD.  
The relationship between subsequent occurrence of CE-COPD and the increased use of SABA, 
deterioration in peak expiratory flow, worsening of symptoms, and physical activity were also 
studied (Jenkins et al 2015, Moy et al 2013).  


 
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In the present trial, SABA use will be monitored electronically concomitant with the CE-COPD 
event. Inspiratory flow values will be used as a surrogate for peak expiratory flow, because the 
study data require no additional patient effort and are also digital and concurrent. SDI is an 
effortless, digital concomitant correlate of sleep disruption, a key COPD symptom complex. 
Furthermore, TDS is an effortless, digital concomitant correlate of dyspnea on exertion, which is 
also a key symptom of COPD deterioration. These parameters therefore are likely to help predict 
the subsequent development of a CE-COPD. 


 
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3. 
STUDY DESIGN 
3.1. 
General Design 
This is a 12-week, multicenter, open-label study to evaluate the relationship between as-needed 
usage of ABS eMDPI and CE-COPD in adult patients at least 40 years of age with exacerbation-
prone COPD. ABS eMDPI is a rescue/reliever agent that includes an eModule on top of the 
approved PROAIR® RESPICLICK inhaler. The on-board electronics and power source are fully 
integrated into the inhaler and are designed to operate for the life of the inhaler without 
intervention. The electronic module records timestamped, pre-defined events such as cap open 
and inhalation parameters. The inclusion of the eModule has been shown to have no impact on 
the dose delivery compared with the approved product without the eModule. 
The study will consist of a screening period of up to 2 weeks and a 12-week intervention period. 
After providing written informed consent, patients will complete a screening visit (visit 1) to 
determine eligibility for the study. Patients will provide medical history (including prior 
medications), complete a physical examination, pregnancy test, if applicable, and review COPD 
exacerbation history. Eligible patients will return to the investigational center within 2 weeks for 
the baseline visit (visit 2). Those meeting entry criteria will be trained on the use of the eMDPI 
device and, upon demonstrated competency, will receive ABS eMDPI devices for use as rescue 
bronchodilators during the study. The screening visit and baseline visit may be combined. 
Patients must use ABS eMDPI as their only rescue agent for the duration of their participation in 
this study and will be advised to place any current rescue pills, inhalers, or nebulizers, including 
SABA, short-acting muscarinic antagonists (SAMAs), or SABA/SAMA combination into 
storage. Patients may continue the use of other COPD and non-COPD medications as advised by 
their physician without changes unless deemed necessary by their physician. Patients will be 
managed according to routine clinical practice by their treating physician with no specific 
study-related instructions provided other than those on the proper use of ABS eMDPI. 
Patients will be contacted by phone on a monthly basis for the collection of information about 
COPD exacerbations and treatments, concomitant medications, and adverse events. A review of 
the instructions for the use of ABS eMDPI and the procedure for replacement and return of ABS 
eMDPI will also occur during the monthly call. 
Patients will receive initial eMDPI devices at visit 2 based on anticipated usage pattern. In the 
event that additional eMDPI devices are needed, patients will be required to visit the 
investigational center to receive them. Patients will be instructed to return all inhalers to the 
investigational center at the last study visit or earlier, including at the early termination visit, as 
well as at any other point if there is a problem with the inhaler. At the last study visit or early 
termination, patients will be queried for adverse events, concomitant medications, and COPD 
exacerbations; a physical examination will be completed; and the patient will subsequently be 
discharged from the trial. 
Two subsets of patients who agree to participate at specific investigational centers and wear an 
accelerometer either on the ankle to measure TDS (n=100) or on the wrist to measure SDI 
(n=100) will be instructed on the proper use of these devices at the baseline visit (visit 2). The 
devices will be worn throughout the 12-week intervention period and will be returned to the 
investigational center at the final visit or upon early termination (visit 5). 


 
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28 
The end of study is defined as the last visit of the last patient.  
The study duration will be approximately 9 months. 
3.2. 
Planned Number of Patients and Countries 
Approximately 500 patients will be screened to achieve 400 enrolled patients. A subset of 
patients (n=100) who agree to participate at specific investigational centers will wear an 
accelerometer on the wrist to measure SDI. A second subset of patients (n=100) who agree to 
participate at specific investigational centers will wear an accelerometer on the ankle to measure 
TDS. 
The number of evaluable patients is planned to be 360. Details on the definition of evaluable 
patients and sample size are given in Section 9. 
The study is planned to be conducted in the United States in approximately 40 investigational 
centers. 
3.3. 
Justification for Study Design and Selection of Population 
The current study is designed to capture the natural history of CE-COPD and to assess the 
relationship of exacerbation events with data that are readily obtainable using ABS eMDPI in a 
routine clinical setting. Thus, there is no control group, and intervention is kept to a minimum 
(ie, only an eModule in surveillance mode and wearable accelerometers are added to routine 
care). 
Prior work has documented a relationship between SABA usage rates and the subsequent 
occurrence of CE-COPD. The hypothesis that SABA reliever use predicts short- and long-term 
exacerbation risk in COPD patients has been evaluated (Jenkins et al 2015). A retrospective 
analysis of data from a study (Sharafkhaneh et al 2012) comparing budesonide/formoterol 
320/9 μg with formoterol 9 μg (both twice daily) in patients with moderate-to-very severe COPD 
was undertaken; reliever salbutamol 90 μg was provided. The first occurrence of reliever use >4 
(low), >10 (medium), and >20 (high) inhalations/day was assessed as a predictor of short-term 
(3-week) exacerbation risk. Mean daily reliever use in the week preceding the 2-month visit was 
investigated as a predictor of the long-term (10-month) exacerbation risk, using intervals of 2 to 
5, 6 to 9, and ≥10 inhalations/day. 
Overall, 810 patients were included (61% male; mean age 63.2 years; post-bronchodilator FEV1 
of 37.7% of predicted). The first occurrence of low, medium, or high reliever use was predictive 
of an exacerbation within the following 3 weeks; exacerbation risk increased significantly with 
increasing reliever use. Mean reliever use over 1 week was predictive of long-term exacerbation 
risk. Patients with a mean use of 2 to 5, 6 to 9, and ≥10 inhalations/day exhibited 21%, 67%, and 
135% higher exacerbation rates, respectively, in the following 10 months, compared with those 
with <2 inhalations/day. Budesonide/formoterol was associated with lower short- and long-term 
exacerbation risk than formoterol in all reliever-use groups. The authors concluded that SABA 
reliever use is a predictor of short- and long-term exacerbation risk in moderate-to-very-severe 
COPD patients with a history of exacerbations receiving budesonide/formoterol or formoterol. 
Previous work has also documented a relationship between physical activity and the subsequent 
occurrence of CE-COPD. In an observational cohort study of 169 persons with COPD 


 
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29 
(Moy et al 2013), physical activity was directly assessed using the StepWatch Activity Monitor, 
an ankle-worn accelerometer that measures daily step count. Also assessed were exercise 
capacity, using the 6-minute walk test (6MWT), and patient-reported physical activity using the 
St. George’s Respiratory Questionnaire Activity Score (SGRQ-AS). Adverse events and 
COPD-related hospitalizations were assessed and validated prospectively over a median of 
16 months. 
Mean daily step count was 5804±3141 steps. Over 209 person-years of observation, there were 
263 adverse events (incidence rate 1.36±1.6 per person-year) and 116 COPD-related 
hospitalizations (incidence rate 0.56±1.09 per person-year). Adjusting for FEV1 percent 
predicted and prednisone use for adverse events in the previous year, for each 1000 fewer steps 
per day walked at baseline, there was an increased rate of adverse events (rate ratio 1.07; 95% 
CI=1.003 to 1.15) and COPD-related hospitalizations (rate ratio 1.24; 95% CI=1.08 to 1.42). 
There was a significant linear trend in decreasing daily step count by quartiles and increasing 
rate ratios for adverse events (p=0.008) and COPD-related hospitalizations (p=0.003). Each 
30-m decrease in 6MWT distance was associated with an increased rate ratio of 1.07 (95% 
CI=1.01 to 1.14) for adverse events and 1.18 (95% CI=1.07 to 1.30) for COPD-related 
hospitalizations. Worsening of SGRQ-AS by 4 points was associated with an increased rate ratio 
of 1.05 (95% CI=1.01 to 1.09) for adverse events and 1.10 (95% CI=1.02 to 1.17) for 
COPD-related hospitalizations. Lower daily step count, lower 6MWT distance, and worse 
SGRQ-AS predict future adverse events and COPD-related hospitalizations, independent of 
pulmonary function and previous adverse event history. These results support the importance of 
assessing physical activity in patients with COPD and provide the rationale to promote physical 
activity as part of exacerbation-prevention strategies.  
The results of the studies reviewed above suggest that patients who develop severe CE-COPDs 
will have a predictable change in their clinical course that could be used to identify patients at 
risk for a severe event. In the current study, information from the eMDPI and the accelerometers 
will be used to determine if changes in these measures can predict the development of severe 
CE-COPD. If appropriate predictors of risk can be determined, patients at risk for severe 
morbidity and possibly mortality could be identified and receive interventions that could change 
the subsequent clinical outcomes. 
3.4. 
Stopping Rules for the Study 
There are no formal rules for early termination of this study. During the conduct of the study, 
serious adverse events will be reviewed as they are reported from the investigational centers to 
identify safety concerns (Section 7.1.5). 
The study may be terminated by the sponsor for any reason at any time. For example, the 
sponsor should terminate the study in the event of: 
• new toxicological or pharmacological findings or safety issues invalidating the earlier 
positive benefit-risk assessment 
• discontinuation of the development of the IMP 
• the number of severe CE-COPDs collected 


 
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If the whole study will be stopped, the patients that are terminated early will be followed 
according to Withdrawal Criteria and Procedures for the Patient (Section 4.3). 
3.5. 
Schedule of Study Procedures and Assessments 
Study procedures and assessments with their time points are presented in Table 1. Detailed 
descriptions of each procedure and assessment are provided in Section 6 (endpoint assessments) 
and Section 7 (safety assessments). Study procedures and assessments by visit are listed in 
Appendix B. 


 
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Table 1: 
Study Procedures and Assessments 
Study period 
Pre-intervention 
 
Intervention 
Visit number 
V1 
V2 
V3a 
V4a 
Vz 
V5 
Day and allowed time windows 
Day -14 to Day 1 
Day 1 
 
Day 28 
±7 days 
Day 56 
± 7 days 
Up to 14 days 
after CE-
COPD start 
date 
Day 84 
±14 days 
Procedures and assessments 
Screening 
Baseline  Phone 
visit 
Phone 
visit 
Exacerbation 
visit 
Final/early 
termination 
visit 
Informed consent 
X 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
Assign patient number 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Prior medication and treatment 
history 
X 
 
 
 
 
 
Physical examination, including 
height and weightb  
X 
 
 
 
X 
X 
Vital signs measurementc  
X 
 
 
 
 
 
Urine pregnancy test for women of 
childbearing potential  
X 
 
 
 
 
X 
Inform patients of study compliance 
for eMDPI and accelerometer and 
requirement for provider visit in the 
event of CE-COPD 
X 
X 
X 
X 
 
 
Assess for COPD exacerbations 
X 
X 
X 
X 
 
X 
Adverse events inquiry 
 
X 
X 
X 
X 
X 
Wearable accelerometers: dispense, 
training, and collectiond  
 
X 
 
 
 
X 
ABS eMDPI: dispense, training, 
collection, and accountabilitye 
 
X 
 
 
X 
X 
Concomitant medication inquiry 
X 
X 
X 
X 
X 
X 
a Investigational centers must obtain source documentation for all COPD exacerbations that occur during the 
treatment period to confirm the accuracy of the information obtained from the patient. 
b Height will be measured at the screening visit only. 
c Vital signs measurements will include blood pressure, respiratory rate, and heart rate. 
d Wearable accelerometers for a subset of patients who agree to participate at specific investigational centers will be 
dispensed at visit 2, and SDI and TDS data will be collected continuously from visit 2 through visit 5 via the 
wearable accelerometer. Instructions for proper use of the devices will be provided to patients at visit 2. The 
devices will be collected at visit 5.  
e Patients will receive initial eMDPI devices at visit 2 based on anticipated usage pattern. In the event that additional 
eMDPI devices are needed, patients will be required to visit the investigational center to receive them. Patients 
will be instructed to return all inhalers to the investigational center at the last study visit or earlier, including at the 
early termination visit, as well as at any other point if there is a problem with the inhaler. Instructions for 
dispensing, proper clinical use, and collecting ABS eMDPI will be provided to patients at visit 2 and reviewed 
during the monthly calls. 


 
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ABS = albuterol sulfate; CE-COPD = clinical exacerbation of chronic obstructive pulmonary disease; COPD= 
chronic obstructive pulmonary disease; eMDPI=multidose dry powder inhaler with an eModule; SDI = sleep 
disruption index; TDS=total daily step; V = visit. 
Note: Screening and baseline visits may be combined. 


 
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4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Prospective waivers (exceptions) from study inclusion and exclusion criteria to allow patients to 
be enrolled are not granted by Teva (Appendix C). 
4.1. 
Patient Inclusion Criteria 
Patients may be enrolled in this study only if they meet all of the following criteria: 
a. The patient is male or female, 40 years of age or older, with a physician diagnosis of 
COPD. The diagnosis should include a history of FEV1/forced vital capacity <70% 
predicted and FEV1 <80% predicted documented in the patient’s chart. 
b. The patient is currently using a SABA reliever plus at least one of the following: 
long-acting beta agonist (LABA), an ICS/LABA, a long-acting muscarinic antagonist 
(LAMA), or a LABA/LAMA. 
c. The patient has had at least 1 episode of moderate or severe CE-COPD as described 
in Section 6.1.1 over the past 12 months before screening. 
d. The patient must be able to demonstrate appropriate use of albuterol from the ABS 
eMDPI. 
e. The patient is able to provide written informed consent. 
f. The patient must be willing and able to comply with study requirements as specified 
in the protocol, including the use of a wearable accelerometer for the subset of 
patients who consent to use of the device. 
g. The patient is willing to discontinue all other rescue or maintenance SABA or 
short-acting anti-muscarinic agents and replace them with the study-provided ABS 
eMDPI for the duration of the trial. 
h. Women of childbearing potential (not surgically sterile or ≥2 years postmenopausal) 
must have exclusively same-sex partners or use a highly effective or acceptable 
method of birth control and must agree to continue the use of this method for the 
duration of the study and for 30 days after discontinuation of the IMP. Highly 
effective methods of birth control are defined as those, alone or in combination, that 
result in a low failure rate (ie, <1% per year) when used consistently and correctly. 
Highly effective methods of birth control in this study include combined (estrogen- 
and progestogen-containing) or progestogen-only hormonal contraception associated 
with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing 
system, bilateral tubal occlusion, vasectomized partner, and sexual abstinence. 
Acceptable birth control methods that result in a failure rate of more than 1% per year 
include: progestogen-only oral hormonal contraception, for which the inhibition of 
ovulation is not the primary mode of action; male or female condom with or without 
spermicide; and cap, diaphragm, or sponge with spermicide. The combination of male 
condom with either cap, diaphragm, or sponge with spermicide (double barrier 
methods) are also considered acceptable, but not highly effective, methods of birth 
control. Additional details can be found in Appendix E.  


 
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4.2. 
Patient Exclusion Criteria 
Patients will not be enrolled in this study if they meet any of the following criteria: 
a. The patient has any clinically significant medical condition (treated or untreated) that, 
in the opinion of the investigator, would interfere with participation in the study. 
b. The patient has any other confounding underlying lung disorder other than COPD. 
c. The patient has used an investigational drug within 5 half-lives of it being 
discontinued, or within 1 month of visit 2, whichever is longer.  
d. The patient is a pregnant or lactating woman or plans to become pregnant during the 
study. Note: Any woman becoming pregnant during the study will be withdrawn from 
the study. 
e. The patient is either an employee or an immediate relative of an employee of the 
investigational center. 
f. The patient is known to be allergic to albuterol or any of the excipients in the IMP or 
rescue medication formulation (ie, lactose [milk protein]). Dietary lactose intolerance 
does not exclude the patient from inclusion in the study or as per the investigator’s 
medical discretion. 
g. The patient has a history of drug or alcohol abuse within 2 years prior to the screening 
visit. 
h. The patient has a history of positive testing for human immunodeficiency virus 
types 1 and 2, hepatitis B, hepatitis C, and tuberculosis. Note: A history of a positive 
tuberculosis skin test without active tuberculosis may be acceptable only if the patient 
has received an accepted prophylactic treatment regimen and has no clinical evidence 
of active disease. Patients with a history of hepatitis C who have undergone treatment 
and achieved a sustained virologic response may be eligible if they meet all other 
selection criteria and receive medical monitor approval. 
i. The patient has symptomatic congestive heart failure. 
j. A member of the patient’s household is participating in the study at the same time. 
4.3. 
Withdrawal Criteria and Procedures for the Patient 
Each patient is free to withdraw from the study at any time, without prejudice to their continued 
care. Patients must be withdrawn from the study if any of the following events occur: 
a. Patient withdraws consent or requests discontinuation from the study for any reason. 
b. Patient develops an illness that would interfere with his/her continued participation. 
c. Patient is noncompliant with the study procedures and assessments or administration 
of ABS eMDPI, in the opinion of the investigator. 
d. Patient takes prohibited concomitant medications as defined in this protocol. 
e. A female patient has a confirmation of pregnancy during the study from a positive 
pregnancy test. 


 
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35 
f. The sponsor requests withdrawal of the patient. 
g. Patient experiences an adverse event or other medical condition that indicates to the 
investigator that continued participation is not in the best interest of the patient. 
Patients should be treated with standard of care after withdrawal from or termination of the 
study, as appropriate. 
Investigators should attempt to obtain information on patients in the case of withdrawal or 
discontinuation. Results of any evaluations and observations, together with a narrative describing 
the reason(s) for withdrawal, must be recorded in the source documents. The electronic case 
report form (eCRF) must document the primary reason for withdrawal or discontinuation. 
See Appendix F for information regarding how the study will define and address patients who 
are lost to follow-up to help limit the amount and impact of missing data. 
If the reason for withdrawal is an adverse event, monitoring will be continued as applicable 
(eg, until the event has resolved or stabilized, until the patient is referred to the care of a 
healthcare professional, or until a determination of a cause unrelated to the IMP or study 
procedure is made). The specific event or test result (including repeated test results, as 
applicable) must be recorded both on the source documentation and in the eCRF; both the 
adverse events eCRF and termination eCRF will be completed at that time. 
All assessments should be performed according to the protocol for the final visit or early 
termination (visit 5) if possible. Patients are required to return the ABS eMDPI (used and 
unused) upon withdrawal from the study.  
4.4. 
Replacement of Patients 
A patient who is enrolled but does not complete the 12-week intervention period will not be 
replaced. 
4.5. 
Rescreening 
A patient who is screened but not enrolled (eg, because inclusion and exclusion criteria were not 
met or enrollment did not occur within the specified time) may be considered for screening again 
if, eg, there is a change in the patient’s medical background or a modification of study inclusion 
and exclusion criteria. 
If the patient is rescreened, an informed consent form (ICF) will need to be re-signed. 
4.6. 
Screening Failure 
Screening failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled. Minimal information includes, but is not limited to, demography, 
screening failure details, eligibility criteria, and any serious adverse events. 


 
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36 
5. 
TREATMENTS 
5.1. 
Investigational Medicinal Products Used in the Study 
Patients will receive initial eMDPI devices at visit 2 based on anticipated usage pattern. In the 
event that additional eMDPI devices are needed, patients will be required to visit the 
investigational center to receive them. Patients will be instructed on proper use of the device, 
including the requirement for use within 60 seconds of opening the cap. Patients will be 
instructed to return all inhalers to the investigational center at the last study visit or earlier, 
including at the early termination visit (visit 5), as well as at any other point if there is a problem 
with the inhaler. Compliance to ABS eMDPI administration will be monitored.  
5.1.1. 
Test Investigational Medicinal Product 
ABS eMDPI is an inhalation-driven MDPI containing a blend of ABS and alpha-lactose 
monohydrate. The inhaler contains 200 actuations, each delivering 90 mcg of albuterol base 
ex-mouthpiece; the inhaler is equipped with a dose counter that shows only even numbers and 
counts down to “0”. 
The plastic inhaler comprises a reservoir containing inhalation powder, a metering system, a 
mouthpiece with dust cover, and an eModule sitting on top of the drug delivery compartment. 
The on-board electronics and power source are fully integrated into the inhaler and are designed 
to operate for the life of the inhaler without intervention. The electronic module records 
timestamped, predefined events such as cap opening and inhalation. 
Additional details may be found in Table 2 and in the IB. 
5.1.1.1. 
Starting Dose and Dose Levels 
The prescribed dose will be 90 mcg, 1 to 2 inhalations every 4 hours as needed. No dose 
escalations are planned.  
5.1.1.2. 
Dose Modification and Dose Stratification 
Not applicable. 
5.1.2. 
Reference Investigational Medicinal Product 
Not applicable. 
5.1.3. 
Placebo Investigational Medicinal Product 
Not applicable. 


 
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37 
Table 2: 
Investigational Medicinal Products Used in the Study 
IMP name 
Test IMP 
Placebo IMP 
Reference IMP 
Trade name  
ABS eMDPI 
Not applicable 
Not applicable 
Formulation 
Inhalation powder 
Not applicable 
Not applicable 
Unit dose strength 
90 mcg 
Not applicable 
Not applicable 
Route of administration 
Inhalation 
Not applicable 
Not applicable 
Dosing instructions 
1 to 2 inhalations every 4 hours 
as needed 
Not applicable 
Not applicable 
Packaging 
IMP will be provided in a box 
Not applicable 
Not applicable 
Manufacturer 
Teva Pharmaceutical 
Industries, Ltd.  
Jerusalem, Israel 
Not applicable 
Not applicable 
ABS=albuterol sulfate; eMDPI=multidose dry powder inhaler with an eModule; IMP=Investigational Medicinal 
Product; Ltd=limited. 
5.2. 
Preparation, Handling, Labeling, Storage, and Accountability for 
Investigational Medicinal Products 
5.2.1. 
Storage and Security 
The investigator or designee must confirm that appropriate temperature conditions have been 
maintained for all IMPs received, and any discrepancies are reported and resolved before use of 
the IMP. 
The IMP must be stored at monitored room temperature (15°C to 25°C [59°F to 77°F]) and not 
exposed to extreme heat, cold, or humidity. 
5.2.2. 
Labeling 
Supplies of IMP will be labeled according to the current International Council for Harmonisation 
(ICH) guidelines on Good Clinical Practice (GCP) and Good Manufacturing Practice and will 
include any locally required statements. 
5.2.3. 
Accountability 
Each IMP shipment will include a packing slip listing the contents of the shipment, return 
instructions, and any applicable forms. 
The investigator is responsible for ensuring that deliveries of IMPs for initial distribution to 
patients and other study materials from the sponsor are correctly received, recorded, handled, and 
safely and properly stored in accordance with the Code of Federal Regulations (CFR) and used 
in accordance with this protocol. All additional dispensing of the IMP will take place at the 
investigational center as needed.  
Only patients enrolled in the study may receive IMP. The investigator (or designee) will instruct 
the patient to store the IMP according to the instructions on the label, if applicable, or will give 
instructions in an appropriate form. Patients will be instructed to return all IMP (empty, partially 


 
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38 
used, and unused inhalers) to the investigational center at the final visit or earlier, including at 
the early termination visit, as well as at any other point if there is a problem with the inhaler. 
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IMP accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). Patients will return all inhalers at the end of the 
study to the investigational center for reconciliation. 
A record of IMP accountability (ie, IMP and other study materials received, used, retained, and 
returned) must be prepared and signed by the principal investigator or designee, with an account 
given for any discrepancies. Empty, partially used, and unused inhalers will be disposed of at the 
end of the study following collection of data from the device and with sponsor’s approval. 
Further guidance and information may be provided in the Study Reference Manual. 
5.3. 
Justification for Investigational Medicinal Products 
5.3.1. 
Justification for Dose of Test Investigational Medicinal Product 
The prescribed dose of ABS eMDPI used in this study (ie, 90 mcg, 1 to 2 inhalations every 
4 hours as needed) was selected based on the prescribing information for PROAIR® 
RESPICLICK, which has the same drug delivery design as ABS eMDPI.  
PROAIR® RESPICLICK is indicated in patients 4 years of age and older for the treatment or 
prevention of bronchospasm with reversible obstructive airway disease and for the prevention of 
EIB. For the relief of acute bronchospasm symptoms, PROAIR® RESPICLICK is recommended 
at a dosage of 2 inhalations (ie, 180 mcg of albuterol base ex-mouthpiece) repeated every 4 to 
6 hours. More frequent administration or a larger number of inhalations is not recommended. In 
some patients, 1 inhalation every 4 hours may be sufficient. The recommended dosage for 
PROAIR® RESPICLICK for prevention of EIB in adults and children 4 years of age or older is 
2 inhalations 15 to 30 minutes before exercise. To date, the overall results of clinical studies 
provide robust and consistent evidence that PROAIR® RESPICLICK is effective for the 
treatment or prevention of bronchospasm in adult and adolescent patients with obstructive airway 
disease. 
5.4. 
Treatment After the End of the Study 
No treatment is planned by the sponsor after the end of the study. Patients should be treated with 
standard of care after withdrawal from or termination of the study, as appropriate. 
5.5. 
Restrictions 
There are no additional restrictions beyond the inclusion and exclusion criteria in this study. 
5.6. 
Prior and Concomitant Medication or Therapy 
Any prior or concomitant medication a patient has had within 30 days before enrollment and up 
to the end of study will be recorded on the eCRF. Trade name and international nonproprietary 
name (if available), indication, dose, and start and end dates of the administered medication will 


 
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39 
be recorded. The sponsor will encode all medication according to the World Health Organization 
drug dictionary. 
The following medications will be prohibited during this study: 
• any immunosuppressive or immunomodulatory agents including, but not limited to, 
methotrexate, cyclosporine, and interferon-α for 2 months prior to Visit 2 
• levalbuterol during the 12-week intervention period 
• other forms of albuterol MDI during the 12-week intervention period 
• any rescue nebulizer (SABA, SAMA or SABA/SAMA) outside of a CE-COPD 
At each investigational center visit and during monthly phone calls, the patients will be asked 
whether they have taken any medications (other than IMP), including over-the-counter 
medications, vitamins, or herbal or nutritional supplements, since the previous visit. 
Concomitant medication and treatment will be recorded through visit 5. 
5.7. 
Procedures for Monitoring Patient Compliance 
The investigator will be responsible for monitoring patient compliance. A check of compliance 
with IMP intake will be performed during each monthly phone call after the IMP has been 
dispensed, and IMP accountability records will be completed. 
If the investigator or the sponsor determines that the patient is not in compliance with the study 
protocol, the investigator and the sponsor should determine whether the patient should be 
withdrawn from the study. 
Exposure to IMP will be assessed as required. 
5.8. 
Randomization and Blinding 
This is a nonrandomized study. All patients will use the one Test IMP, the ABS eMDPI. 
Blinding is not applicable. 
5.9. 
Total Blood Volume 
No blood will be collected for study-related assessments.  


 
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6. 
ASSESSMENT OF EFFICACY 
Efficacy will not be assessed in this study. 
The endpoints of the trial are the primary outcome measure (ie, CE-COPD) and the primary 
outcome predictor (ie, albuterol use) alone or in combination with secondary predictors (ie, other 
study data). These predictors of CE-COPD will be modeled to determine which patterns best 
predict the subsequent development of CE-COPD. Albuterol use, inspiratory flow, SDI, TDS, 
disease state at baseline and demographics at baseline, will be used to evaluate these endpoints. 
6.1. 
Assessments 
6.1.1. 
Clinical Exacerbation of Mild, Moderate, and Severe CE-COPD 
The diagnosis of CE-COPD will be determined by investigators using the following definitions, 
which are based on the GOLD guidelines and those from a publication by Anzueto et al, 
Dransfield et al, and Wedzicha et al. 
In this study, “CE-COPD” is an occurrence of either “severe CE-COPD” or “moderate 
CE-COPD.” “Mild CE-COPD” is defined below for investigator information but is not used 
either for entry criteria or as a measure in this study. 
• Severe CE-COPD is defined as an event that involves worsening respiratory 
symptoms for at least 2 consecutive days requiring treatment with systemic 
corticosteroids (SCS; at least 10 mg prednisone equivalent above baseline [Table 3]) 
and/or systemic antibiotics and a hospitalization for CE-COPD. 
• Moderate CE-COPD is defined as an event that involves worsening respiratory 
symptoms for at least 2 consecutive days requiring treatment with SCS (at least 
10 mg prednisone equivalent above baseline [Table 3]), and/or systemic antibiotics, 
and an unscheduled encounter (such as a phone call, an office visit, an urgent care 
visit, or an emergency care visit) for a CE-COPD, but not a hospitalization. 
• Mild CE-COPD is defined as a worsening of respiratory symptoms for at least 
2 consecutive days requiring self-management by the patient, such as increased 
inhaler use, but not requiring treatment with SCS and/or antibiotics, nor an 
unscheduled visit of any kind. 


 
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Table 3: 
Systemic Glucocorticoid Treatment Equivalent to 10 mg of Prednisone 
Glucocorticoid Treatment 
Dose (mg) Equivalent to 10 mg of 
Prednisone 
Comment 
Cortisone  
50 
Includes parenteral 
Hydrocortisone 
40 
Cortisol 
Prednisolone 
10 
- 
Methylprednisolone 
8 
Medrol: includes parenteral SOLU-
MEDROL® 
Triamcinolone 
8 
- 
Betamethasone 
0.4 
- 
Dexamethasone 
0.4 
Oral or parenteral DECADRON® 
6.1.2. 
Albuterol Use 
Albuterol usage data will be downloaded using extraction software directly from eMDPI devices 
collected from the patients at their final study visit after return of the device to the depot.  
For albuterol use, parameters of interest will include (1) the total number of inhalations in the 
days preceding the peak of a CE-COPD, (2) the number of days prior to the peak of a CE-COPD 
when albuterol use increased, and (3) the number of albuterol uses in the 24 hours preceding a 
CE-COPD. 
6.1.3. 
Inspiratory Flow Values Upon Albuterol Dosing 
Inspiratory flow values will include (1) maximal inhalational flow (MIF), (2) inhalational 
volume, (3) inhalational duration and (4) time to MIF. The inhalational flow data will be 
downloaded using extraction software directly from eMDPI devices collected from the patients 
at their final study visit after return of the device to the depot. 
6.1.4. 
Accelerometry 
From a subset of patients who agree to participate at specific investigational centers, SDI and 
TDS data will be downloaded using extraction software directly from the wearable accelerometer 
devices collected from the patients at their final study visit. A description of the analysis is 
provided in the Statistical Analysis Plan. 
The wearable Philips accelerometer falls into a product classification that the Food and Drug 
Administration (FDA) has deemed 510(k) exempt. 
See the User Guide for a description of care and use of wearable devices. 


 
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7. 
ASSESSMENT OF SAFETY 
In this study, safety will be assessed by qualified study personnel by evaluating reported adverse 
events and physical examinations. 
7.1. 
Adverse Events 
7.1.1. 
Definition of an Adverse Event 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment. 
An adverse event can, therefore, be any unfavorable and unintended physical sign, symptom, or 
laboratory parameter that develops or worsens in severity during the course of this study, or 
significant worsening of the disease under study, or of any concurrent disease, whether or not 
considered related to the test IMP. A new condition or the worsening of a pre-existing condition 
will be considered an adverse event. Stable chronic conditions (such as arthritis) that are present 
before study entry and do not worsen during this study will not be considered adverse events. 
Accordingly, an adverse event can include any of the following: 
• intercurrent illnesses 
• physical injuries 
• events possibly related to concomitant medication 
• drug interactions 
All CE-COPD events require documentation by the Investigator in the CE-COPD Exacerbation 
Page in the eCRF. All evaluations entered into the CE-COPD exacerbation page require an 
in-person visit (Vz “Exacerbation Visit”, see Table 1). This visit can coincide with an 
unscheduled provider visit (Section 6.1.1) or can be scheduled separately if an unscheduled 
provider visit has not occurred. Investigational centers must obtain source documentation of all 
exacerbations of COPD that occur during the treatment period to confirm the accuracy of the 
information obtained from the patient. 
7.1.2. 
Recording and Reporting of Adverse Events 
For recording of adverse events, the study period is defined for each patient as the time period 
from signature of the ICF to the end of visit 5 (Table 1). The period for reporting 
treatment-emergent adverse events is defined as the period after the 1st dose of IMP is 
administered and until end of visit 5. 
All adverse events that occur during the defined study period must be recorded both on the 
source documentation and in the electronic data capture (EDC) system on the adverse event 
eCRF, regardless of the severity of the event or the site investigator’s assessment of the 
relationship of the event to the test IMP. For serious adverse events, the serious adverse event 
form must be completed, and the serious adverse event must be reported in the EDC system 
within 24 hours of knowledge of the event (Section 7.1.5.3.1). The investigator does not need to 
actively monitor patients for adverse events after the defined period. 


 
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At each contact with the patient, the investigator or designee must question the patient about 
adverse events by asking an open-ended question such as “Have you had any unusual symptoms 
or medical problems since the last visit? If yes, please describe.” All reported or observed signs 
and symptoms will be recorded individually, except when considered manifestations of a 
medical condition or disease state. A precise diagnosis will be recorded whenever possible. 
When such a diagnosis is made, all related signs, symptoms, and any test findings will be 
recorded collectively as a single diagnosis on the eCRF and, if it is a serious adverse event, on 
the serious adverse event form, which will then automatically result in the distribution of an 
email to the sponsor. 
The clinical course of each adverse event will be monitored at suitable intervals until resolved, 
stabilized, or returned to baseline; or until the patient is referred for continued care to a 
healthcare professional; or until a determination of a cause unrelated to the test IMP or study 
procedure is made. 
The onset and end dates, duration (in case of adverse event duration of less than 24 hours), action 
taken regarding IMP, treatment administered, and outcome for each adverse event must be 
recorded both on the source documentation and on the eCRF. 
The relationship of each adverse event to test IMP and study procedures and the severity and 
seriousness of each adverse event, as judged by the investigator, must be recorded as described 
below. 
Further details are given in the Safety Monitoring Plan. 
7.1.3. 
Severity of an Adverse Event 
The severity of each adverse event must be recorded as one of the following: 
• Mild: No limitation of usual activities 
• Moderate: Some limitation of usual activities 
• Severe: Inability to carry out usual activities 
7.1.4. 
Relationship of an Adverse Event to the Test Investigational Medicinal Product 
The relationship of an adverse event to the test IMP is characterized as follows: 


 
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Table 4: 
The Relationship of an Adverse Event to the Test IMP 
Term 
Definition 
Clarification 
No reasonable 
possibility 
(not related) 
This category applies to adverse 
events that, after careful 
consideration, are clearly due to 
extraneous causes (disease, 
environment, etc) or to adverse 
events that, after careful medical 
consideration at the time they are 
evaluated, are judged to be unrelated 
to the IMP. 
The relationship of an adverse event may be considered 
“no reasonable possibility” if it is clearly due to 
extraneous causes or if at least 2 of the following apply: 
• 
It does not follow a reasonable temporal sequence 
from the administration of the IMP. 
• 
It could readily have been produced by the patient’s 
clinical state, environmental or toxic factors, or 
other modes of therapy administered to the patient. 
• 
It does not follow a known pattern of response to 
the IMP. 
• 
It does not reappear or worsen when the IMP is 
re-administered. 
Reasonable 
possibility 
(related) 
This category applies to adverse 
events for which, after careful 
medical consideration at the time 
they are evaluated, a connection 
with the administration of IMP 
cannot be ruled out with certainty. 
The relationship of an adverse event may be considered 
“reasonable possibility” if at least 2 of the following 
apply: 
• 
It follows a reasonable temporal sequence from 
administration of the IMP. 
• 
It cannot be reasonably explained by the known 
characteristics of the patient’s clinical state, 
environmental or toxic factors, or other modes of 
therapy administered to the patient. 
• 
It disappears or decreases on cessation or reduction 
in dose. There are important exceptions when an 
adverse event does not disappear after 
discontinuation of the IMP, yet an IMP relationship 
clearly exists. 
• 
It follows a known pattern of response to the IMP. 
7.1.5. 
Serious Adverse Events 
7.1.5.1. 
Definition of a Serious Adverse Event 
A serious adverse event is an adverse event occurring at any dose that results in any of the 
following outcomes or actions: 
• results in death 
• is life-threatening adverse event (ie, 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 
• requires inpatient hospitalization or prolongation of existing hospitalization, which 
means that hospital inpatient admission or prolongation of hospital stay were required 
for treatment of an adverse event, or that they occurred as a consequence of the event  
Hospitalizations scheduled before the patient signed the ICF will not be considered 
serious adverse events, unless there was worsening of the pre-existing condition 
during the patient’s participation in this study. 


 
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• results in persistent or significant disability/incapacity (refers to a substantial 
disruption of one’s ability to conduct normal life functions) 
• is a congenital anomaly/birth defect 
• an important medical event that may not result in death, be life-threatening, or require 
hospitalization, but may jeopardize the patient and may require medical intervention 
to prevent one of the outcomes listed in this definition 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; or the development of drug dependency or drug abuse. Note: Any 
suspected transmission of an infectious agent via a medicinal product is considered an 
important medical event. 
All occurrences of possible drug-induced liver injury that meet Hy’s law criteria, defined as all 
of the below, must be reported by the investigator to the sponsor as a serious adverse event by 
completing the serious adverse event form in the EDC system: 
• alanine aminotransferase or aspartate aminotransferase increase of >3x the upper limit 
of normal (ULN) 
• total bilirubin increase of >2x ULN 
• absence of initial findings of cholestasis (ie, no substantial increase of alkaline 
phosphatase) 
An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a nonserious adverse event and recorded on the adverse event form as indicated in 
Section  7.1.2. 
7.1.5.2. 
Expectedness 
A serious adverse event that is not included in the Adverse Reaction section of the relevant 
reference safety information (RSI) by its specificity, severity, outcome, or frequency is 
considered an unexpected adverse event. The RSI of the ABS eMDPI in this study is the IB. 
A serious adverse event that is not included in the Listing of Adverse Reactions in the IB by its 
specificity, severity, outcome, or frequency is considered an unexpected adverse event. 
The sponsor’s Global Patient Safety and Pharmacovigilance (GPSP) will determine the 
expectedness for all serious adverse events. 
For the purpose of suspected unexpected serious adverse reaction (SUSAR) reporting, the 
version of the IB at the time of occurrence of the SUSAR applies. 
7.1.5.3. 
Reporting a Serious Adverse Event 
7.1.5.3.1. Investigator Responsibility 
To satisfy regulatory requirements, all serious adverse events that occur during the study, 
regardless of judged relationship to administration of the test IMP, must be reported to the 
sponsor by the investigator. The event must be reported within 24 hours of when the investigator 


 
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learns about it. Completing the serious adverse event form and reporting the event must not be 
delayed, even if not all the information is available. The investigator does not need to actively 
monitor patients for adverse events once this study has ended. 
Serious adverse events occurring to a patient after completion of that patient’s last administration 
of IMP should be reported to the sponsor if the investigator becomes aware of such serious 
adverse events. 
The investigator/qualified designee will enter the required information (detailed below) 
regarding the serious adverse event into the appropriate module of the serious adverse event 
form, which will automatically result in distribution of the information to the appropriate sponsor 
contact. If the EDC system is temporarily unavailable or the study has ended, the event, 
including the investigator-determined relationship to IMP, should be reported via a paper 
back-up serious adverse event form to the appropriate sponsor contact. Upon return of the 
availability of the EDC system, the serious adverse event information must be entered into the 
form in the system.  
The following information should be provided to record the event accurately and completely: 
• study number 
• investigator and investigational center identification 
• patient number 
• onset date and detailed description of adverse event 
• investigator’s assessment of the relationship of the adverse event to the test IMP (no 
reasonable possibility, reasonable possibility) 
Additional information includes: 
• age and sex of patient 
• date of first dose of IMP 
• date and amount of last administered dose of IMP 
• action taken 
• outcome, if known 
• severity 
• explanation of assessment of relatedness 
• concomitant medication (including doses, routes of administration, and regimens) and 
treatment of the event 
• pertinent laboratory or other diagnostic test data 
• medical history 
• results of dechallenge/rechallenge, if known 
• for an adverse event resulting in death 
− cause of death (whether or not the death was related to IMP) 


 
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− autopsy findings (if available) 
Each report of a serious adverse event will be reviewed and evaluated by the investigator and the 
sponsor to assess the nature of the event and the relationship of the event to the test IMP, study 
procedures, and to underlying disease. 
Follow-up: When additional relevant information becomes available, the investigator will record 
follow-up information according to the same process used for reporting the initial event as 
described above. The investigator will follow all reportable events until resolved, stabilized, or 
returned to baseline; or until the patient is referred for continued care to a healthcare 
professional; or until a determination of a cause unrelated to the test IMP or study procedure is 
made. 
Duke Clinical Research Institute (DCRI) Safety Surveillance will follow all serious adverse 
events until resolution, stabilization, until otherwise explained, or until the last subject completes 
the final follow-up, whichever occurs first. DCRI Safety Surveillance will report all serious 
adverse events to the sponsor within 1 to 2 business day(s) of receipt. 
For all countries, the sponsor’s GPSP will distribute the Council for International Organizations 
of Medical Sciences form/Extensible Markup Language file to the contract research organization 
(CRO) for submission to the competent authorities, Independent Ethics Committee/Institutional 
Review Board (IEC/IRBs), and investigators, according to regulations. The investigator must 
ensure that the IEC/IRB is also informed of the event in accordance with national and local 
regulations. 
7.1.5.3.2. Sponsor Responsibility 
If a serious unexpected adverse event is believed to be related to the test IMP or study 
procedures, the sponsor will take appropriate steps to notify all investigators participating in 
sponsored clinical studies of ABS eMDPI and the appropriate competent authorities (and 
IEC/IRB, as appropriate). 
In addition to notifying the investigators and competent authorities (and IEC/IRB, as 
appropriate), other action may be required, including the following: 
• altering existing research by modifying the protocol 
• discontinuing or suspending the study 
• modifying the existing consent form and informing all study participants of new 
findings 
• modifying listings of expected toxicities to include adverse events newly identified as 
related to ABS eMDPI 
7.1.6. 
Protocol-Defined Adverse Events not for Expedited Reporting 
For purposes of this protocol, there are no anticipated or previously recognized serious adverse 
events or reactions to be reported to competent authorities in an expedited procedure. 
7.1.7. 
Protocol-Defined Adverse Events of Special Interest 
No protocol-defined adverse events of special interest were identified for this study. 


 
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7.1.8. 
Protocol Deviations Because of an Adverse Event 
If a patient experiences an adverse event or medical emergency, deviations from the protocol 
may be allowed on a case-by-case basis. To ensure patient safety, after the event has stabilized or 
treatment has been administered (or both), the investigator or other physician in attendance must 
contact the physician identified in the Clinical Study Personnel Contact Information section of 
this protocol as soon as possible to discuss the situation. The investigator, in consultation with 
the sponsor, will decide whether the patient should continue to participate in the study. 
7.2. 
Pregnancy 
Any female patient becoming pregnant during the study will discontinue the test IMP. 
All pregnancies of women participating in the study that occur during the study, within at least 
5 half-lives after the end of study are to be reported immediately to the individual identified in 
the Clinical Study Personnel Contact Information section of this protocol, and the investigator 
must provide the sponsor (local safety officer/CRO) with the completed pregnancy form, which 
is a form outside of the eCRF (Section 7.1.5.3). 
The investigator is not required to report patients who are found to be pregnant between 
screening and baseline, provided no protocol-related procedures were applied. 
All female patients who become pregnant will be monitored for the outcome of the pregnancy 
(including spontaneous, elective, or voluntary abortion). If the pregnancy continues to term, the 
outcome (health of the infant up to 8 weeks of age), including details of birth and presence or 
absence of any birth defect, congenital abnormalities, or maternal and newborn complications, 
will be reported to the sponsor. Any complication of pregnancy during the study and any 
complication of pregnancy that the investigator becomes aware of after withdrawal from the 
study will be reported as an adverse event or serious adverse event, as appropriate. 
If the pregnancy in the woman participating in the study does not continue to term, one of the 
following actions will be taken: 
• For a spontaneous abortion, report as a serious adverse event and on the pregnancy 
form. 
• For an elective abortion due to developmental anomalies, report as a serious adverse 
event and on the pregnancy form. 
• For an elective abortion not due to developmental anomalies, report on the pregnancy 
form; do not report as an adverse event. 
7.3. 
Medication Error and Special Situations Related to the 
Investigational Medicinal Products 
Any administration of IMP that is not in accordance with the study protocol should be reported 
either as a violation, if it meets the violation criteria specified in the protocol (Appendix C), or as 
a deviation, in the patient’s source documents, regardless of whether or not an adverse event 
occurs as a result. When meeting protocol violation criteria, all instances of incorrect IMP 
administration should be categorized as “Non-Compliance to investigational medicinal product 
(IMP).” 


 
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The following are types of medication errors and special situations: 
1. Medication error: Any unintentional error in the prescribing, dispensing, or 
administration of a medicinal product while in the control of the healthcare professional, 
patient, or consumer. 
2. Overdose: Administration of a quantity of a medicinal product given per administration 
or cumulatively which is above the maximum recommended dose according to the 
authorized product information. Clinical judgment should always be applied. Any dose of 
IMP (whether the test IMP, reference IMP, or placebo IMP), whether taken intentionally 
or unintentionally, in excess of that prescribed must be immediately reported to the 
sponsor.  
3. Misuse: Situations where the IMP is intentionally and inappropriately used not in 
accordance with the authorized product information. 
4. Abuse: Persistent or sporadic, intentional excessive use of IMP which is accompanied by 
harmful physical or psychological effects. 
5. Off-label use: Situations where an IMP is intentionally used for a medical purpose not in 
accordance with the authorized product information. 
6. Occupational exposure: Exposure to an IMP, as a result of one’s professional or 
non-professional occupation. 
7. Breastfeeding: Suspected adverse reactions which occur in infants following exposure to 
a medicinal product from breast milk. 
7.4. 
Clinical Laboratory Tests 
Any patient who experiences menarche following screening will be required to have a negative 
urine pregnancy test prior to dosing with IMP. If a patient has a positive urine pregnancy test, 
then they will be discontinued from the study. Procedures for reporting pregnancy are provided 
in Section 7.1.5.3. 
7.5. 
Physical Examinations 
Physical examinations, including height (to be obtained at the screening visit only) and weight, 
will be performed at the time points detailed in Table 1.  
A physical examination will include, at a minimum, skin, lungs, cardiovascular, respiratory, 
gastrointestinal, and neurological assessments. Height (to be obtained at the screening visit only) 
and weight will also be measured and recorded. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
7.6. 
Vital Signs 
Vital signs (blood pressure [systolic/diastolic], respiratory rate, and heart rate) will be measured 
at the screening visit (Table 1) for inclusion criteria assessment only and will not be used for 
safety assessment.  


 
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7.7. 
Electrocardiography 
Electrocardiogram will not be measured in this study.  


 
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8. 
ASSESSMENT OF PHARMACOKINETICS/ 
PHARMACODYNAMICS/ 
BIOMARKERS/PHARMACOGENOMICS/ IMMUNOGENICITY/ 
ANCILLARY STUDIES 
Pharmacokinetic, pharmacodynamic, biomarker, pharmacogenomics, immunogenicity, or other 
ancillary parameters will not be evaluated in this study. 


 
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9. 
STATISTICS 
This section describes the statistical 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. After finalization of the statistical analysis plan, any additional analyses or 
changes to analyses that may be required will be fully disclosed and justified in the clinical study 
report (CSR). 
9.1. 
Sample Size and Power Considerations 
Assuming an expected dropout rate of 10%, it is recommended that 400 patients be enrolled so 
that 360 evaluable patients complete the study. These conclusions are based on a review of the 
relevant literature, as follows. 
Based on previous studies of an exacerbation-prone COPD cohort (Dransfield et al 2013, 
Vogelmeier et al 2011, Wedzicha et al 2013, Wedzicha et al 2016), it is expected that 91 (range, 
73 to 110) CE-COPD events will occur over the 12-week evaluation period in this study based 
on reported CE-COPD exacerbation rates of 1.05 and 1.14 events per year. Furthermore, it is 
expected that 14% (14) of total exacerbations will be severe. 
This sample size (ie, n=400 patients, 73 to 110 CE-COPD events) is considered adequate for the 
fulfillment of the study objectives to evaluate the relationship of albuterol use, inspiratory flow, 
SDI, and TDS data associated with a subsequent CE-COPD event. Per a previous study (Jenkins 
et al 2013), a statistically significant relationship was established between daily SABA usage and 
subsequent CE-COPD. 
In the present study, approximately 73 to 110 CE-COPD events are desired because the model’s 
fitting of the current study involves the analysis of multiple predictors as described in more detail 
below. Because the largest model considered has 7 covariates, it is desirable to have at least 
70 events. The probability to observe at least 70 CE-COPD events is higher than 0.99. 
Risk models published in the literature have typically included between 4 and 6 covariates/risk 
factors (Bateman et al 2015, Greenberg et al 2012, Quezada et al 2016) to examine the 
relationship between possible risk factors and a disease. When there is more than 1 covariate 
(risk factor) in the model, multiple logistic regression may be used to estimate the relationship of 
a specific covariate of interest (ie, albuterol use) to a primary outcome (ie, CE-COPD), adjusting 
for the other/remaining covariates (risk factors). In this case, the required sample size to estimate 
such a relationship is greater than that for univariate logistic regression.  
The number of events per variable has been suggested as a criterion for the size of a data set 
(Harrell et al 1984, Laupacis et al 1997, Peduzzi et al 1996,). The rule of thumb when building 
logistic regression models is 1 predictor variable for every 10 events (Peduzzi et al 1996, 
Vittinghoff and McCulloch 2007). Therefore, this sample size would be adequate for predicting 
the primary outcome (CE-COPD) using multiple logistic regression, including the covariate of 
primary interest (ie, albuterol use) and the remaining multiple predictors (inspiratory flow values, 
SDI, and TDS) as potential risk factors for CE-COPD in the model for this patient population. 


 
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9.2. 
Analysis Sets 
9.2.1. 
Intent-to-Treat Analysis Set 
The intent-to-treat (ITT) analysis set will include all enrolled patients regardless of whether or 
not a patient took any IMP. A patient is considered enrolled according to the status reported in 
the database. This analysis population will be used for summarization of patient disposition. 
9.2.2. 
Modified Intent-to-Treat Analysis Set 
The modified intent-to-treat (mITT) analysis set is a subset of the ITT analysis set that will 
include only the patients who used the IMP at least once during the study. This analysis 
population will be used for endpoint analyses. 
9.2.3. 
Safety Analysis Set 
The safety analysis set will include all enrolled patients who receive at least 1 dose of the test 
IMP. This analysis population will be used for analysis and summarization of safety data.  
9.3. 
Data Handling Conventions 
For all variables, only the observed data from the patients will be used in the statistical analyses, 
that is, there is no plan to estimate (impute) missing data, unless otherwise specified in the 
analysis plan.  
9.3.1. 
Handling Withdrawals and Missing Data 
Missing data will not be imputed, unless otherwise specified in the statistical analysis plan. 
9.4. 
Study Population 
The cohort will consist of patients 40 years of age or older with moderate or severe CE-COPD 
(see Section 6.1.1) in the past 12 months.  
9.4.1. 
Patient Disposition 
Data from patients screened; patients screened but not enrolled and reason for non-enrollment; 
patients who are enrolled; patients enrolled but not treated; patients in the ITT, safety, and mITT 
analysis sets; patients who complete the study; and patients who withdraw from the study will be 
summarized using descriptive summary statistics (n, %). Data from patients who withdraw from 
the study will also be summarized by reason for withdrawal using descriptive statistics. 
9.4.2. 
Demographic and Baseline Characteristics 
Patient demographic and baseline characteristics, including medical history and prior 
medications and therapies, will be summarized using descriptive statistics. For continuous 
variables, descriptive statistics (number, mean, standard deviation, median, minimum, and 
maximum) will be provided. For categorical variables, patient counts and percentages will be 
provided. Categories for missing data will be presented if necessary. This will be based on the 
ITT analysis population. 


 
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9.5. 
Endpoint Analysis 
9.5.1. 
Endpoints 
The endpoints of the trial are the primary outcome measure (ie, CE-COPD) and the primary 
outcome predictor (ie, albuterol use) alone or in combination with secondary predictors (ie, other 
study data, including inspiratory flow, SDI, TDS, disease state at baseline, and demographics at 
baseline) of CE-COPD. These predictors of CE-COPD will be modeled to determine which 
patterns best predict the subsequent development of CE-COPD. For albuterol use, examples of 
correlates of CE-COPD of interest include (1) the total number of inhalations in the days 
preceding the peak of a CE-COPD, (2) the number of days prior to the peak of a CE-COPD 
when albuterol use increased, and (3) the number of albuterol uses in the 24 hours preceding a 
CE-COPD.  
Albuterol use and inspiratory flow values are obtained from the eMDPI, SDI is obtained for a 
subset of patients (n=100) from an accelerometer worn on the wrist, and TDS is obtained for a 
subset of patients (n=100) from an accelerometer worn on the ankle. Baseline disease state and 
demographic information will be obtained at screening.  
The following 8 surrogate measures of sleep disruption are available from the accelerometer 
worn on the wrist: (i) sleeptime average total time in bed, (ii) sleeptime average total sleep time, 
(iii) sleeptime average sleep latency time, (iv) sleeptime average wakening after sleep onset, 
(v) total time awake at night, (vi) longest sleeptime wake episode, (vii) daytime average minutes 
asleep, and (viii) longest daytime sleep episode.  
The SDI for analysis in this study is the composite endpoint derived from the summation of 
sleeptime average sleep latency time, longest sleeptime wake episode, and total time awake at 
night. These 3 surrogate measures were correlated significantly with SABA rescue use 
(sleeptime average sleep latency time (r=0.78), longest sleeptime wake episode (r=0.73), and 
total time awake at night (r=0.65) (Krouse et al 2008). 
9.5.2. 
Planned Method of Analysis 
The mITT analysis set (Section 9.2.2) will be used for all endpoint analyses. Individual listings 
will be presented by patient. 
9.5.2.1. 
Endpoint Analysis 
The relationship between albuterol usage and CE-COPD will be analyzed as follows, without 
controlling for multiplicity. 
The multiple device-use-measures will be used as predictors of CE-COPD in the following 
stepwise selection logistic regression models to select significant predictors in a forward manner: 
1. albuterol usage 
2. albuterol usage + inspiratory flow values 
3. albuterol usage + SDI 
4. albuterol usage + TDS 
5. albuterol usage + inspiratory flow values + SDI 


 
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6. albuterol usage + inspiratory flow values + TDS 
The selection of covariates will be performed at the 0.2 level. 
Demographic variables and disease state information collected at study enrollment will also be 
considered as predictors. Because the device-use-measures will be collected continuously over 
time, these measures could be used to derive many potential predictors of risk. For example, with 
respect to albuterol use, a subject using the inhaler 3 times in the span of a 2-day or 3-day period 
could be a strong predictor of a CE-COPD, but a better marker for risk might be 10 times in the 
span of a week. There are no prior robust data to inform these decisions; 1 possible benefit of 
this work will be to examine the relationship between multiple functional forms for the 
device-use-measures to determine which forms have predictive power. 
Furthermore, the effect of including interaction terms in the model (ie, testing the assumption of 
additivity of predictors on the log odds scale) will also be studied. Pair-wise interactions will be 
assessed at the 0.01 significance level to avoid weak interaction signals that would potentially 
not translate when applying the risk score to new cohorts. Goodness-of-fit tests may be applied 
to make sure that the finally selected model fits the data closely. The C-statistic (Hosmer et al 
2013) will be used to compare the goodness of fit of various logistic regression models in terms 
of how well the predictor(s) discriminate between patients with and without CE-COPD.  
9.5.2.2. 
Sensitivity Analysis 
There will be no sensitivity analysis performed in this study. 
9.6. 
Multiple Comparisons and Multiplicity 
Because a goal of all of the analyses in this study is to explore a risk-prediction model, no 
adjustment for multiplicity will be applied. 
9.7. 
Safety Analysis 
Safety analyses will be performed on the safety analysis set (Section 9.2.3). 
Safety assessments and time points are provided in Table 1. 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities. Each 
patient will be counted only once in each preferred term or System Organ Class category for the 
analyses of safety. Summaries will be presented for all adverse events (overall and by severity), 
adverse events determined by the investigator to be related to test IMP (ie, reasonable possibility 
[Section 7.1.4], defined as related or with missing relationship; overall and by severity), serious 
adverse events, and adverse events leading to withdrawal from the study. Patient listings of 
serious adverse events and adverse events leading to withdrawal will be presented. 
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics. 
For continuous variables, descriptive statistics (number, mean, standard deviation, median, 
minimum, and maximum) will be provided for actual values and changes from baseline to each 
time point. For categorical variables, patient counts and percentages will be provided. 
Descriptive summaries of serious adverse events, patient withdrawals due to adverse events, and 


 
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potentially clinically significant abnormal values (physical examination) based on predefined 
criteria will be provided as well. 
If any patient dies during the study, a listing of deaths will be provided, and all relevant 
information will be discussed in the patient narrative included in the CSR. 
9.8. 
Tolerability Analysis 
Tolerability was not specifically defined. 
9.9. 
Planned Interim Analysis 
There will be no formal interim analysis performed in this study. 
9.10. 
Reporting Deviations from the Statistical Analysis Plan 
Deviations from the statistical analysis plan, along with the reasons for the deviations, will be 
described in protocol amendments, the statistical analysis plan, the CSR, or any combination of 
these, as appropriate, and in accordance with applicable national, local, and regional 
requirements and regulations. 


 
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10. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Refer to Appendix C for information regarding quality control and quality assurance. This 
includes information about protocol amendments, deviations and violations, responsibilities of 
the investigator to study personnel, study monitoring, and audit and inspection. 
Details are given in the Study Reference Manual. 


 
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11. 
COMPLIANCE STATEMENT 
This study will be conducted in full accordance with the ICH Harmonised Tripartite Guideline 
for GCP E6 and any applicable national and local laws and regulations (eg, Title 21 CFR 
[21CFR] Parts 11, 50, 54, 56, 312, and 314, Directive 2001/20/EC of the European Parliament 
and of the Council on the approximation of the laws, regulations and administrative provisions of 
the Member States relating to the implementation of GCP in the conduct of clinical trials on 
medicinal products for human use). Any episode of noncompliance will be documented. 
The investigator is responsible for performing the clinical study in accordance with this protocol 
and the applicable GCP guidelines referenced above for collecting, recording, and reporting the 
data accurately and properly. Agreement of the investigator to conduct and administer this 
clinical study in accordance with the protocol will be documented in separate clinical study 
agreements with the sponsor and other forms as required by national competent authorities in the 
country where each investigational center is located. 
The investigator is responsible for ensuring the privacy, health, and welfare of the patients during 
and after the clinical study; and must ensure that trained personnel are immediately available in 
the event of a medical emergency. The investigator and the involved clinical study personnel 
must be familiar with the background and requirements of the study; and with the properties of 
the IMPs as described in the IB or prescribing information. 
The principal investigator at each investigational center has the overall responsibility for the 
conduct and administration of the clinical study at that investigational center and for contacts 
with study management, with the IEC/IRB, and with competent authorities. 
See Appendix D for the ethics expectations of informed consent or assent, competent authorities 
and IEC and IRB, confidentiality regarding study patients, and requirements for registration of 
the clinical study. 


 
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12. 
DATA MANAGEMENT AND RECORD KEEPING 
See Appendix H for information regarding data management and record keeping. This includes 
direct access to source data and documents, data collection, data quality control, and archiving of 
eCRFs and source documents.  
Investigational centers must obtain source documentation of all COPD exacerbations that occur 
during the treatment period to confirm the accuracy of the information obtained from the patient 
at monthly phone calls during the 12-week intervention period. 


 
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13. 
FINANCING AND INSURANCE 
A separate clinical study agreement, including a study budget, will be signed between each 
principal investigator and the sponsor (or the CRO designated by the sponsor) before the IMP is 
delivered. 
Patients in this clinical study are insured in accordance with applicable legal provisions. The 
policy coverage is subject to the full policy terms, conditions, extensions, and exclusions. 
Excluded from the insurance coverage are inter alia, damages to health, and worsening of 
previous existing disease that would have occurred or continued if the patient had not taken part 
in the clinical study. 
The policy of Clinical Trials Insurance will be provided to the investigational centers by the 
sponsor. 
For covered clinical studies (see 21CFR54), the investigator will provide the sponsor with 
financial information required to complete FDA 3454 form. Each investigator will notify the 
sponsor of any relevant changes during the conduct of the study and for 1 year after the study has 
been completed. 


 
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14. 
PUBLICATION POLICY 
See Appendix I for information regarding the publication policy. 


 
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15. 
REFERENCES 
A Comparison of SYMBICORT® pMDI with Formoterol Turbuhaler® in Subjects with COPD. 
ClinicalTrials.gov registration: NCT00419744. 
Allen SC, Jain M, Ragab S, Malik N. Acquisition and short-term retention of inhaler techniques 
require intact executive function in elderly subjects. Age Ageing 2003;32:299-302. 
American Lung Association. Trends in COPD (chronic bronchitis and emphysema): morbidity 
and mortality. American Lung Association, Research and Program Services Division, 
Epidemiology and Statistics Unit 2011. [Accessed 20 June 2016]. Available from: 
http://www.lung.org/finding-cures/our-research/trend-reports/copd-trend-report.pdf. 
Anzueto A, Ferguson GT, Feldman GT, Chinsky K, Seibert A, Emmett A, et al. Effect of 
fluticasone propionate/salmeterol (250/50) on COPD exacerbations and impact on patient 
outcomes. COPD 2009;6:320-9. 
Bateman ED, Buhl R, O’Byrne PM, Humbert M, Reddel HK, Sears MR, et al. Development and 
validation of a novel risk score for asthma exacerbations: the risk score for exacerbations. 
J Allergy Clin Immunol 2015;135:1457-64. 
Dransfield MT, Bourbeau J, Jones PW, Hanania, NA et al. Once-daily inhaled fluticasone 
furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two 
replicate double-blind, parallel-group, randomised controlled trials. Lancet Respir Med 
2013;1:210-23. 
Dolovich MB, Ahrens RC, Hess DR, Anderson P, Dhand R, Rau JL, et al. Device selection and 
outcomes of aerosol therapy: evidence-based guidelines. American College of Chest 
Physicians/American College of Asthma, Allergy, and Immunology. Chest 2005;127:335-71. 
Forest Laboratories, Inc. 2012 COPD Physician Study: Proprietary for Forest Laboratories. 
PowerPoint Presentation. 2012. On file. 
Forest Laboratories, Inc. National Health & Wellness, Restricted to Severe Patients, U.S. 2009: 
Severe Emphysema and/or Chronic Bronchitis. PowerPoint Presentation. 2009. On file. 
Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, 
Management, and Prevention of Chronic Obstructive Pulmonary Disease. Updated 2011. 
[Accessed 20 June 2016]. Available from: 
http://www.goldcopd.org/uploads/users/files/GOLD_Report_2011_Jan21.pdf. 
Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive 
Pulmonary Disease. GOLD, Updated 2016. Accessed www.goldcopd.org. 
Greenberg S, Liu N, Kaur A, Lakshminarayanan M, Zhou Y, Nelsen L, et al. The asthma disease 
activity score: a discriminating, responsive measure predicts future asthma attacks. J Allerg Clin 
Immunol 2012;130:1071-7. 
Harrell FE, Lee K, Califf RM, Pryor DB, Rosati RA. Regression modeling strategies for 
improved prognostic prediction. Stat Med 1984;3:143-52. 
Hosmer DW, Lemeshow S, Sturdivant RX. Applied Logistic Regression (3rd Edition). John 
Wiley and Sons; 2013. 


 
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Jenkins CR, Postma DS, Anzueto AR, Make BJ, Peterson S, Eriksson G, et al. Reliever 
salbutamol use as a measure of exacerbation risk in chronic obstructive pulmonary disease. BMC 
Pulm Med 2015;15:97. 
Kamps AW, van Ewijk EB, Roorda RJ, Brand PL. Poor inhalation technique, even after 
inhalation instructions, in children with asthma. Pediatr Pulmonol 2000;29:39-42. 
Krouse HJ, Yarandi H, McIntosh J, Cowen C, Selim V. Assessing sleep quality and daytime 
wakefulness in asthma using wrist actigraphy, J Asthma 2008;45(5):389-95. 
Larsen JS, Hahn M, Ekholm B, Wick KA. Evaluation of conventional press-and-breathe 
metered-dose inhaler technique in 501 patients. J Asthma 1994;31:193-9. 
Laupacis A, Sekar N, Stiell IG. Clinical prediction rules: a review and suggested modifications 
of methodological standards. JAMA 1997;277:488-94. 
Lenney J, Innes JA, Crompton GK. Inappropriate inhaler use: assessment of use and patient 
preference of seven inhalation devices. EDICI. Respir Med 2000;94:496-500. 
Miniño AM, Xu JQ, Kochanek KD. Deaths: preliminary data for 2008. Natl Vital Stat Rep 
2010;59(2):1-52.  
Molimard M, Raherison C, Lignot S, Depont F, Abouelfath A, Moore N. Assessment of handling 
of inhaler devices in real life: an observational study in 3811 patients in primary care. J Aerosol 
Med 2003;16:249-54. 
Moy ML, Teylan M, Weston NA, Gagnon DR, Garshick E. Daily step count predicts acute 
exacerbations in a US cohort with COPD. PLoS One 2013;8(4):e60400. 
Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein AR. A simulation study of the number 
of events per variable in logistic regression analysis. J Clin Epidemiol 1996;49(12):1373-9. 
Price DB, Pearce L, Powell SR, Shirley J, Sayers MK. Handling and acceptability of the 
Easi-Breathe device compared with a conventional metered dose inhaler by patients and practice 
nurses. Int J Clin Pract 1999;53:31-6. 
Quezada W, Kwak ES, Reibman J, Rogers L, Mastronarde J, Teague WG, et al. Predictors of 
asthma exacerbation among patients with poorly controlled asthma despite inhaled corticosteroid 
treatment. Ann Allergy Asthma Immunol 2016;116:112-7.  
Reilly JJ Jr, Silverman EK, Shapiro SD. Chronic obstructive pulmonary disease. In: Fauci AS, 
Braunwald E, Kasper DL, et al. Harrison’s Principles of Internal Medicine (18th ed). McGraw 
Hill; 2011:2151-9. 
Sharafkhaneh A, Southard JG, Goldman M, Uryniak T, Martin UJ. Effect of 
budesonide/formoterol pMDI on COPD exacerbations: a double-blind, randomized study. Respir 
Med 2012;106(2):257-68. 
US Department of Health and Human Services, National Institutes of Health, National Heart, 
Lung and Blood Institute. Morbidity and Mortality: 2009 Chartbook on Cardiovascular, Lung 
and Blood Diseases. http://www.nhlbi.nih.gov/resources/docs/2009_ChartBook.pdf. Accessed 
June 20, 2016. 


 
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Vittinghoff E, McCulloch CE. Relaxing the rule of ten events per variable in logistic and Cox 
regression. Am J Epidemiol 2007;165:710-8. 
Vogelmeier C, Hederer B, Glaab T, Schmidt H, et al. Tiotropium versus Salmeterol for the 
prevention of exacerbations of COPD. N Engl J Med 2016;364:1093-103. 
Wedzicha JA, Banerji D, Chapman KR, Vestbo J, et al. Indacaterol-Glycopyrronium versus 
Salmeterol-Fluticasone for COPD. N Engl J Med 2016;374:2222-34. 
Wedzicha JA, Decramer M, Ficker JH, Niewoehner DE, et al. Analysis of chronic obstructive 
pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with 
glycopyrronium and tiotropium (SPARK): a randomized, double-blind, parallel-group study. 
Lancet Respir Med 2013;1:199-209. 
Wedzicha JA, Wilkinson T. Impact of chronic obstructive pulmonary disease exacerbations on 
patients and payers. Proc Am Thorac Soc 2006;3(3):218-21. 


 
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16. 
SUMMARY OF CHANGES TO PROTOCOL 
16.1. 
Amendment 03 Dated 26 June 2017 
The primary reason for this amendment is to clarify the population and endpoint events regarding 
moderate and severe clinical exacerbation of chronic obstructive pulminary disease (CE-COPD). 
Additionally, safety reporting processes were streamlined to facilitate single source reporting 
through the electronic data capture (EDC) system. This amendment is considered to be 
substantial (ie, it requires approval by Competent Authority, Independent Ethics Committee 
[IEC], and/or Institutional Review Board [IRB]) by the sponsor. All text that was removed is 
denoted by a strikethrough, and all added text is underlined. Table 1 (Study Procedures and 
Assessments) has been revised to reflect changes described below. Other nonsubstantial changes 
have been made to the protocol (and protocol synopsis, as appropriate). These changes are 
unlikely to affect the safety or rights (physical or mental integrity) of the patients in this clinical 
study or the scientific value of the clinical study. 


 
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Changes to the Protocol 
Original text with changes shown 
New wording 
Reason/justification for change 
CLINICAL STUDY PROTOCOL SYNOPSIS (Other section affected by these changes: Global) 
Number of Patients Planned (Total): Approximately 
500 patients will be screened to achieve 400 enrolled 
patients. A subset of patients (n=100) who agree to 
participate at specific sites investigational centers will 
wear an accelerometer on the wrist to measure sleep 
disruption index (SDI). A second subset of patients 
(n=100) who agree to participate at specific sites 
investigational centers will wear an accelerometer on the 
ankle to measure total daily steps (TDS). 
Number of Patients Planned (Total): Approximately 
500 patients will be screened to achieve 400 enrolled 
patients. A subset of patients (n=100) who agree to 
participate at specific investigational centers will wear 
an accelerometer on the wrist to measure sleep 
disruption index (SDI). A second subset of patients 
(n=100) who agree to participate at specific 
investigational centers will wear an accelerometer on 
the ankle to measure total daily steps (TDS). 
The word “site” was replaced by 
“investigational center” throughout to 
maintain consistency in terminology. 
CLINICAL STUDY PROTOCOL SYNOPSIS (Other section affected by these changes: Section 2.1, Section 9.4) 
Study Population: The cohort will consist of patients 
40 years of age or older with “severe”moderate or severe 
clinical exacerbation of COPD (CE-COPD; defined in 
Section 6.1.1 of the protocol) in the past 12 months. 
Study Population: The cohort will consist of patients 
40 years of age or older with moderate or severe 
clinical exacerbation of COPD (CE-COPD; defined in 
Section 6.1.1 of the protocol) in the past 12 months. 
This change was made to specify that 
CE-COPD can include moderate as 
well as severe exacerbation. 


 
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CLINICAL STUDY PROTOCOL SYNOPSIS (Other sections affected by these changes: Section 1.1, Section 1.3, Section 2, Section 3.1, Section 6, 
Section 6.1.2, Section 9.1, Section 9.5.1) 
Objectives and Endpoints: 
The endpoints of the trial are the primary outcome 
measure (ie, CE-COPD/severe CE COPD) and the 
primary outcome predictor (ie, albuterol use) alone or in 
combination with secondary predictors (ie, other study 
data). These predictors of CE-COPD/severe CE COPD 
will be modeled to determine which patterns best predict 
the subsequent development of CE-COPD/severe CE
COPD. 
For albuterol use, parameters of interest will include (1) 
the total number of inhalations in the days preceding the 
peak of a severe CE-COPD, (2) the number of days prior 
to the peak of a severe CE-COPD when albuterol use 
increased, and (3) the number of albuterol uses in the 24 
hours preceding a severe CE-COPD. Therefore, 
endpoints are not designated as either primary or 
secondary. 
In addition to albuterol use, inspiratory flow values 
(maximal inhalational flow [MIF], inhalational volume, 
inhalation duration, and time to MIF), SDI, TDS, and 
baseline information regarding disease state and 
demographics will be studied. These data will be 
analyzed using both a univariate and multivariate 
approach, to determine which patterns best predict the 
subsequent development of a CE-COPD or severe CE
COPD. 
Objectives and Endpoints: 
The endpoints of the trial are the primary outcome 
measure (ie, CE-COPD) and the primary outcome 
predictor (ie, albuterol use) alone or in combination 
with secondary predictors (ie, other study data). These 
predictors of CE-COPD will be modeled to determine 
which patterns best predict the subsequent 
development of CE-COPD. 
For albuterol use, parameters of interest will include 
(1) the total number of inhalations in the days 
preceding the peak of a CE-COPD, (2) the number of 
days prior to the peak of a CE-COPD when albuterol 
use increased, and (3) the number of albuterol uses in 
the 24 hours preceding a CE-COPD. Therefore, 
endpoints are not designated as either primary or 
secondary. 
In addition to albuterol use, inspiratory flow values 
(maximal inhalational flow [MIF], inhalational 
volume, inhalation duration, and time to MIF), SDI, 
TDS, and baseline information regarding disease state 
and demographics will be studied. These data will be 
analyzed using both a univariate and multivariate 
approach, to determine which patterns best predict the 
subsequent development of a CE-COPD 
This change was made to allow for 
inclusion of all CE-COPD events, not 
just severe events. 
CLINICAL STUDY PROTOCOL SYNOPSIS (Other sections affected by these changes: Section 3.1, Section 3.5 [Table 1, footnote e], Section 5.1, 
Section 5.2.3) 
General Design: Patients will be instructed to return all 
inhalers to the siteinvestigational center at the last study 
visit, at the CE COPD visit, or earlier, including at the 
early termination visit, as well as at any other point if 
there is a problem with the inhaler. 
General Design: Patients will be instructed to return 
all inhalers to the investigational center at the last study 
visit or earlier, including at the early termination visit, 
as well as at any other point if there is a problem with 
the inhaler. 
This parameter was added to clarify 
when the patients should return their 
inhaler to the investigational center. 


 
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CLINICAL STUDY PROTOCOL SYNOPSIS (Other sections affected by these changes: Section 1.3, Section 5.8) 
Method of Randomization and Blinding: This is a 
nonrandomized open label study and there will be no 
blindingsstudy. All patients will use the one Test IMP, 
the ABS eMDPI. Blinding is not applicable. 
Method of Randomization and Blinding: This is a 
nonrandomized study. All patients will use the one 
Test IMP, the ABS eMDPI. Blinding is not applicable. 
The term “open-label” was removed 
from all non-title related text because 
the study does not involve 
randomization. 
CLINICAL STUDY PROTOCOL SYNOPSIS (Other sections affected by these changes: Section 3.1) 
Duration of Patient Participation and Maximal 
Exposure to IMP: The total duration of patient 
participation in the study is planned to be up to 14 weeks 
(2 weeks a screening period of up to 2 weeks and a 12- 
weeks intervention period). 
Duration of Patient Participation and Maximal 
Exposure to IMP: The total duration of patient 
participation in the study is planned to be up to 
14 weeks (a screening period of up to 2 weeks and a 
12-week intervention period). 
This change was made to indicate that 
patient participation in the study 
includes a screening period that is 
2 weeks in duration or less. 
CLINICAL STUDY PROTOCOL SYNOPSIS (Other sections affected by these changes: Section 4.1) 
Inclusion Criteria: Patients may be enrolled in the study 
only if they meet all of the following criteria:  
a. 
The patient is male or female, 40 years of age or 
older, with a physician diagnosis of COPD. The 
diagnosis should include a history within the past 
3 months of forced expiratory volume in 1 second 
(FEV1)/forced vital capacity <70% predicted and FEV1 
<80% predicted documented in the patient’s chart. 
g. The patient is willing to discontinue all other rescue 
or maintenance SABA or short-acting anti-muscarinic 
agents and replace them with the study-provided ABS 
eMDPI for the duration of the trial. 
h. Women of childbearing potential (not surgically 
sterile or ≥2 years postmenopausal) must have 
exclusively same-sex partners or use a highly effective 
method or acceptable method of birth control and must 
agree to continue the use of this method for the duration 
of the study and for 30 days after discontinuation of the 
IMP. Highly effective methods of birth control are 
defined as those, alone or in combination, that result in a 
low failure rate (ie, <1% per year) when used 
consistently and correctly. Highly effective methods of 
birth control in this study include combined (estrogen- 
and progestogen-containing) or progestogen-only 
Inclusion Criteria: Patients may be enrolled in the 
study only if they meet all of the following criteria:  
a. 
The patient is male or female, 40 years of age or 
older, with a physician diagnosis of COPD. The 
diagnosis should include a history of forced expiratory 
volume in 1 second (FEV1)/forced vital capacity <70% 
predicted and FEV1 <80% predicted documented in the 
patient’s chart. 
g. The patient is willing to discontinue all other 
rescue or maintenance SABA or short-acting 
anti-muscarinic agents and replace them with the 
study-provided ABS eMDPI for the duration of the 
trial. 
h. Women of childbearing potential (not surgically 
sterile or ≥2 years postmenopausal) must have 
exclusively same-sex partners or use a highly effective 
or acceptable method of birth control and must agree to 
continue the use of this method for the duration of the 
study and for 30 days after discontinuation of the IMP. 
Highly effective methods of birth control are defined 
as those, alone or in combination, that result in a low 
failure rate (ie, <1% per year) when used consistently 
and correctly. Highly effective methods of birth control 
in this study include combined (estrogen- and 
Clarification added around patient’s 
medical history. 
Verbiage added around acceptable 
method of birth control. 


 
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hormonal contraception associated with inhibition of 
ovulation, intrauterine device, intrauterine hormone-
releasing system, bilateral tubal occlusion, vasectomized 
partner, and sexual abstinence. Acceptable birth control 
methods that result in a failure rate of more than 1% per 
year include: progestogen-only oral hormonal 
contraception, for which the inhibition of ovulation is not 
the primary mode of action; male or female condom with 
or without spermicide; and cap, diaphragm, or sponge 
with spermicide. The combination of male condom with 
either cap, diaphragm, or sponge with spermicide (double 
barrier methods) are also considered acceptable, but not 
highly effective, methods of birth control. 
progestogen-containing) or progestogen-only hormonal 
contraception associated with inhibition of ovulation, 
intrauterine device, intrauterine hormone-releasing 
system, bilateral tubal occlusion, vasectomized partner, 
and sexual abstinence. Acceptable birth control 
methods that result in a failure rate of more than 1% 
per year include: progestogen-only oral hormonal 
contraception, for which the inhibition of ovulation is 
not the primary mode of action; male or female 
condom with or without spermicide; and cap, 
diaphragm, or sponge with spermicide. The 
combination of male condom with either cap, 
diaphragm, or sponge with spermicide (double barrier 
methods) are also considered acceptable, but not highly 
effective, methods of birth control. 


 
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CLINICAL STUDY PROTOCOL SYNOPSIS (Other sections affected by these changes: Section 9.1) 
Statistical Considerations:  
Sample Size Rationale: 
Based on previous studies of an exacerbation-prone 
COPD cohort (Dransfield et al 2013, Vogelmeier et al 
2011, Wedzicha et al 2013, Wedzicha et al 2016), it is 
expected that 9199 (range, 7395 to 110103) CE-COPD 
events will occur over the 12-week evaluation period in 
this study based on reported CE-COPD exacerbation 
rates of 1.05 and 1.14 events per year. Furthermore, it is 
expected that 14% (14) of total exacerbations will be 
severe. 
This sample size (ie, n=400 patients, 7395 to 110103 CE-
COPD events) is considered adequate for the fulfillment 
of the study objectives using univariate and multivariate 
analyses to evaluate the relationship of the pattern of 
albuterol use, inspiratory flow, SDI, and TDS data 
associated with athe subsequent development of a CE-
COPD event. Per a previous study (Jenkins et al 2013), a 
statistically significant relationship was established 
between daily SABA usage and subsequent CE-COPD. 
In the present study, approximately 7395 to 110103 
CE-COPD events are desired because the model’s fitting 
of the current study involves the analysis of multiple 
predictors as described in more detail below. Because the 
largest model considered has 7 covariates, it is desirable 
to have at least 70 events. The probability to observe at 
least 70 CE-COPD events is higher than 0.99. 
Statistical Considerations:  
Sample Size Rationale: 
Based on previous studies of an exacerbation-prone 
COPD cohort (Dransfield et al 2013, Vogelmeier et al 
2011, Wedzicha et al 2013, Wedzicha et al 2016), it is 
expected that 91 (range, 73 to 110) CE-COPD events 
will occur over the 12-week evaluation period in this 
study based on reported CE-COPD exacerbation rates 
of 1.05 and 1.14 events per year. Furthermore, it is 
expected that 14% (14) of total exacerbations will be 
severe. 
This sample size (ie, n=400 patients, 73 to 110 
CE-COPD events) is considered adequate for the 
fulfillment of the study objectives to evaluate the 
relationship of albuterol use, inspiratory flow, SDI, and 
TDS data associated with a subsequent CE-COPD 
event. Per a previous study (Jenkins et al 2013), a 
statistically significant relationship was established 
between daily SABA usage and subsequent CE-COPD. 
In the present study, approximately 73 to 110 
CE-COPD events are desired because the model’s 
fitting of the current study involves the analysis of 
multiple predictors as described in more detail below. 
Because the largest model considered has 7 covariates, 
it is desirable to have at least 70 events. The 
probability to observe at least 70 CE-COPD events is 
higher than 0.99. 
The range of values in the prior sample 
size estimate was based on the mean 
results reported in the literature. The 
updated sample size estimate correctly 
incorporates sample variability into the 
range likely in this study. 
CLINICAL STUDY PROTOCOL SYNOPSIS (Other sections affected by these changes: Section 9.5.2.1) 
Analysis of Endpoints: The relationship between 
albuterol usage and CE-COPD will be analyzed as 
follows, without controlling for multiplicity. 
The multiple device-use-measures will be used as 
predictors of CE-COPD in the following stepwise 
selection logistic regression models to select significant 
predictors in a forward manner: 
Analysis of Endpoints: The relationship between 
albuterol usage and CE-COPD will be analyzed as 
follows, without controlling for multiplicity. 
The multiple device-use-measures will be used as 
predictors of CE-COPD in the following stepwise 
selection logistic regression models to select 
significant predictors in a forward manner: 
Text was added to clarify the multiple 
comparisons within the analyses listed 
below, as well as the addition of a rule 
for covariate selection.  
Text was deleted because the modeling 
of secondary analyses is not part of the 
hypothesis-testing procedure. 


 
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1. albuterol usage 
2. albuterol usage + inspiratory flow values 
3. albuterol usage + SDI 
4. albuterol usage + TDS 
5. albuterol usage + inspiratory flow values + SDI 
6. albuterol usage + inspiratory flow values + TDS 
The selection of covariates will be performed at the 0.2 
level. 
Furthermore, the effect of including interaction terms in 
the model (ie, testing the assumption of additivity of 
predictors on the log odds scale) will also be studied. The 
primary hypothesis under consideration is that >12 
inhalations of SABA dosing will have higher odds of 
CE COPD risk relative to 0 to 12 inhalations per day. 
This dosing scheme is consistent with the approved 
labeling for albuterol inhalation products. Pair-wise 
interactions will be assessed at the 0.01 significance level 
to avoid weak interaction signals that would potentially 
not translate when applying the risk score to new cohorts.  
1. albuterol usage 
2. albuterol usage + inspiratory flow values 
3. albuterol usage + SDI 
4. albuterol usage + TDS 
5. albuterol usage + inspiratory flow values + SDI 
6. albuterol usage + inspiratory flow values + TDS 
The selection of covariates will be performed at the 0.2 
level. 
Furthermore, the effect of including interaction terms 
in the model (ie, testing the assumption of additivity of 
predictors on the log odds scale) will also be studied. 
Pair-wise interactions will be assessed at the 0.01 
significance level to avoid weak interaction signals that 
would potentially not translate when applying the risk 
score to new cohorts. 
SECTION 3.5 STUDY PROCEDURES AND ASSESSMENTS (TABLE 1) (Other section affected by this change: Appendix B [Section 3]) 
Intervention 
Vz 
ABS eMDPI: dispense, training, collection, and 
accountability X 
Intervention 
Vz 
ABS eMDPI: dispense, training, collection, and 
accountability X 
This parameter was added to ensure 
that patients return their inhalers if use 
is continued until the CE-COPD visit. 
SECTION 4.3 WITHDRAWAL CRITERIA AND PROCEDURES FOR THE PATIENT (Other sections affected by these changes: Global) 
The electronic case report form (CRFeCRF) must 
document the primary reason for withdrawal or 
discontinuation. 
The electronic case report form (eCRF) must document 
the primary reason for withdrawal or discontinuation. 
“CRF” was changed to “eCRF” 
globally in order to specify that all 
CRFs are now electronic. 
The specific event or test result (including repeated test 
results, as applicable) must be recorded both on the 
source documentation and in the CRFeCRF; both the 
adverse events eCRFpage and termination page of the 
CRFeCRF will be completed at that time. 
The specific event or test result (including repeated test 
results, as applicable) must be recorded both on the 
source documentation and in the eCRF; both the 
adverse events eCRF and termination eCRF will be 
completed at that time. 
Clarification regarding use of the 
eCRF. 
SECTION 5.1 INVESTIGATIONAL MEDICINAL PRODUCTS USED IN THE STUDY 


 
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Patients will be instructed to return all inhalers to the 
investigational center at the last study visit or earlier, 
including at the early termination visit (visit 5), as well as 
at any other point if there is a problem with the inhaler. 
Patients will be instructed to return all inhalers to the 
investigational center at the last study visit or earlier, 
including at the early termination visit, as well as at 
any other point if there is a problem with the inhaler. 
Text was removed to maintain 
consistency with identical text 
throughout the document. 
SECTION 5.6 PRIOR AND CONCOMITANT MEDICATION OR THERAPY 
The following medications will be prohibited during this 
study: 
• 
any immunosuppressive or immunomodulatory 
agents including, but not limited to, methotrexate, 
cyclosporine, and interferon-α for 2 months prior to 
Visit 2 
• 
levalbuterol during the 12-week intervention period 
• 
other forms of albuterol MDI during the 12-week 
intervention period 
• 
any albuterolrescue nebulizer (SABA, SAMA or 
SABA/SAMA) outside of a CE-COPD 
The following medications will be prohibited during 
this study: 
• 
any immunosuppressive or immunomodulatory 
agents including, but not limited to, methotrexate, 
cyclosporine, and interferon-α for 2 months prior to 
Visit 2 
• 
levalbuterol during the 12-week intervention 
period 
• 
other forms of albuterol MDI during the 12-week 
intervention period 
• 
any rescue nebulizer (SABA, SAMA or 
SABA/SAMA) outside of a CE COPD 
Clarification added regarding 
prohibited nebulizer medications 
during the study. 
SECTION 6.1.1 CLINICAL EXACERBATION OF MILD, MODERATE, AND SEVERE CE-COPD 
The diagnosis of CE-COPD will be determined by 
investigators using the following definitions, which are 
based on the GOLD guidelines and those from a 
publication by Anzueto et al, Dransfield et al, and 
Wedzicha et al. (GOLD 2016, Anzueto et al 2009). 
In this study, “CE-COPD” is an occurrence of either 
“severe CE-COPD” or “moderate CE-COPD.” “Mild 
CE-COPD” is defined below for investigator information 
but is not used either for entry criteria or as a measure in 
this study. 
• 
Severe CE-COPD is defined as an event CE COPD 
that involves worsening respiratory symptoms for at least 
2 consecutive days requiring treatment with systemic 
corticosteroids (SCS; at least 10 mg prednisone 
equivalent above baseline [Table 3]) and/or systemic 
antibiotics, and an unscheduled provider visit such as an 
office visit, urgent care visit, emergency care visit, or and 
a hospitalization for CE-COPD. 
The diagnosis of CE-COPD will be determined by 
investigators using the following definitions, which are 
based on the GOLD guidelines and those from a 
publication by Anzueto et al, Dransfield et al, and 
Wedzicha et al. 
In this study, “CE-COPD” is an occurrence of either 
“severe CE-COPD” or “moderate CE-COPD.” “Mild 
CE-COPD” is defined below for investigator 
information but is not used either for entry criteria or 
as a measure in this study. 
• 
Severe CE-COPD is defined as an event that 
involves worsening respiratory symptoms for at least 
2 consecutive days requiring treatment with systemic 
corticosteroids (SCS; at least 10 mg prednisone 
equivalent above baseline [Table 3]) and/or systemic 
antibiotics and a hospitalization for CE-COPD. 
• 
Moderate CE-COPD is defined as an event that 
involves worsening respiratory symptoms for at least 
The definitions for the varying levels 
of severity of CE-COPD were 
modified. 


 
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• 
Moderate CE-COPD is defined as an event CE
COPD that involves worsening respiratory symptoms for 
at least 2 consecutive days requiring treatment with 
systemic corticosteroidsSCS (at least 10 mg prednisone 
equivalent above baseline [Table 3]), and/or systemic 
antibiotics, but NOTand an unscheduled encounter 
provider visit (such as a phone call, an office visit, an 
urgent care visit, or an emergency care visit), or for a 
CE-COPD, but not a hospitalization. 
• 
Mild CE-COPD is defined as a worsening of 
respiratory symptoms for at least 2 consecutive days 
requiring, self-managedment by the patient, such as 
increased inhaler use,and butdoes not requireing 
treatment with systemic corticosteroidsSCS and/or 
antibiotics, nor an unscheduled visit of any kind. 
2 consecutive days requiring treatment with SCS (at 
least 10 mg prednisone equivalent above baseline 
[Table 3]), and/or systemic antibiotics, and an 
unscheduled encounter (such as a phone call, an office 
visit, an urgent care visit, or an emergency care visit) 
for a CE-COPD, but not a hospitalization. 
• 
Mild CE-COPD is defined as a worsening of 
respiratory symptoms for at least 2 consecutive days 
requiring self-management by the patient, such as 
increased inhaler use, but not requiring treatment with 
SCS and/or antibiotics, nor an unscheduled visit of any 
kind. 
SECTION 6.1.2 ALBUTEROL USE 
For albuterol use, parameters of interest will include (1) 
the total number of inhalations in the days preceding the 
peak of a CE-COPD, (2) the number of days prior to the 
peak of a CE-COPD when albuterol use increased, and 
(3) the number of albuterol uses in the 24 hours 
preceding a CE COPD. 
For albuterol use, parameters of interest will include 
(1) the total number of inhalations in the days 
preceding the peak of a CE-COPD, (2) the number of 
days prior to the peak of a CE-COPD when albuterol 
use increased, and (3) the number of albuterol uses in 
the 24 hours preceding a CE COPD. 
Text was added to maintain 
consistency with identical text 
throughout the document. 
SECTION 7.1.2 RECORDING AND REPORTING OF ADVERSE EVENTS (Other sections affected by these changes: Section 7.1.5.1) 
All adverse events that occur during the defined study 
period must be recorded both on the source 
documentation and in the electronic data capture (EDC) 
system on the adverse event eCRF, regardless of the 
severity of the event or judged the site investigator’s 
assessment of the relationship of the event to the test 
IMP. For serious adverse events, the serious adverse 
event form must be completed, and the serious adverse 
event must be reported immediately in the EDC system 
within 24 hours of knowledge of the event 
(Section 7.1.5.3.1). 
When such a diagnosis is made, all related signs, 
symptoms, and any test findings will be recorded 
collectively as a single diagnosis on the eCRF and, if it is 
All adverse events that occur during the defined study 
period must be recorded both on the source 
documentation and in the electronic data capture 
(EDC) system on the adverse event eCRF, regardless 
of the severity of the event or the site investigator’s 
assessment of the relationship of the event to the test 
IMP. For serious adverse events, the serious adverse 
event form must be completed, and the serious adverse 
event must be reported in the EDC system within 24 
hours of knowledge of the event (Section 7.1.5.3.1). 
When such a diagnosis is made, all related signs, 
symptoms, and any test findings will be recorded 
collectively as a single diagnosis on the eCRF and, if it 
is a serious adverse event, on the serious adverse event 
These changes were made to specify 
the use of eCRFs and the serious 
adverse event form in the EDC system. 


 
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a serious adverse event, on the serious adverse event 
form, which will then automatically result in distribution 
of an email to the sponsor. 
form, which will then automatically result in 
distribution of an email to the sponsor. 
SECTION 7.1.5.3.1 INVESTIGATOR RESPONSIBILITY 
Serious adverse events occurring to a patient after 
completion of that patient’sthe last administration of IMP 
of that patient has ended should be reported to the 
sponsor if the investigator becomes aware of such serious 
adverse eventsthem. 
The investigator/qualified designee will enter the 
required information (detailed below) regarding the 
serious adverse event into the appropriate module of the 
serious adverse event form, which will automatically 
result in distribution of the information to the appropriate 
sponsor contact. If the EDC system is temporarily 
unavailable or the study has ended, the event, including 
the investigator-determined relationship to IMP, should 
be reported via a paper back-up serious adverse event 
form to the appropriate sponsor contact. Upon return of 
the availability of the EDC system, the serious adverse 
event information must be entered into the form in the 
system.The serious adverse event form should be sent to 
the local safety officer (LSO) or designee (a contract 
research organization [CRO] in a country without a 
sponsor LSO) (contact information is in the Clinical 
Study Personnel Contact Information section); the LSO 
will forward the report to the sponsor’s GPSP. 
Follow up: When additional relevant information 
becomes available, the investigator will record follow-up 
information according to the same process used for 
reporting the initial event as described above. The 
investigator will follow all reportable events until 
resolved, stabilized, or returned to baseline; or until the 
patient is referred for continued care to a healthcare 
professional; or until a determination of a cause unrelated 
to the test IMP or study procedure is made. 
Duke Clinical Research Institute (DCRI) Safety 
Surveillance will follow all serious adverse events until 
Serious adverse events occurring to a patient after 
completion of that patient’s last administration of IMP 
should be reported to the sponsor if the investigator 
becomes aware of such serious adverse events. 
The investigator/qualified designee will enter the 
required information (detailed below) regarding the 
serious adverse event into the appropriate module of 
the serious adverse event form, which will 
automatically result in distribution of the information 
to the appropriate sponsor contact. If the EDC system 
is temporarily unavailable or the study has ended, the 
event, including the investigator-determined 
relationship to IMP, should be reported via a paper 
back-up serious adverse event form to the appropriate 
sponsor contact. Upon return of the availability of the 
EDC system, the serious adverse event information 
must be entered into the form in the system. 
Follow-up: When additional relevant information 
becomes available, the investigator will record 
follow-up information according to the same process 
used for reporting the initial event as described above. 
The investigator will follow all reportable events until 
resolved, stabilized, or returned to baseline; or until the 
patient is referred for continued care to a healthcare 
professional; or until a determination of a cause 
unrelated to the test IMP or study procedure is made. 
Duke Clinical Research Institute (DCRI) Safety 
Surveillance will follow all serious adverse events until 
resolution, stabilization, until otherwise explained, or 
until the last subject completes the final follow-up, 
whichever occurs first. DCRI Safety Surveillance will 
report all serious adverse events to the sponsor within 1 
to 2 business day(s) of receipt. 
These changes were made to reflect the 
process of reporting of serious adverse 
events and following up on them until 
resolution. Additionally, changes 
include a contingency plan if the 
electronic systems are temporarily 
unavailable for reporting of events. 


 
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resolution, stabilization, until otherwise explained, or 
until the last subject completes the final follow-up, 
whichever occurs first. DCRI Safety Surveillance will 
report all serious adverse events to the sponsor within 
1 to 2 business day(s) of receipt.Additional information 
(follow up) about any serious adverse event unavailable 
at the initial reporting should be forwarded by the 
investigator within 24 hours of when it becomes known 
to the same address as the initial report. 
For all countries, the sponsor’s GPSP will distribute the 
Council for International Organizations of Medical 
Sciences form/Extensible Markup Language file to the 
LSO/contract research organization (CRO) for 
submission to the competent authorities, Independent 
Ethics Committee/Institutional Review Board 
(IEC/IRBs), and investigators, according to regulations. 
For all countries, the sponsor’s GPSP will distribute 
the Council for International Organizations of Medical 
Sciences form/Extensible Markup Language file to the 
contract research organization (CRO) for submission to 
the competent authorities, Independent Ethics 
Committee/Institutional Review Board (IEC/IRBs), 
and investigators, according to regulations. 
SECTION 7.2 PREGNANCY 
All pregnancies of women participating in the study that 
occur during the study, within at least 5 half-lives after 
the end of study are to be reported immediately to the 
individual identified in the Clinical Study Personnel 
Contact Information section of this protocol, and the 
investigator must provide the sponsor (LSOlocal safety 
officer/CRO) with the completed pregnancy form. The 
process for reporting a pregnancy is the same as that for 
reporting a serious adverse event but using the , which is 
a form outside of the eCRF pregnancy form (Section 
7.1.5.3). 
• 
For a spontaneous abortion, report as a serious 
adverse event and on the pregnancy form. 
• 
For an elective abortion due to developmental 
anomalies, report as a serious adverse event and on the 
pregnancy form. 
All pregnancies of women participating in the study 
that occur during the study, within at least 5 half-lives 
after the end of study are to be reported immediately to 
the individual identified in the Clinical Study 
Personnel Contact Information section of this protocol, 
and the investigator must provide the sponsor (local 
safety officer/CRO) with the completed pregnancy 
form, which is a form outside of the eCRF (Section 
7.1.5.3). 
• 
For a spontaneous abortion, report as a serious 
adverse event and on the pregnancy form. 
• 
For an elective abortion due to developmental 
anomalies, report as a serious adverse event and on the 
pregnancy form. 
These changes were made to indicate 
that pregnancy-related events should 
also be reported on a special pregnancy 
form outside of the eCRF. 
SECTION 7.3 MEDICATION ERROR AND SPECIAL SITUATIONS RELATED TO THE INVESTIGATIONAL MEDICINAL PRODUCTS 
(Other section affected by this change: Appendix C [Protocol Violations]) 


 
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Any administration of IMP that is not in accordance with 
the study protocol should be reported on the CRF either 
as a violation, if it meets the violation criteria specified in 
the protocol (Appendix C), or as a deviation, in the 
patient’s source documents, regardless of whether or not 
an adverse event occurs as a result. When meeting 
protocol violation criteria, all instances of incorrect IMP 
administration should be categorized on the eCRF as 
“Non-Compliance to investigational medicinal product 
(IMP).” 
Any administration of IMP that is not in accordance 
with the study protocol should be reported either as a 
violation, if it meets the violation criteria specified in 
the protocol (Appendix C), or as a deviation, in the 
patient’s source documents, regardless of whether or 
not an adverse event occurs as a result. When meeting 
protocol violation criteria, all instances of incorrect 
IMP administration should be categorized as “Non-
Compliance to investigational medicinal product 
(IMP).” 
Clarification was made to indicate that 
protocol violations are not recorded on 
the eCRF. 
SECTION 9.2 ANALYSIS SETS 
9.2.2 Modified Intent-to-Treat Analysis Set 
The modified intent-to-treat (mITT) analysis set is a 
subset of the ITT analysis set that will include only the 
patients who used the IMP at least onceany time during 
the study. This analysis population will be used for 
endpoint analyses. 
9.2.3 Safety Analysis Set 
The safety analysis set will include all enrolled patients 
who receive at least 1 dose of the test IMP. In this 
analysis population, treatment will be assigned based on 
the treatment patients actually received unless otherwise 
specified. This analysis population will be used for 
analysis and summarization of safety data.  
9.2.2 Modified Intent-to-Treat Analysis Set 
The modified intent-to-treat (mITT) analysis set is a 
subset of the ITT analysis set that will include only the 
patients who used the IMP at least once during the 
study. This analysis population will be used for 
endpoint analyses. 
9.2.3 Safety Analysis Set 
The safety analysis set will include all enrolled patients 
who receive at least 1 dose of the test IMP. This 
analysis population will be used for analysis and 
summarization of safety data. 
Text was deleted because it is not 
applicable to this study. 
SECTION 9.3 DATA HANDLING CONVENTIONS 
9.3 Data Handling Conventions 
For all variables, only the observed data from the patients 
will be used in the statistical analyses, that is, there is no 
plan to estimate (impute) missing data, unless otherwise 
specified in the analysis plan. Detailed data imputation 
rules will be described in the statistical analysis plan, if 
applicable. 
9.3.1 Handling Withdrawals and Missing Data 
Missing data will not be imputed, unless otherwise 
specified in the statistical analysis plan. 
9.3 Data Handling Conventions 
For all variables, only the observed data from the 
patients will be used in the statistical analyses, that is, 
there is no plan to estimate (impute) missing data, 
unless otherwise specified in the analysis plan.  
9.3.1 Handling Withdrawals and Missing Data 
Missing data will not be imputed, unless otherwise 
specified in the statistical analysis plan. 
Minor edit made for clarification. 


 
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SECTION 9.6 MULTIPLE COMPARISONS AND MULTIPLICITY 
Because aSince the goal of all of the this analysesis in 
this study is to explorebuild a risk-prediction model, no 
adjustment for multiplicity will be applied. 
Because a goal of all of the analyses in this study is to 
explore a risk-prediction model, no adjustment for 
multiplicity will be applied. 
Text was edited to add precision of 
language. 
APPENDIX A CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND INSTITUTIONS 
Sponsor’s Representative of Global Patient Safety 
and Pharmacovigilance 
 
, Teva Pharmaceuticals 
 
 
For serious adverse events: 
Send by email to the local safety officer/contract research 
organization (LSO/CRO). The email address will be 
provided in the serious adverse event report form. In the 
event of difficulty transmitting the form, contact the 
sponsor’s study personnel identified above for further 
instruction. 
Sponsor’s Representative of Global Patient Safety 
and Pharmacovigilance 
 
, Teva Pharmaceuticals 
 
 
Instruction no longer applicable per the 
eCRF reporting process. 
Representative’s email address has 
been added. 
APPENDIX G PRODUCT COMPLAINTS 
2. Handling of Investigational Medicinal Product(s) at 
the Investigational Center(s) 
The investigator is responsible for retaining the product 
in question in a location separate from the investigator’s 
clinical study supplies. The sponsor may request that the 
investigator return the product for further evaluation 
and/or analysis. If this is necessary, the clinical study 
monitor or designee will provide the information needed 
for returning the IMP. 
If it is determined that the investigational center must 
return all IMP, the sponsor will provide the information 
needed to handle the return. 
The integrity of the randomization code and 
corresponding blinded clinical supplies will be 
maintained whenever possible. A serious adverse event 
or the potential for a product quality problem existing 
2. Handling of Investigational Medicinal Product(s) 
at the Investigational Center(s) 
The investigator is responsible for retaining the product 
in question in a location separate from the 
investigator’s clinical study supplies. The sponsor may 
request that the investigator return the product for 
further evaluation and/or analysis. If this is necessary, 
the clinical study monitor or designee will provide the 
information needed for returning the IMP. 
If it is determined that the investigational center must 
return all IMP, the sponsor will provide the 
information needed to handle the return. 
Text removed because the study does 
not involve randomization. All patients 
will use the one Test IMP, the ABS 
eMDPI. Blinding not applicable. 


 
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beyond the scope of the complaint may be a reason to 
unblind the clinical supplies for an affected patient. 
APPENDIX H DATA MANAGEMENET AND RECORD KEEPING 
Data Collection 
If data are processed from other sources, these data will 
be sent to the investigational center, where they will be 
retained but not transcribed to the eCRF, unless 
otherwise noted in the protocol. These data may also be 
sent electronically to the sponsor (or organization 
performing data management). All patient data must have 
supportive original source documentation in the medical 
records, or equivalent, before they are transcribed to the 
CRF. Data may not be recorded directly on the CRF and 
considered as source data unless the sponsor provides 
written instructions specifying which data are permitted 
to be recorded directly to the CRF. 
Data Collection 
If data are processed from other sources, these data 
will be sent to the investigational center, where they 
will be retained but not transcribed to the eCRF, unless 
otherwise noted in the protocol. These data may also 
be sent electronically to the sponsor (or organization 
performing data management).  
Duplicate text deleted. 


 
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16.2. 
Amendment 02 Dated 21 March 2017 
The primary reason for this amendment is a re-evaluation of the sample size needed to meet the 
study endpoints. This amendment is considered to be substantial (ie, it requires approval by 
Competent Authority, IEC, and/or IRB) by the Sponsor. All text that was removed is denoted by 
a strikethrough, and all added text is underlined. Table 1 (Study Procedures and Assessments) 
has been revised to reflect changes described below. Other nonsubstantial changes have been 
made to the protocol (and protocol synopsis, as appropriate). These changes are unlikely to affect 
the safety or rights (physical or mental integrity) of the patients in this clinical study or the 
scientific value of the clinical study. 


 
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Changes to the Protocol 
Original text with changes shown 
New wording 
Reason/justification for change 
CLINICAL STUDY PROTOCOL SYNOPSIS (Other section affected by these changes: Section 3.2) 
Number of Investigational Centers Planned: 
50Approximately 40 
Number of Investigational Centers Planned: 
Approximately 40 
The word “approximately” was added to 
match text in the body of the protocol. 
The number of sites was also reduced. 
CLINICAL STUDY PROTOCOL SYNOPSIS (Other sections affected by these changes: Section 3.2 and 9.1) 
Number of Patients Planned (Total): Approximately 
600500 patients will be screened to achieve 
approximately 500400 enrolled patients. 
Approximately 500 patients will be screened to achieve 
400 enrolled patients. 
The sample size was re-evaluated and 
adjusted to meet study endpoints. The 
second instance of the word 
“approximately” was removed from this 
sentence to match text in the body of the 
protocol. 
SECTION 3.1 GENERAL DESIGN 
Those meeting entry criteria will be trained on the use of 
the eMDPI device and, upon demonstrated competency, 
will receive 3 ABS eMDPI devices for use as rescue 
bronchodilators during the study. 
Those meeting entry criteria will be trained on the use of 
the eMDPI device and, upon demonstrated competency, 
will receive ABS eMDPI devices for use as rescue 
bronchodilators during the study. 
The number of devices was removed 
from the sentence to allow for changes 
in the number of devices, if necessary. 
SECTION 3.1 GENERAL DESIGN (Other sections affected by these changes: Section 3.5 [Table 1, footnote e], Section 5.1, and Section 5.2.3) 
Patients will receive initial eMDPI devices at visit 2 and 
subsequently by courier as needed, based on usage 
pattern.based on anticipated usage pattern. In the event 
that additional eMDPI devices are needed, patients will 
be required to visit the investigational center to receive 
them. 
Patients will receive initial eMDPI devices at visit 2 
based on anticipated usage pattern. In the event that 
additional eMDPI devices are needed, patients will be 
required to visit the investigational center to receive 
them. 
This change was made to remove the 
direct-to-patient shipments. Patients will 
be required to visit the site for additional 
eMDPI devices. 
SECTION 3.2 PLANNED NUMBER OF PATIENTS AND COUNTRIES (Other section affected by these changes: Section 9.1) 
The number of evaluable patients is planned to be 
450360. Details on the definition of evaluable patients 
and sample size are given in Section 9. 
The number of evaluable patients is planned to be 360. 
Details on the definition of evaluable patients and sample 
size are given in Section 9. 
The sample size was re-evaluated and 
adjusted to meet study endpoints. 


 
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Original text with changes shown 
New wording 
Reason/justification for change 
SECTION 3.5 STUDY PROCEDURES AND ASSESSMENTS (TABLE 1) (Other section affected by this change: Appendix B [Sections 1, 2, and 3]) 
Pre-intervention 
V1 
Day -14 to Day 01 
Intervention  
V2 
Day 1 ±7 days 
Vz 
±Up to 14 days after CE-COPD start date 
Pre-intervention 
V1 
Day -14 to Day 1 
Intervention 
V2 
Day 1 
Vz 
Up to 14 days after CE-COPD start date 
Day and allowed time windows for 
study visits were corrected for accuracy.  
Descriptive text was added to clarify the 
timeframe for the exacerbation visit 
(Vz). A sentence with similar wording 
was added to Appendix B, Section 3, for 
clarity. 
SECTION 3.5 STUDY PROCEDURES AND ASSESSMENTS (TABLE 1) (Other section affected by this change: Appendix B [Section 2]) 
Intervention 
V5 
Physical examination, including height and weight X 
Intervention 
V5 
Physical examination, including height and weight X 
For consistency with text elsewhere in 
the document, a time point was added to 
clarify that a physical examination will 
be performed at visit 5. 
SECTION 4.1 INCLUSION CRITERIA 
c. 
The patient has had at least 1 episode of moderate or 
severe CE-COPD as described in Section 6.1.1 over the 
past 12 months before screening. 
c. 
The patient has had at least 1 episode of moderate or 
severe CE-COPD as described in Section 6.1.1 over the 
past 12 months before screening. 
Inclusion Criteria “c” was revised to 
include patients who experienced at 
least 1 episode of moderate CE-COPD 
in the 12 months prior to screening. 


 
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Original text with changes shown 
New wording 
Reason/justification for change 
SECTION 4.2 EXCLUSION CRITERIA 
c. 
The patient has used an investigational drug within 
5 half-lives of it being discontinued, or within 1 month of 
visit 2, whichever is longer. 
f. 
The patient is known to be allergic to albuterol or 
any of the excipients in the IMP or rescue medication 
formulation (ie, lactose [milk protein]). Dietary lactose 
intolerance does not exclude the patient from inclusion in 
the study or as per the investigator’s medical 
discretion.or lactose (milk protein). 
h. The patient has a history or presence of “silent” 
infections, includingof positive testing for human 
immunodeficiency virus types 1 and 2, hepatitis B, 
hepatitis C, and tuberculosis. 
c. 
The patient has used an investigational drug within 
5 half-lives of it being discontinued, or within 1 month of 
visit 2, whichever is longer. 
f. 
The patient is known to be allergic to albuterol or 
any of the excipients in the IMP or rescue medication 
formulation (ie, lactose [milk protein]). Dietary lactose 
intolerance does not exclude the patient from inclusion in 
the study or as per the investigator’s medical discretion. 
h. The patient has a history of positive testing for 
human immunodeficiency virus types 1 and 2, hepatitis 
B, hepatitis C, and tuberculosis. 
“Visit 2” was added to Exclusion 
Criteria “c” for clarity. Exclusion 
Criteria “f” was revised to include 
allergy to excipients of the IMP or 
rescue medication formulation; 
clarification regarding lactose 
intolerance was also added. Exclusion 
Criteria “h” was revised to reflect that 
testing to confirm presence of silent 
infections will not be performed in this 
study. 
SECTION 6.1.1 CLINICAL EXACERBATION OF MILD, MODERATE, AND SEVERE CE-COPD 
6.1.1. 
Clinical Exacerbation of Mild, Moderate, and 
Severe CE-COPD 
• 
Severe CE-COPD is defined as a CE-COPD that 
involves worsening respiratory symptoms for at least 2 
consecutive days requiring treatment with systemic 
corticosteroids (at least 10 mg prednisone equivalent 
above baseline [Table 3]) and/or systemic antibiotics, 
and an unscheduled provider visit such as an office visit, 
urgent care visit, emergency care visit, or hospitalization. 
• 
Moderate CE-COPD is defined as a CE-COPD that 
involves worsening respiratory symptoms for at least 2 
consecutive days requiring treatment with systemic 
corticosteroids (at least 10 mg prednisone equivalent 
above baseline [Table 3]) and/or systemic antibiotics, but 
NOT an unscheduled provider visit such as an office 
visit, urgent care visit, emergency care visit, or 
hospitalization. 
• 
Mild CE-COPD is defined as worsening of 
symptoms, self-managed by the patient, and does not 
6.1.1. 
Clinical Exacerbation of Mild, Moderate, and 
Severe CE-COPD 
• 
Severe CE-COPD is defined as a CE-COPD that 
involves worsening respiratory symptoms for at least 2 
consecutive days requiring treatment with systemic 
corticosteroids (at least 10 mg prednisone equivalent 
above baseline [Table 3]) and/or systemic antibiotics, 
and an unscheduled provider visit such as an office visit, 
urgent care visit, emergency care visit, or hospitalization. 
• 
Moderate CE-COPD is defined as a CE-COPD that 
involves worsening respiratory symptoms for at least 2 
consecutive days requiring treatment with systemic 
corticosteroids (at least 10 mg prednisone equivalent 
above baseline [Table 3]) and/or systemic antibiotics, but 
NOT an unscheduled provider visit such as an office 
visit, urgent care visit, emergency care visit, or 
hospitalization. 
• 
Mild CE-COPD is defined as worsening of 
symptoms, self-managed by the patient, and does not 
The title for Section 6.1.1 was revised to 
include the varying levels of severity of 
CE-COPD. The definition of mild 
CE-COPD was added to this section.  
Table 3 (Systemic Glucocorticoid 
Treatment Equivalent to 10 mg of 
Prednisone) was added to this section. 


 
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require treatment with systemic corticosteroids or 
antibiotics. 
 
Table 3: Systemic Glucocorticoid Treatment 
Equivalent to 10 mg of Prednisone 
Glucocorticoid 
Treatment 
Dose (mg) 
Equivalent 
to 10 mg of 
Prednisone 
Comment 
Cortisone  
50 
Includes 
parenteral 
Hydrocortisone 
40 
Cortisol 
Prednisolone 
10 
- 
Methylprednisolone 
8 
Medrol: 
includes 
parenteral 
SOLU-
MEDROL® 
Triamcinolone 
8 
- 
Betamethasone 
0.4 
- 
Dexamethasone 
0.4 
Oral or 
parenteral 
DECADRON® 
require treatment with systemic corticosteroids or 
antibiotics. 
 
Table 3: Systemic Glucocorticoid Treatment 
Equivalent to 10 mg of Prednisone 
Glucocorticoid 
Treatment 
Dose (mg) 
Equivalent 
to 10 mg of 
Prednisone 
Comment 
Cortisone  
50 
Includes 
parenteral 
Hydrocortisone 
40 
Cortisol 
Prednisolone 
10 
- 
Methylprednisolone 
8 
Medrol: 
includes 
parenteral 
SOLU-
MEDROL® 
Triamcinolone 
8 
- 
Betamethasone 
0.4 
- 
Dexamethasone 
0.4 
Oral or 
parenteral 
DECADRON® 


 
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SECTION 6.1.4 ACCELEROMETRY 
From a subset of patients who agree to participate at 
specific sites, SDI and TDS data will be downloaded 
using extraction software directly from the wearable 
accelerometer devices collected from the patients at their 
final study visit or transmitted to the central data center 
via Wi Fi on a daily basis. A description of the analysis 
is provided in the Statistical Analysis Plan. 
The wearable Philips accelerometer to be used in this 
study has been cleared by falls into a product 
classification that the Food and Drug Administration 
(FDA) has deemedthrough a 50101(k) exempt with 
intended uses consistent with those described in this 
study. 
See the Study Reference ManualUser Guide for a 
detailed description of care and use of wearable devices. 
From a subset of patients who agree to participate at 
specific sites, SDI and TDS data will be downloaded 
using extraction software directly from the wearable 
accelerometer devices collected from the patients at their 
final study visit. A description of the analysis is provided 
in the Statistical Analysis Plan. 
The wearable Philips accelerometer falls into a product 
classification that the Food and Drug Administration 
(FDA) has deemed 510(k) exempt. 
See the User Guide for a description of care and use of 
wearable devices. 
The text was revised to reflect that 
accelerometer data will not be 
transmitted via Wi-Fi on a daily basis. 
The location of the description of the 
analysis for SDI and TDS data has been 
added for completeness. The product 
classification was updated. The location 
of the description of care and use of 
wearable devices was corrected. 
SECTION 9.1 SAMPLE SIZE AND POWER CONSIDERATIONS 
Based on previous studies of an exacerbation-prone 
COPD cohort (Dransfield et al 2013, Vogelmeier et al 
2011, Wedzicha et al 2013, Wedzicha et al 2016), it is 
expected that 9399 (range, 78 95 to 107103) CE-COPD 
events will occur over the 12-week evaluation period in 
this study based on reported CE-COPD exacerbation 
rates of 1.05 and 1.14 events per year. Furthermore, it is 
the expected that 14% (14) of total exacerbations will be 
severenumber of CE COPD events requiring systemic 
corticosteroids is 62 (range, 43 to 82) and the expected 
number of severe CE COPD events is 11 (range 10 to 
13). 
This sample size (ie, n=450400 patients, 7895 to 107103 
CE-COPD events) is considered adequate for the 
fulfillment of the study objectives using univariate and 
multivariate analyses to evaluate the relationship of the 
pattern of albuterol use, inspiratory flow, SDI, and TDS 
data associated with the subsequent development of a 
moderate CE-COPD or severe CE-COPD event. Per a 
Based on previous studies of an exacerbation-prone 
COPD cohort (Dransfield et al 2013, Vogelmeier et al 
2011, Wedzicha et al 2013, Wedzicha et al 2016), it is 
expected that 99 (range, 95 to 103) CE-COPD events 
will occur over the 12-week evaluation period in this 
study based on reported CE-COPD exacerbation rates of 
1.05 and 1.14 events per year. Furthermore, it is expected 
that 14% (14) of total exacerbations will be severe. 
This sample size (ie, n=400 patients, 95 to 103 CE-
COPD events) is considered adequate for the fulfillment 
of the study objectives using univariate and multivariate 
analyses to evaluate the relationship of the pattern of 
albuterol use, inspiratory flow, SDI, and TDS data 
associated with the subsequent development of a 
moderate CE-COPD or severe CE-COPD event. Per a 
previous study (Jenkins et al 2013), a statistically 
significant relationship was established between daily 
SABA usage and subsequent CE-COPD. 
The sample size justification and power 
considerations have been revised in light 
of the new sample size. The duration of 
the evaluation period has been 
corrected. 


 
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previous study (Jenkins et al 2013), a statistically 
significant relationship was established between daily 
SABA usage and subsequent CE-COPD. 
In the present study, approximately 7895 to 1037 CE-
COPD events are desired because the model’s fitting of 
the current study involves the analysis of multiple 
predictors as described in more detail below. 
In the present study, approximately 95 to 103 CE-COPD 
events are desired because the model’s fitting of the 
current study involves the analysis of multiple predictors 
as described in more detail below. 
SECTION 9.5.1 ENDPOINTS 
The following 8 surrogate measures of sleep disruption 
are available from the accelerometer worn on the wrist; 
(i) sleeptime average total time in bed, (ii) sleeptime 
average total sleep time, (iii) sleeptime average sleep 
latency time, (iv) sleeptime average wakening after sleep 
onset, (v) total time awake at night, (vi) longest sleeptime 
wake episode, (vii) daytime average minutes asleep, and 
(viii) longest daytime sleep episode.  
The SDI for analysis in this study is the composite 
endpoint derived from the summation of sleeptime 
average sleep latency time, longest sleeptime wake 
episode, and total time awake at night. These 3 surrogate 
measures were correlated significantly with SABA 
rescue use (sleeptime average sleep latency time 
(r=0.78), longest sleeptime wake episode (r=0.73), and 
total time awake at night (r=0.65) (Krouse et al 2008). 
 
The following 8 surrogate measures of sleep disruption 
are available from the accelerometer worn on the wrist; 
(i) sleeptime average total time in bed, (ii) sleeptime 
average total sleep time, (iii) sleeptime average sleep 
latency time, (iv) sleeptime average wakening after sleep 
onset, (v) total time awake at night, (vi) longest sleeptime 
wake episode, (vii) daytime average minutes asleep, and 
(viii) longest daytime sleep episode.  
The SDI for analysis in this study is the composite 
endpoint derived from the summation of sleeptime 
average sleep latency time, longest sleeptime wake 
episode, and total time awake at night. These 3 surrogate 
measures were correlated significantly with SABA 
rescue use (sleeptime average sleep latency time 
(r=0.78), longest sleeptime wake episode (r=0.73), and 
total time awake at night (r=0.65) (Krouse et al 2008). 
 
The surrogate measures of sleep 
disruption available from the 
accelerometer were added. The analysis 
of the SDI endpoints in this study was 
explained. 
APPENDIX A CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND INSTITUTIONS 
Contract Research Organization 
PPDDCRI 
Contract Research Organization 
DCRI 
The Contract Research Organization 
used in this study was changed. 
APPENDIX B STUDY PROCEDURES AND ASSESSMENTS BY VISIT (SECTION 2.C) 
• 
collect wearable accelerometer, if applicable 
• 
collect wearable accelerometer, if applicable 
“If applicable” was added for clarity. 


 
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16.3. 
Amendment 01 Dated 29 September 2016 
The primary reason for this amendment is to clarify the definition, collection, and recording of 
CE-COPD events. This amendment is considered to be substantial (ie, it requires approval by 
Competent Authority, IEC. and/or IRB) by the Sponsor. All text that was removed is denoted by 
a strikethrough, and all added text is underlined. Other nonsubstantial changes have been made 
to the protocol (and protocol synopsis, as appropriate). These changes are unlikely to affect the 
safety or rights (physical or mental integrity) of the patients in this clinical study or the scientific 
value of the clinical study. 


 
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Changes to the Protocol 
Original text with changes shown 
New wording 
Reason/justification for change 
Section 1.1 Introduction (Other sections affected by these changes: Sections 2.1, 3.1, 3.2, 3.5 [Table 1, Footnote d], and 6.1.4) 
In addition, a subset of patients who agree to participate 
at specific sites will wear an accelerometer on the wrist 
as a marker of nighttime awakening sleep disruption, 
and a second subset of patients who agree to participate 
at specific sites will wear an accelerometer on the ankle 
to quantify daily physical activity. 
In addition, a subset of patients who agree to 
participate at specific sites will wear an accelerometer 
on the wrist as a marker of sleep disruption, and a 
second subset of patients who agree to participate at 
specific sites will wear an accelerometer on the ankle 
to quantify daily physical activity. 
“At specific sites” was added to denote 
that the accelerometer will be given at 
sites that agree to support the use of the 
accelerometer. 
Clarification: “nighttime awakening” was 
changed to “sleep disruption” and 
“physical” was added to daily activity to 
more appropriately describe these 
measurements.  
Section 1.3.1 Known and Potential Benefits and Risks (Other sections affected by these changes: Sections 2.1, 2.1.1, and 9.1) 
This open-label study is being undertaken to determine 
if a specific pattern of changes in ABS eMDPI use can 
predict a patient’s risk for subsequent development of a 
moderate CE-COPD or severe CE-COPD event. 
This open-label study is being undertaken to 
determine if a specific pattern of changes in ABS 
eMDPI use can predict a patient’s risk for subsequent 
development of a moderate CE-COPD or severe 
CE-COPD event. 
This change was made to clarify that this 
study’s endpoints will focus on moderate 
and severe CE-COPD events and not all 
CE-COPD events.  
Section 2.1 Study Objectives and Endpoints 
The objectives of this study are to determine explore the 
pattern and amount of albuterol use (as captured in the 
ABS eMDPI), alone or in combination with other study 
data,  
The objectives of this study are to explore the pattern 
and amount of albuterol use (as captured in the ABS 
eMDPI), alone or in combination with other study 
data, 
This change was made because 
“determine” was not the correct verb. 
Section 2.1 Study Objectives and Endpoints (Other sections affected by these changes: Sections 6.1.2, and 9.5.1) 
For albuterol use, parameters of interest will include 
(1) the total number of inhalations in the days preceding 
the peak of a severe CE-COPD, (2) the number of days 
prior to the peak of a severe CE-COPD when albuterol 
use increased, and (3) the number of albuterol uses in 
the 24 hours preceding a severe CE-COPD. 
For albuterol use, parameters of interest will include 
(1) the total number of inhalations in the days 
preceding the peak of a severe CE-COPD, (2) the 
number of days prior to the peak of a severe CE-
COPD when albuterol use increased, and (3) the 
number of albuterol uses in the 24 hours preceding a 
severe CE-COPD. 
This change was made to further define 
the parameters that will be assessed as 
endpoints in this study. 


 
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Section 3.1 General Design (Other sections affected by this change: Section 3.5 [Table 1, Footnote e] and 5.1) 
Patients will be instructed to return all inhalers to the 
site at the last study visit or early termination. At the 
last study visit, sites must obtain all ABS eMDPI 
devices; patients will be queried for adverse events, 
concomitant medications, and asthma exacerbations; a 
physical examination will be completed; and the patient 
will subsequently be discharged from the trial. 
Patients will be instructed to return all inhalers to the 
site at the last study visit or early termination. At the 
last study visit, patients will be queried for adverse 
events, concomitant medications, and asthma 
exacerbations; a physical examination will be 
completed; and the patient will subsequently be 
discharged from the trial. 
The text “or early termination. At the last 
study visit” was added for clarification. 
The text “sites must obtain all ABS 
eMDPI devices” was removed as 
redundant. 
Section 3.1 General Design (Other sections affected by these changes: Section 3.2) 
The study duration will be approximately 9 months., 
from the 4th quarter of 2016 through the 3rd quarter of 
2017. 
The study duration will be approximately 9 months. 
This change was made to allow flexibility 
in the start and stop times of the study.  
Two subsets of patients who agree to participate at 
specific sites and wear an accelerometer either on the 
ankle to measure daily activity TDS (n=100) or on the 
wrist to measure sleep quality SDI (n=100) will be 
instructed on the proper use of these devices at the 
baseline visit 
Two subsets of patients who agree to participate at 
specific sites and wear an accelerometer either on the 
ankle to measure TDS (n=100) or on the wrist to 
measure SDI (n=100) will be instructed on the proper 
use of these devices at the baseline visit 
SDI and TDS were used for consistency 
after defined at first use in Section 1.3.1. 
Section 3.3 Justification for Study Design and Selection of Population 
Of relevance to current study design, Prior work has 
documented a relationship between SABA usage rates 
and the subsequent occurrence of CE-COPD. 
Prior work has documented a relationship between 
SABA usage rates and the subsequent occurrence of 
CE-COPD. 
This change was made because the 
language was superfluous.  
Section 3.5 Study Procedures and Assessments, Table 1, Footnote a (Other sections affected by these changes: Section 12) 
a 
Investigational centers must obtain source 
documentation of all COPD exacerbations that occur 
during the treatment period to confirm the accuracy of 
the information obtained from the patient. 
a 
Investigational centers must obtain source 
documentation of all COPD exacerbations that occur 
during the treatment period to confirm the accuracy of 
the information obtained from the patient. 
This change was made to clarify the time 
period for which collection and 
documentation of CE-COPD events is 
required.  


 
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Original text with changes shown 
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Section 4.2 Exclusion Criteria 
d. The patient has or has had CAE within 4 weeks of 
baseline. 
d. [Criterion deleted] 
Exclusion Criterion d was deleted 
because the risk of CE-COPD is highest 
in the 30-day period following an 
exacerbation, and the pattern of albuterol 
use is of great interest from the research 
and clinical perspective. 
i. 
The patient has symptomatic congestive heart 
failure. 
j. 
The patient has symptomatic congestive heart 
failure. 
This exclusion criterion was added 
because these patients are at highest risk 
of worsened dyspnea, for which the 
etiology is often unclear. Therefore, 
rescue albuterol use may be particularly 
inaccurate in these patients. 
Section 5.1 Investigational Medicinal Products Used in the Study 
Patients will be instructed on the proper use of the 
device, including the requirement for use within 
60 seconds of opening the cap.  
Patients will be instructed on the proper use of the 
device, including the requirement for use within 
60 seconds of opening the cap.  
This change was made to specify the need 
to use the device within 60 seconds of 
opening the cap or it will time out, and no 
inhalation data will be collected. 
Section 5.1 Investigational Medicinal Products Used in the Study (Table 2 Investigational Medicinal Products Used in the Study) 
Packaging: IMP will be provided in a foil pouch within 
a box 
Packaging: IMP will be provided in a box 
Language was updated to correct the 
description of the packaging of IMP 
Section 5.2.1 Storage and Security 
The IMP must be stored at monitored room temperature 
(15ºC to 25ºC [59ºF to 77ºF] and not exposed to 
extreme heat, cold, or humidity.  
The IMP must be stored at monitored room 
temperature (15ºC to 25ºC [59ºF to 77ºF] and not 
exposed to extreme heat, cold, or humidity. 
Language updated to ensure the 
investigational centers keep the IMP in 
monitored conditions. 


 
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Section 5.2.3 Accountability 
Patients will be instructed to return all IMP (empty, 
partially used, and unused inhalers) to the 
investigational center at the final visit or at early 
termination. 
The investigator, institution, or the head of the medical 
institution (where applicable) is responsible for IMP 
accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition 
records). Patients will return all inhalers at the end of 
the study to the site for reconciliation. 
Patients will be instructed to return all IMP (empty, 
partially used, and unused inhalers) to the 
investigational center at the final visit or at early 
termination. 
The investigator, institution, or the head of the 
medical institution (where applicable) is responsible 
for IMP accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final 
disposition records). Patients will return all inhalers at 
the end of the study to the site for reconciliation. 
These changes were made to further 
instruct the investigational centers on the 
need for patients to return all devices at 
the end of the study.  
Section 6.1.1 Clinical Asthma Exacerbation 
In this study, “CE-COPD” is an occurrence of either 
“severe CE-COPD” or “moderate CE-COPD.” 
• 
Severe CE-COPD is defined as a CE-COPD that 
involves worsening respiratory symptoms for at least 2 
consecutive days requiring treatment with systemic 
corticosteroids (at least 10 mg prednisone equivalent 
above baseline) and/or systemic antibiotics, and an 
unscheduled provider visit such as an office visit, urgent 
care visit, emergency care visit, or hospitalization.  
• 
Moderate CE-COPD is defined as a CE-COPD that 
involves worsening respiratory symptoms for at least 2 
consecutive days requiring treatment with systemic 
corticosteroids (at least 10 mg prednisone equivalent 
above baseline) and/or systemic antibiotics, but NOT an 
unscheduled provider visit such as an office visit, urgent 
care visit, emergency care visit, or hospitalization. 
In this study, “CE-COPD” is an occurrence of either 
“severe CE-COPD” or “moderate CE-COPD.” 
• 
Severe CE-COPD is defined as a CE-COPD that 
involves worsening respiratory symptoms for at least 
2 consecutive days requiring treatment with systemic 
corticosteroids (at least 10 mg prednisone equivalent 
above baseline) and/or systemic antibiotics, and an 
unscheduled provider visit such as an office visit, 
urgent care visit, emergency care visit, or 
hospitalization.  
• 
Moderate CE-COPD is defined as a CE-COPD 
that involves worsening respiratory symptoms for at 
least 2 consecutive days requiring treatment with 
systemic corticosteroids (at least 10 mg prednisone 
equivalent above baseline) and/or systemic antibiotics, 
but NOT an unscheduled provider visit such as an 
office visit, urgent care visit, emergency care visit, or 
hospitalization. 
This text was added to further define 
severe CE-COPD and moderate CE-
COPD for clearer diagnosis of CE-COPD 
by the investigator. 


 
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Original text with changes shown 
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Reason/justification for change 
Section 6.1.1 Clinical Asthma Exacerbation (Other sections affected by these changes: Section 7.1.1) 
All CE COPD events require a visit to the 
investigational center and will be documented by the 
investigator in the CE COPD Exacerbation Page in the 
CRF. Investigational centers must obtain source 
documentation of all COPD exacerbations to confirm 
the accuracy of the information obtained from the 
patient. 
All CE-COPD events require documentation by the 
Investigator in the CE-COPD Exacerbation Page in 
the CRF. All evaluations entered into the CE-COPD 
exacerbation page require an in-person visit (Vz 
“Exacerbation Visit”, see Table 1). This visit can 
coincide with an unscheduled provider visit (Section 
6.1.1) or can be scheduled separately if an 
unscheduled provider visit has not occurred. 
Investigational centers must obtain source 
documentation of all exacerbations of COPD that 
occur during the treatment period to confirm the 
accuracy of the information obtained from the patient. 
The text was moved from Section 6.1 to 
Section 7.1.1 because it is the more 
appropriate section for discussing adverse 
events. The text was updated to provide 
clearer instructions on the collecting and 
reporting requirements for CE-COPD. 
Section 6.1.2 Albuterol Use (Other sections affected by this change: Section 6.1.3) 
Albuterol usage data will be downloaded using 
extraction software directly from eMDPI devices 
collected from the patients at their first study visit after 
return of the device to the depot. 
Albuterol usage data will be downloaded using 
extraction software directly from eMDPI devices 
collected from the patients at their first study visit 
after return of the device to the depot. 
Language was added for clarification. 
Section 6.1.4 Accelerometry 
The wearable accelerometer to be used in this study has 
been cleared by the Food and Drug Administration 
(FDA) through a 501(k) with intended uses consistent 
with those described in this study. 
The wearable accelerometer to be used in this study 
has been cleared by the Food and Drug Administration 
(FDA) through a 501(k) with intended uses consistent 
with those described in this study. 
This language was added to provide 
information on the accelerometer used in 
the study.  
Section 7.4 Clinical Laboratory Tests 
Any patient who experiences menarche following 
screening will be required to have a negative urine 
pregnancy test prior to dosing with IMP at 
randomization. 
Any patient who experiences menarche following 
screening will be required to have a negative urine 
pregnancy test prior to dosing with IMP. 
This change was made to remove the 
reference to randomization, as this study 
is open-label.  
Section 9.5.2.1 Endpoint Analysis 
7. albuterol usage + SDI + TDS  
8. albuterol usage + inspiratory flow values + 
SDI + TDS 
 
Models 7 and 8 cannot be measured as 
originally proposed because SDI and TDS 
are subsets of patients. Therefore, the 
models were deleted 


 
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Original text with changes shown 
New wording 
Reason/justification for change 
Furthermore, the effect of including interaction terms in 
the model (ie, testing the assumption of additivity of 
predictors on the log odds scale) will also be studied. 
The primary hypothesis under consideration is that >12 
inhalations of SABA dosing will have higher odds of 
CE-COPD risk relative to 0 to 12 inhalations per day. 
This dosing scheme is consistent with the approved 
labelling for albuterol inhalation products. Pair-wise 
interactions will be assessed at the 0.01 significance 
level to avoid weak interaction signals that would 
potentially not translate when applying the risk score to 
new cohorts 
Furthermore, the effect of including interaction terms 
in the model (ie, testing the assumption of additivity 
of predictors on the log odds scale) will also be 
studied. The primary hypothesis under consideration 
is that >12 inhalations of SABA dosing will have 
higher odds of CE-COPD risk relative to 0 to 12 
inhalations per day. This dosing scheme is consistent 
with the approved labelling for albuterol inhalation 
products. Pair-wise interactions will be assessed at the 
0.01 significance level to avoid weak interaction 
signals that would potentially not translate when 
applying the risk score to new cohorts 
This change was made to further explain 
the analysis model for the endpoints of 
the study. 
Appendix G Product Complaints 
 
Added Appendix G - Product Complaints 
This appendix was added because of an 
oversight from the original protocol that it 
should be included. 


 
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APPENDIX A. CLINICAL LABORATORIES AND OTHER 
DEPARTMENTS AND INSTITUTIONS 
Sponsor’s Authorized Representative 
 
 
 Teva Pharmaceuticals 
 
Sponsor’s Medical Expert/Contact Point Designated 
by the Sponsor for Further Information on the Study 
 
 
 Teva Pharmaceuticals 
 
Sponsor’s Representative of Global Patient Safety 
and Pharmacovigilance 
 
, Teva Pharmaceuticals 
 
 
Contract Research Organization 
DCRI 
Digital Wearable Device Vendor 
This information will be provided in the Trial Master 
File. 


 
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APPENDIX B. STUDY PROCEDURES AND ASSESSMENTS BY VISIT 
1. Procedures During Screening Visit (Visit 1, Day -14 to Day 1) 
The screening visit (visit 1) will take place not more than 2 weeks before the baseline visit 
(visit 2) and may occur at the same time as the baseline visit (visit 2). The following 
procedures will be performed at visit 1: 
• obtain written informed consent before any study-related procedures are performed 
• review inclusion and exclusion criteria 
• assign patient number 
• obtain medical history 
• obtain prior medication and treatment history 
• physical examination, including height and weight 
• vital signs measurements, including blood pressure, respiratory rate, and heart rate 
• urine pregnancy test for women of childbearing potential 
• inform patients of study compliance for multidose dry powder inhaler with an 
eModule (eMDPI) and accelerometer and requirement for provider visit in the event 
of a clinical exacerbation of COPD (CE-COPD) 
• assess for COPD exacerbations 
• prior and concomitant medication inquiry 
2. Procedures During Intervention Period 
a. Baseline Visit (Visit 2, Day 1) 
Patients who meet the inclusion and exclusion criteria at visit 1 may continue to visit 2, when 
baseline assessments will be conducted (visits 1 and 2 may be combined). 
The following procedures will be performed at visit 2: 
• review inclusion and exclusion criteria 
• inform patients of study compliance for eMDPI and accelerometer and requirement 
for provider visit in the event of a CE-COPD 
• assess for COPD exacerbations 
• inquire about adverse events 
• train on use of wearable accelerometers and dispense to the subset of patients who 
consent to using the devices  
• train on the use, collection, and accountability of inhaler and dispense albuterol 
sulfate (ABS) eMDPI 
• concomitant medication inquiry 
b. Phone Visits (Visits 3 and 4, Days 28 and 56±7 days, respectively) 


 
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Patients will be contacted by phone and do not need to visit the investigational center. 
The following information will be discussed during the phone call: 
• assess for COPD exacerbations and treatments (Investigational centers must obtain 
source documentation for all COPD exacerbations to confirm the accuracy of the 
information obtained from the patient.) 
• inquire about adverse events 
• concomitant medication inquiry 
• inform patients of study compliance for eMDPI and accelerometer and requirement 
for provider visit in the event of COPD 
c. Final Visit/Early Termination Visit (Visit 5, Day 84 ±14 days) 
The following procedures and assessments will be performed at visit 5 or Early Termination 
Visit: 
• physical examination, including height and weight 
• urine pregnancy test for women of childbearing potential 
• assess for COPD exacerbations 
• inquire about adverse events 
• collect wearable accelerometer, if applicable. 
• collect ABS eMDPI 
• concomitant medication inquiry 
3. Exacerbation Visit (Vz [Up to 14 days after CE-COPD start date]) 
In the case of a CE-COPD (defined in Section 6.1.1 of the protocol), the patient will be 
required to return to the investigational center. The exacerbation visit should be conducted up 
to 14 days after the CE-COPD start date. The date and reason for the unscheduled visit will 
be recorded on the electronic case report form as well as any other data obtained from 
procedures and assessments. 
Procedures performed during exacerbation visit include the following: 
• physical examination, including weight 
• inquire about adverse events 
• concomitant medication inquiry 
• collect all ABS eMDPI devices used prior to CE-COPD and dispense additional ABS 
eMDPI if needed 


 
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APPENDIX C. QUALITY CONTROL AND QUALITY ASSURANCE 
Protocol Amendments and Protocol Deviations and Violations 
Protocol Amendments 
No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favorable opinion of a written amendment by the Independent Ethics Committee 
(IEC)/Institutional Review Board (IRB) and national and local competent authorities, as 
applicable, except when necessary to address immediate safety concerns to the patients or when 
the change involves only nonsubstantial logistics or administration. The principal investigator at 
each investigational center, the coordinating investigator (if applicable), and the sponsor will 
sign the protocol amendment. 
Protocol Violations 
Any deviation from the protocol that affects, to a significant degree, (a) the safety, physical, or 
mental integrity of the patients in the study and/or (b) the scientific value of the study will be 
considered a protocol violation. Protocol violations may include non-adherence on the part of the 
patient, the investigator, or the sponsor to protocol-specific inclusion and exclusion criteria, 
objective variable criteria, or Good Clinical Practice (GCP) guidelines; noncompliance to 
investigational medicinal product (IMP) administration; or use of prohibited medications. 
Protocol violations will be identified and recorded by investigational center personnel. All 
protocol violations will be reported to the responsible IEC/IRB, as required. 
When a protocol violation is reported, the sponsor will determine whether to discontinue the 
patient from the study or permit the patient to continue in the study, with documented approval 
from the medical expert. The decision will be based on ensuring the safety of the patient and 
preserving the integrity of the study. 
Changes in the inclusion and exclusion criteria of the protocol are not prospectively granted by 
the sponsor. If the investigational center personnel learns that a patient who did not meet 
protocol inclusion and exclusion criteria entered the study, they must immediately inform the 
sponsor of the protocol violation. If such patient has already completed the study or has 
withdrawn early, no action will be taken but the violation will be recorded. 
Information to Study Personnel 
The investigator is responsible for giving information about the study to all personnel members 
involved in the study or in any element of patient management, both before starting the study and 
during the course of the study (eg, when new personnel become involved). The investigator must 
ensure that all study personnel are qualified by education, experience, and training to perform 
their specific task. These study personnel members must be listed on the investigational center 
authorization form, which includes a clear description of each personnel member’s 
responsibilities. This list must be updated throughout the study, as necessary. 
The study monitor is responsible for explaining the protocol to all study personnel, including the 
investigator, and for ensuring they comply with the protocol. 


 
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Study Monitoring 
To ensure compliance with GCP guidelines, the study monitor or representative is responsible 
for ensuring that patients have signed the informed consent form (ICF) and the study is 
conducted according to applicable Standard Operating Procedures (SOPs), the protocol, and 
other written instructions and regulatory guidelines. 
The study monitor is the primary association between the sponsor and the investigator. The main 
responsibilities of the study monitor are to visit the investigator before, during, and after the 
study to ensure adherence to the protocol, that all data are correctly and completely recorded and 
reported, and that informed consent is obtained and recorded for all patients before they 
participate in the study and when changes to the consent form are warranted, in accordance with 
IEC/IRB approvals. 
The study monitor will contact the investigator and visit the investigational center according to 
the monitoring plan. The study monitor will be permitted to review and verify the various 
records (electronic case report forms and other pertinent source data records, including specific 
electronic source document relating to the study) to verify adherence to the protocol and to 
ensure the completeness, consistency, and accuracy of the data being recorded. 
As part of the supervision of study progress, other sponsor personnel may, on request, 
accompany the study monitor on visits to the investigational center. The investigator and 
assisting personnel must agree to cooperate with the study monitor to resolve any problems, 
errors, or possible misunderstandings concerning the findings detected during the course of these 
monitoring visits or provided in follow-up written communication. 
Audit and Inspection 
The sponsor may audit the investigational center to evaluate study conduct and compliance with 
protocols, SOPs, GCP guidelines, and applicable regulatory requirements. The sponsor’s Global 
Clinical Quality Assurance, independent of Global Specialty Development, is responsible for 
determining the need for (and timing of) an investigational center audit. 
The investigator must accept that competent authorities and sponsor representatives may conduct 
inspections and audits to verify compliance with GCP guidelines. 


 
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APPENDIX D. ETHICS 
Informed Consent 
The investigator, or a qualified person designated by the investigator, should fully inform the 
patient of all pertinent aspects of the study, including the written information approved by the 
Independent Ethics Committee/Institutional Review Board (IEC/IRB). All written and oral 
information about the study will be provided in a language as nontechnical as practical to be 
understood by the patient. The patient should be given ample time and opportunity to inquire 
about details of the study and to decide whether or not to participate in the study. The above 
should be detailed in the source documents. 
Written informed consent will be obtained from each patient before any study-specific 
procedures or assessments are done and after the aims, methods, anticipated benefits, and 
potential hazards are explained. The patient’s willingness to participate in the study will be 
documented in the informed consent form (ICF), which will be signed and personally dated by 
the patient and by the person who conducted the informed consent discussion. The investigator 
will keep the original ICFs, and copies will be given to the patients. It will also be explained to 
the patients that the patient is free to refuse participation in the study and free to withdraw from 
the study at any time without prejudice to future treatment. 
The investigator, or a qualified person designated by the investigator, should fully inform the 
patient and parent/legally acceptable representative of all pertinent aspects of the study, 
including the written information approved by the IEC/IRB. All written and oral information 
about the study will be provided in a language as nontechnical as practical to be understood by 
the parent/legally acceptable representative and the patient. The patient and parent/legally 
acceptable representative should be given ample time and opportunity to inquire about details of 
the study and to decide whether or not to participate in the study. The above should be detailed in 
the source documents. 
A personally signed and dated ICF will be obtained from the parent/legally acceptable 
representative, and a signed and dated assent form will be obtained from each patient (if the 
patient is able) before any study-specific procedures or assessments are done and after the aims, 
methods, anticipated benefits, and potential hazards are explained; according to IEC/IRB 
requirements. The forms will be signed and dated also by the person who conducted the 
informed consent discussion. The investigator will keep the original informed consent and assent 
forms, and copies will be given to the patients (and parent/legally acceptable representative). It 
will also be explained to the patients (and parent/legally acceptable representative) that they are 
free to refuse participation in the study and free to withdraw from the study at any time without 
prejudice to future treatment. 
Adult patients with a legally acceptable representative should provide informed consent 
according to national and local requirements. 
Competent Authorities and Independent Ethics Committees/Institutional Review Boards 
Before this study starts, the protocol will be submitted to the national competent authority and to 
the respective IEC/IRB for review. As required, the study will not start at a given investigational 
center before the IEC/IRB and competent authority (as applicable) for the investigational center 
give written approval or a favorable opinion. 


 
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Confidentiality Regarding Study Patients 
The investigator must ensure that the privacy of the patients, including their identity and all 
personal medical information, will be maintained at all times. In electronic case report forms 
(eCRFs) and other documents or image material submitted to the sponsor, patients will be 
identified not by their names, but by an identification number. 
Personal medical information may be reviewed for the purpose of patient safety or for verifying 
data in the source and the eCRF. This review may be conducted by the study monitor, properly 
authorized persons on behalf of the sponsor, Global Quality Assurance, or competent authorities. 
Personal medical information will always be treated as confidential. 
Registration of the Clinical Study 
In compliance with national and local regulations and in accordance with Teva standard 
procedures, this clinical study will be registered on trials registry websites. 


 
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APPENDIX E. 
WOMEN OF CHILDBEARING POTENTIAL AND BIRTH 
CONTROL METHODS 
Contraception recommendations and pregnancy testing should encompass all investigational 
medicinal products (IMPs) as well as non-investigational medicinal products, eg, background 
therapy, and the measures to be followed should be based on the medicinal product with highest 
risk. 
Assessment of likelihood of possible interaction between IMP or concomitant medications and 
hormonal contraception should be conducted. Hormonal contraception may be susceptible to 
interaction with the IMP, which may reduce the efficacy of the contraception method, eg, 
cytochrome P450 4A inducers. In case of suspected interaction, hormonal contraceptive alone 
may not be sufficient. In the absence of clinical pharmacokinetic interaction study data in IMPs 
with demonstrated or suspected human teratogenicity/fetotoxicity, recommendation for use of 
hormonal contraceptives should be thoroughly justified by the sponsor. Additional contraceptive 
methods, including supplementary barrier methods, may be considered. 
Women of childbearing potential are defined as: 
• not surgically (documented hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy) or congenitally sterile 
• 1 year postmenopausal (no menses for 12 months without alternative medical cause 
plus an increased concentration of follicle stimulating hormone [FSH] of more than 
35 U/L) in women not using hormonal contraception or hormonal replacement 
therapy) 
Recommendations for application of birth control methods: 
• IMPs with Marketing Authorisation (MA) 
− SmPC: In case of no contraception recommendations, the principles of IMPs 
without MA should be applied 
• IMPs without MA 
− All female reproduction toxicity studies and standard battery of genotoxicity tests 
should be completed prior to the inclusion, in any clinical trial, of women of 
childbearing potential not using highly effective birth control or whose pregnancy 
status is unknown (in compliance with International Council for Harmonisation 
M2) 
− Unavailable or insufficient nonclinical data should be considered as “effects 
detected” and the highest risk category assumed. 
• IMP with demonstrated or suspected human teratogenicity/fetotoxicity 
− Highly effective contraception using methods with low user dependency 
− Contraception during treatment and until the end of relevant systemic exposure. 
This period should be extended by 30 days in case of genotoxicity. 


 
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− Monthly pregnancy testing to be maintained until end of relevant systemic 
exposure – should be extended by 30 days in case of genotoxicity. Shorter testing 
intervals are to be considered depending on drug dosing schedule. 
• IMP with possible human teratogenicity/fetotoxicity 
− Highly effective method of contraception 
− Contraception during treatment and until the end of relevant systemic exposure 
− Additional pregnancy testing to be considered; as a minimum, at the end of 
relevant systemic exposure 
− In each case of delayed menstrual period (over 1 month between menstruations) 
confirmation of absence of pregnancy is strongly recommended. This 
recommendation also applies to women of childbearing potential with infrequent 
or irregular menstrual cycles. 
• IMP with unlikely risk of human teratogenicity/fetotoxicity, for which assessment of 
the completed necessary nonclinical studies does not indicate 
teratogenicity/fetotoxicity, in early pregnancy and human data are not available or do 
not contradict these findings or there is already sufficient evidence for lack of risk 
based on human data 
− An acceptable effective method of contraception unless an absence of risk of 
human teratogenicity/fetotoxicity in early pregnancy can be justified 
− As a minimum, contraception until treatment discontinuation 
Highly effective birth control methods: 
Highly effective birth control methods are methods that can achieve a failure rate of less than 1% 
per year when used consistently and correctly are considered. Such methods include: 
• Combined estrogen and progestogen hormonal contraception (oral, intravaginal, 
transdermal) associated with inhibition of ovulation; these should be initiated at least 
7 days (for IMPs without suspected teratogenicity/genotoxicity) and 1 month (for 
IMPs potentially teratogenic/genotoxic) before the first dose of IMP 
• Progestogen-only hormonal contraception (oral, injectable, implantable) associated 
with inhibition of ovulation; these should be initiated at least 7 days (for IMPs 
without suspected teratogenicity/genotoxicity) and 1 month (for IMPs potentially 
teratogenic/genotoxic) before the first dose of IMP 
• Intrauterine device and intrauterine hormone-releasing system need to be in place at 
least 2 months before screening 
• Bilateral tubal occlusion and vasectomized partner provided he is the sole sexual 
partner and has received medical assessment of the surgical process 
• Sexual abstinence is only considered a highly effective method if defined as 
refraining from heterosexual intercourse in the defined period. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the clinical study 
and the preferred and usual lifestyle of the patient. 


 
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• Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence for the duration of a study, and withdrawal are not 
acceptable methods of contraception (according to the Medicines and Healthcare 
Products Regulatory Agency). 
Acceptable birth control methods: 
Acceptable birth control methods that result in a failure rate of more than 1% per year include: 
progestogen-only oral hormonal contraception, for which the inhibition of ovulation is not the 
primary mode of action; male or female condom with or without spermicide; and cap, 
diaphragm, or sponge with spermicide. The combination of male condom with either cap, 
diaphragm, or sponge with spermicide (double barrier methods) are also considered acceptable, 
but not highly effective, methods of birth control. 
Unacceptable birth control methods: 
Periodic abstinence (calendar, symptothermal, and post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method are not acceptable methods 
of contraception. Female condom and male condom should not be used together. 
Male contraception: 
Male patients must always use a condom, except in cases of no genotoxicity or demonstrated or 
suspected human teratogenicity/fetotoxicity. 
Vasectomy: 
Use of contraceptive methods applies also to vasectomized men, because of the risk associated 
with transfer of a drug via seminal fluid. 


 
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APPENDIX F. LOST TO FOLLOW-UP 
A patient will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the investigational center. 
The following actions must be taken if a patient fails to return to the investigational center for a 
required study visit: 
• The investigational center must attempt to contact the patient and reschedule the 
missed visit as soon as possible and counsel the patient on the importance of 
maintaining the assigned visit schedule and ascertain whether or not the patient 
wishes to and/or should continue in the study. 
• In cases in which the patient is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the patient (where possible, 3 telephone 
calls and, if necessary, a certified letter to the patient’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the 
patient’s medical record. 
• Should the patient continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of “lost to follow-up.” 


 
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APPENDIX G. PRODUCT COMPLAINTS 
Clinical Product Complaints 
A clinical product complaint is defined as a problem or potential problem with the physical 
quality or characteristics of clinical investigational medicinal product (IMP) supplies or clinical 
device supplies used in a clinical research study sponsored by Teva. Examples of a product 
complaint include but are not limited to: 
• suspected contamination 
• questionable stability (eg, color change, flaking, crumbling, etc) 
• defective components 
• missing or extra units (eg, primary container is received at the investigational center 
with more or less than the designated number of units inside) 
• incorrect packaging, or incorrect or missing labeling/labels 
• unexpected or unanticipated taste or odor, or both 
• device not working correctly or appears defective in some manner 
Each investigational center will be responsible for reporting a possible clinical product complaint 
by completing the product complaint form provided by Teva and emailing it to 
 within 48 hours of becoming aware of the issue. 
For complaints involving a device or other retrievable item, it is required that the device (or 
item) be sent back to the sponsor for investigative testing whenever possible. For complaints 
involving an IMP, all relevant samples (eg, the remainder of the patient’s IMP supply) should be 
sent back to the sponsor for investigative testing whenever possible. 
1. Product Complaint Information Needed from the Investigational Center 
In the event that the product complaint form cannot be completed, the investigator will provide 
the following information, as available: 
• investigational center number and principal investigator name 
• name, phone number, and address of the source of the complaint 
• clinical protocol number 
• patient identifier (patient study number) and corresponding visit numbers, if 
applicable 
• product name and strength for open-label studies 
• patient number, bottle, and kit numbers (if applicable) for double-blind or open-label 
studies 
• product available for return Yes/No 
• product was taken or used according to protocol Yes/No 
• description or nature of complaint 


 
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• associated serious adverse event Yes/No 
• clinical supplies unblinded (for blinded studies) Yes/No 
• date and name of person receiving the complaint 
Note: Reporting a product complaint must not be delayed even if not all the required information 
can be obtained immediately. Known information must be reported immediately. The sponsor 
will collaborate with the investigator to obtain any outstanding information. 
2. Handling of Investigational Medicinal Product(s) at the Investigational Center(s) 
The investigator is responsible for retaining the product in question in a location separate from 
the investigator’s clinical study supplies. The sponsor may request that the investigator return the 
product for further evaluation and/or analysis. If this is necessary, the clinical study monitor or 
designee will provide the information needed for returning the IMP. 
If it is determined that the investigational center must return all IMP, the sponsor will provide the 
information needed to handle the return. 
3. Adverse Events or Serious Adverse Events Associated with a Product Complaint 
If there is an adverse event or serious adverse event due to product complaint, the protocol 
should be followed for recording and reporting (Section 7.1.2 and Section 7.1.5.3, respectively). 
4. Documenting a Product Complaint 
The investigator will record in the source documentation a description of the product complaint, 
and any actions taken to resolve the complaint and to preserve the safety of the patient. Once the 
complaint has been investigated by the sponsor and the investigator, if necessary, an event 
closure letter may be sent to the investigational center where the complaint originated or to all 
investigational centers using the product. 
Medical device incidents, including those resulting from malfunctions of the device, must be 
detected, documented, and reported by the investigator throughout the study. 


 
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APPENDIX H. DATA MANAGEMENT AND RECORD KEEPING 
Direct Access to Source Data and Documents 
All patient data must have supportive original source documentation in the medical records, or 
equivalent, before they are transcribed to the electronic case report form (eCRF). Data may not 
be recorded directly on the eCRF and considered as source data unless the sponsor provides 
written instructions specifying which data are permitted to be recorded directly to the eCRF. 
If data are processed from other institutions or by other means, the results will be sent to the 
investigational center, where they will be retained but not transcribed to the eCRF, unless 
otherwise noted in the protocol. These data may also be sent electronically to the sponsor (or 
organization performing data management). 
The medical experts, study monitors, auditors, Independent Ethics Committee (IEC)/Institutional 
Review Board (IRB), and inspectors from competent authority (or their agents) will be given 
direct access to source data and documents (eg, medical charts/records, laboratory test results, 
printouts, and videotapes) for source data verification, provided that patient confidentiality is 
maintained in accordance with national and local requirements. 
The investigator must maintain the original records (ie, source documents) of each patient’s data 
at all times. The investigator must maintain a confidential patient identification list that allows 
the unambiguous identification of each patient. 
Data Collection 
Data will be collected using eCRFs that are specifically designed for this study. The data 
collected on the eCRFs will be captured in a clinical data management system (CDMS) that 
meets the technical requirements described in 21CFR Part 11 (United States) and documents of 
other concerned competent authorities. Before using the CDMS, it will be fully validated and all 
users will receive training on the system and study-specific training. After they are trained, users 
will be provided with individual system access rights. 
Data will be collected at the investigational center by appropriately designated and trained 
personnel, and eCRFs must be completed for each patient who provided informed consent. 
Patient identity should not be discernible from the data provided on the eCRF. 
If data are processed from other sources, these data will be sent to the investigational center, 
where they will be retained but not transcribed to the eCRF, unless otherwise noted in the 
protocol. These data may also be sent electronically to the sponsor (or organization performing 
data management).  
For patients who enter a study but do not meet entry criteria, at a minimum, data for screening 
failure reason, demography, and adverse events from the time of informed consent will be 
entered in the eCRF. 
Data Quality Control 
Data Management is responsible for the accuracy, quality, completeness, and internal 
consistency of the data from this study. Oversight will be carried out as described in the 
sponsor’s Standard Operating Procedures (SOPs) for clinical studies. Day to day data 
management tasks for this study are delegated to a contract organization, and these functions 


 
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may be carried out as described in the SOPs for clinical studies at that organization. These SOPs 
will be reviewed by the sponsor before the start of data management activities. 
Data will be verified by the study monitor using the data source, and reviewed by Data 
Management using both automated logical checks and manual review. Data identified as 
erroneous or data that are missing will be referred to the investigational center for resolution 
through data queries. Any necessary changes will be made in the clinical database, and data 
review and validation procedures will be repeated as needed. Data from external sources will be 
compared with the information available in the CDMS and any discrepancies will be queried. 
Applicable terms will be coded according to the coding conventions for this study. 
At the conclusion of the study, the CDMS and all other study data will be locked to further 
additions or corrections. Locking the study data represents the acknowledgement that all data 
have been captured and confirmed as accurate. All data collected will be approved by the 
investigator at the investigational center. This approval acknowledges the investigator’s review 
and acceptance of the data as being complete and accurate. 
Archiving of Case Report Forms and Source Documents 
Sponsor Responsibilities 
The original eCRFs will be archived by the sponsor. Investigational center-specific eCRFs will 
be provided to the respective investigational centers for archiving. 
Investigator Responsibilities 
The investigator must maintain all written and electronic records, accounts, notes, reports, and 
data related to the study and any additional records required to be maintained under country, 
state/province, or national and local laws, including, but not limited to: 
• full case histories 
• signed informed consent forms (ICFs) 
• patient identification lists 
• eCRFs for each patient on a per-visit basis 
• data from other sources (eg, central laboratory, bioanalytical laboratory, and central 
image center) 
• safety reports 
• financial disclosure reports/forms 
• reports of receipt, use, and disposition of the IMPs 
• copies of all correspondence with sponsor, the IEC/IRB, and any competent authority 
The investigator will retain all records related to the study and any additional records required, as 
indicated by the protocol and according to applicable laws and regulations, until the CRO or 
sponsor notifies the institution in writing that records may be destroyed. If, after 25 years from 
study completion, or earlier in the case of the investigational center closing or going out of 
business, the investigator reasonably determines that study record retention has become unduly 
burdensome, and sponsor has not provided written notification of destruction, then the 


 
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investigator may submit a written request to sponsor at least 60 days before any planned 
disposition of study records. After receipt of such request, the sponsor may make arrangements 
for appropriate archival or disposition, including requiring that the investigator deliver such 
records to the sponsor. The investigator shall notify the sponsor of any accidental loss or 
destruction of study records. 


 
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APPENDIX I. PUBLICATION POLICY 
All unpublished information given to the investigator by the sponsor shall not be published or 
disclosed to a third party without the prior written consent of the sponsor. 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results: 
“Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in 
Medical Journals”. Publication of the results will occur in a timely manner according to 
applicable regulations. In accordance with standard editorial and ethical practice, the sponsor 
will generally support publication of multicenter studies only in their entirety and not as 
individual investigational center data. In this case, a coordinating investigator will be designated 
by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements: 
• substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work 
• drafting the work or revising it critically for important intellectual content 
• final approval of the version to be published 
• agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved 
The publications committee established by the sponsor will oversee this process. Additional 
publications may follow. Policies regarding the publication of the study results are defined in the 
financial agreement. 
No patent applications based on the results of the study may be made by the investigator nor may 
assistance be given to any third party to make such an application without the written 
authorization of the sponsor. 

SAP_001.pdf: 
 
 
 
 
Statistical Analysis Plan with Amendment 01 
 
A 12-Week, Open-Label Study to Evaluate the Relationship Between Use of Albuterol 
eMDPI, an Inhaled Short-Acting Beta Agonist “Rescue” Agent with an eModule, and 
Exacerbations in Patients (40 Years of Age or Older) with Chronic Obstructive Pulmonary 
Disease 
 
 
Study Number ABS-COPD-30065 
 
NCT03256695 
 
Statistical Analysis Plan with Amendment 01 Approval Date: 27 April 2018  
 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
1 
 
 
 
Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
 
 
A 12-Week, Open-Label Study to Evaluate the Relationship Between Use of Albuterol 
eMDPI, an Inhaled Short-Acting Beta Agonist “Rescue” Agent with an eModule, and 
Exacerbations in Patients (40 Years of Age or Older) with Chronic Obstructive Pulmonary 
Disease 
 
 
Phase 3B 
 
 
IND Number: 104532 
NDA Number: NA   
EudraCT Number: NA 
 
 
Approval Date: 27 April 2018   
 
 
Sponsor 
Teva Branded Pharmaceutical  
Products R&D, Inc. 
41 Moores Road 
Frazer, Pennsylvania 19355 
United States 
 
 
Prepared by: 
 – Duke Clinical Research Institute 
 
 
 – Duke Clinical Research Institute  
 Teva 
 Teva 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
2 
STATISTICAL ANALYSIS PLAN APPROVAL 
 
Study No.: 
ABS-COPD-30065 
 
Study Title: A 12-Week, Open-Label Study to Evaluate the Relationship Between Use of 
Albuterol eMDPI, an Inhaled Short-Acting Beta Agonist “Rescue” Agent with an eModule, 
and Exacerbations in Patients (40 Years of Age or Older) with Chronic Obstructive 
Pulmonary Disease 
 
Statistical Analysis Plan for:  
 
 Interim Analysis  
 
 Integrated Summary of Efficacy 
 
 Final Analysis 
 
 
 Integrated Summary of Safety 
 
Amendment: 01 
Authors: 
 
 
 
 Duke Clinical Research Institute 
 
 
 
 
 
 
 Duke Clinical Research Institute 
 
 
 
 Teva 
 
                        
 
                        
 
 
 
_ 
 
                     
 
 
 
 
 
 
                       
 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
3 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
STATISTICAL ANALYSIS PLAN APPROVAL ..........................................................................2 
AMENDMENT HISTORY .............................................................................................................8 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................9 
INTRODUCTION .........................................................................................................................11 
1. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................12 
1.1. 
Objectives and Endpoints ...........................................................................................12 
2. 
STUDY DESIGN .......................................................................................................13 
2.1. 
General Design ...........................................................................................................13 
2.1.1. 
Treatment ....................................................................................................................15 
2.1.1.1. 
Investigational Medicinal Products Used in the Study ...............................................15 
2.1.1.2. 
Test Investigational Medicinal Product ......................................................................15 
2.1.1.3. 
Starting Dose and Dose Levels ...................................................................................15 
2.2. 
Randomization and Blinding ......................................................................................15 
2.3. 
Sample Size and Power Considerations .....................................................................15 
2.4. 
Sequence of Planned Analyses ...................................................................................16 
2.4.1. 
Planned Interim Analyses ...........................................................................................16 
2.4.2. 
Final Analyses and Reporting .....................................................................................16 
3. 
ANALYSIS SETS ......................................................................................................17 
3.1. 
Intent to Treat Analysis Set ........................................................................................17 
3.2. 
Modified Intent-to-Treat Analysis Set ........................................................................17 
3.3. 
Safety Analysis Set .....................................................................................................17 
3.4. 
Wrist Accelerometry Analysis Set..............................................................................17 
3.5. 
Ankle Accelerometry Analysis Set .............................................................................17 
4. 
GENERAL ISSUES FOR DATA ANALYSIS ..........................................................18 
4.1. 
General ........................................................................................................................18 
4.2. 
Specification of Baseline Values ................................................................................18 
4.2.1. 
Albuterol Use ..............................................................................................................18 
4.2.2. 
Vital Signs, Physical Examination, Height, and Weight ............................................18 
4.2.3. 
Inhalational Flow Values ............................................................................................18 
4.2.4. 
Total Daily Steps ........................................................................................................18 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
4 
4.2.5. 
Sleep Parameters .........................................................................................................19 
4.3. 
Time on Study .............................................................................................................19 
4.4. 
eMDPI Time on Study ................................................................................................19 
4.5. 
Study Day and Study Week ........................................................................................19 
4.6. 
Handling Withdrawals and Missing Data ...................................................................19 
5. 
STUDY POPULATION .............................................................................................21 
5.1. 
General ........................................................................................................................21 
5.2. 
Patient Disposition ......................................................................................................21 
5.3. 
Demographics and Baseline Characteristics ...............................................................21 
5.4. 
Medical History ..........................................................................................................21 
5.5. 
COPD History .............................................................................................................22 
5.6. 
Clinical COPD Exacerbations History .......................................................................22 
5.7. 
Prior Therapy and Medication ....................................................................................22 
5.8. 
Childbearing Potential and Methods of Contraception ..............................................22 
5.9. 
Study Protocol Violations ...........................................................................................22 
5.10. 
eMDPI Time on Study; Days and Weeks ...................................................................23 
6. 
EFFICACY ANALYSIS ............................................................................................24 
7. 
ENDPOINT ANALYSES ..........................................................................................25 
7.1. 
eMDPI: Albuterol Use ................................................................................................25 
7.1.1. 
Albuterol Use Definition ............................................................................................25 
7.1.2. 
Analysis Methods for Albuterol Use ..........................................................................26 
7.1.2.1. 
Pattern of Baseline Daily and Weekly Albuterol Use ................................................26 
7.1.2.2. 
Total Number of Inhalations in the Days Preceding the Peak of a CE-COPD ...........26 
7.1.2.3. 
Hypothesis: Albuterol Use Will Increase Several Days Prior to a CE-COPD ...........27 
7.1.2.4. 
Number of Days Prior to the Peak of a CE-COPD When Albuterol Use 
Increased .....................................................................................................................28 
7.1.2.5. 
Maximum Number of Inhalations Taken In a 24-Hour Period ..................................28 
7.2. 
Inhalational Flow Values ............................................................................................28 
7.2.1. 
Inhalational Flow Values Definitions .........................................................................28 
7.2.2. 
Analysis Methods for Inhalational Flow Values ........................................................29 
7.2.2.1. 
Actual and Change from Baseline in Study Day X Inhalational Flow Values 
Prior to the Peak of a CE-COPD ................................................................................29 
7.2.2.2. 
Actual and Change from Baseline in Week Y Inhalational Flow Values ...................29 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
5 
7.3. 
Accelerometry: Total Daily Steps ..............................................................................30 
7.3.1. 
Total Daily Steps Definition .......................................................................................30 
7.3.2. 
Analysis Methods for Total Daily Steps .....................................................................30 
7.3.2.1. 
Actual and Change from Baseline in Study Day X Total Daily Steps Prior to 
the Peak of a CE-COPD .............................................................................................30 
7.3.2.2. 
Actual and Change from Baseline in Week Y Total Daily Steps ...............................31 
7.4. 
Accelerometry: Sleep Disruption Index .....................................................................31 
7.4.1. 
Sleep Disruption Index Definition ..............................................................................31 
7.4.2. 
Analysis Methods for Sleep Disruption Indices .........................................................32 
7.4.2.1. 
Actual and Change from Baseline in Study Day X Sleep Disruption Indices 
Prior to the Peak of a CE-COPD ................................................................................32 
7.4.2.2. 
Actual and Change from Baseline in Week Y Sleep Disruption Indices ....................32 
7.5. 
Clinical Exacerbation of COPD ..................................................................................32 
7.5.1. 
Definition of Clinical Exacerbation of COPD ............................................................32 
7.5.2. 
Analysis Methods for Clinical (COPD) Exacerbation ................................................34 
7.5.2.1. 
Within Patient CE-COPD Analyses ...........................................................................34 
7.5.2.2. 
Time to Clinical  (COPD) Exacerbations Short-term Exacerbation Risk (7 
days) ............................................................................................................................35 
7.5.2.3. 
All Days Analysis (Only CE-COPD-free Days) ........................................................35 
7.5.2.4. 
Summary Descriptive Statistics of Initial and Recurrent Clinical COPD 
Exacerbation Rates .....................................................................................................35 
7.5.3. 
Predicting Severe CE-COPD/Moderate CE-COPD from Multiple Device-
Use-Measures .............................................................................................................36 
8. 
SENSITIVITY ANALYSIS .......................................................................................37 
9. 
MULTIPLE COMPARISONS AND MULTIPLICITY ............................................38 
10. 
SAFETY ANALYSIS ................................................................................................39 
10.1. 
General ........................................................................................................................39 
10.2. 
Duration of Exposure to ABS eMDPI ........................................................................39 
10.3. 
Time on Study .............................................................................................................39 
10.4. 
Adverse Events ...........................................................................................................39 
10.5. 
Deaths .........................................................................................................................40 
10.6. 
Clinical Laboratory Tests ...........................................................................................40 
10.7. 
Physical Examinations ................................................................................................40 
10.8. 
Concomitant Medications or Therapies ......................................................................40 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
6 
11. 
TOLERABILITY VARIABLES AND ANALYSIS..................................................41 
12. 
PHARMACOKINETIC ANALYSIS .........................................................................42 
13. 
PHARMACODYNAMIC ANALYSIS ......................................................................43 
14. 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS ..............................44 
15. 
BIOMARKER ANALYSIS........................................................................................45 
16. 
IMMUNOGENICITY ANALYSIS ............................................................................46 
17. 
ANCILLARY STUDIES ANALYSIS .......................................................................47 
18. 
PLANNED INTERIM ANALYSIS ...........................................................................48 
19. 
STATISTICAL SOFTWARE ....................................................................................49 
20. 
CHANGES TO ANALYSES SPECIFIED IN THE STUDY PROTOCOL ..............50 
20.1. 
Intent-To-Treat Analysis Set ......................................................................................50 
20.2. 
Modified Intent-To-Treat Analysis Set ......................................................................51 
20.3. 
Safety Analysis Set .....................................................................................................52 
20.4. 
Predicting Severe CE-COPD/Moderate CE-COPD from Multiple 
Device-Use-Measures .................................................................................................53 
21. 
REFERENCES ...........................................................................................................54 
 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
7 
LIST OF TABLES 
Table 1: 
Study Procedures and Assessments ............................................................................14 
Table 2: 
Systemic Glucocorticoid Treatment Equivalent to 10 mg of Prednisone...................33 
 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
8 
AMENDMENT HISTORY 
The Statistical Analysis Plan for study ABS-COPD-30065 (study protocol with amendment 03 
dated 26 June 2017) has been amended and reissued as follows: 
Amendment 
number 
Date 
Author(s) 
Summary of Changes 
Reason for 
Amendment 
01  
 27 April 2018 
 
Sections 3, 5.2, 5.10, 7, and 10 
updated to indicate that all 
endpoint and safety analyses will 
use the ITT analysis set. 
Decision by study team 
 
Section 4.4 updated to indicate 
whichever comes first. 
Clarification  
 
Section 7.1.1 updated to reflect that 
the category with the highest 
number of inhalations will be 
reported if there is a tie in the most 
frequent usage. 
Clarification 
Section 7.5.2 updated with 
modified analyses. 
For this exploratory 
study, analyses methods 
were updated in the 
spirit of the protocol to 
better address study 
objectives and to align 
with the ancillary 
analytics report. 
Section 7.5.2.4 updated. 
Clarification 
Section 7.5.3 updated to clarify that 
the analyses will be done by the 
data analytics group. 
Clarification 
 
Section 10.4 updated to clarify the 
definition of treatment emergent. 
Clarification 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
9 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
ABS 
albuterol sulfate 
BMI 
body mass index 
CE-COPD 
clinical exacerbation of COPD 
CI 
confidence interval 
COPD 
chronic obstructive pulmonary disease 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
Demdpi 
eMDPI time on study 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eMDPI 
multidose dry powder inhaler with an eModule 
FEV1 
forced expiratory volume in 1 second 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
ICS 
inhaled corticosteroid 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
LABA 
long-acting beta agonist 
LAMA 
Long-acting muscarinic antagonist 
MDI 
metered dose inhaler 
MDPI 
multidose dry powder inhaler 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIF 
maximal inhalational flow 
mITT 
Modified Intent-to-Treat 
PP 
Per-Protocol 
R&D 
Research and Development 
SABA 
short-acting beta2 agonist 
SAMA 
short-acting muscarinic antagonist 
SCS 
systemic corticosteroid 
SD 
standard deviation 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
10 
Abbreviation 
Term 
SDI 
sleep disruption index 
SE 
standard error 
TDS 
total daily steps 
SOC 
system organ class 
SOP 
standard operating procedure 
WHO 
World Health Organization 
 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
11 
INTRODUCTION 
This Statistical Analysis Plan describes the planned analysis and reporting for Teva Branded 
Pharmaceutical Products R&D, Inc. Study ABS-COPD-30065 (A 12-Week, Open-Label Study 
to Evaluate the Relationship Between Use of Albuterol eMDPI, an Inhaled Short-Acting Beta 
Agonist “Rescue” Agent with an eModule, and Exacerbations in Patients (40 Years of Age or 
Older) with Chronic Obstructive Pulmonary Disease), and was written in accordance with 
standard operating procedure (SOP) GBP_RD_702 (Statistical Analysis Plan). 
The reader of this Statistical Analysis Plan is encouraged to read the study protocol for details on 
the conduct of this study, the operational aspects of clinical assessments, and the timing for 
completing the participation of a patient in this study. The Statistical Analysis Plan is intended to 
be in agreement with the protocol. However, the Statistical Analysis Plan may contain more 
details regarding these particular points of interest, or other types of analyses (eg, other 
endpoints). When differences exist in descriptions or explanations provided in the study protocol 
and this document, the Statistical Analysis Plan prevails; the differences will be explained in the 
clinical study report (CSR) or in this document. 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
12 
1. 
STUDY OBJECTIVES AND ENDPOINTS 
1.1. 
Objectives and Endpoints 
The objectives of this study are to explore the pattern and amount of albuterol use (as captured in 
the albuterol sulfate (ABS) multidose dry powder inhaler with an eModule (eMDPI), alone or in 
combination with other study data, preceding a moderate or severe CE-COPD (as diagnosed by 
the investigators per the protocol). The hypothesis is that albuterol use will increase several days 
prior to a moderate or severe CE-COPD and can serve as a marker of COPD deterioration. 
The endpoints of the trial are the primary outcome measure (ie, CE-COPD) and the primary 
outcome predictor (ie, albuterol use) alone or in combination with secondary predictors (ie, other 
study data). These predictors of CE-COPD will be modeled to determine which patterns best 
predict the subsequent development of CE-COPD.  
For albuterol use, parameters of interest will include (1) the total number of inhalations in the 
days preceding the peak of a CE-COPD, (2) the number of days prior to the peak of a CE-COPD 
when albuterol use increased, and (3) the number of albuterol uses in the 24 hours preceding a 
CE-COPD. Therefore, endpoints are not designated as either primary or secondary.  
In addition to albuterol use, inspiratory flow values (maximal inhalational flow (MIF), 
inhalational volume, inhalation duration, and time to MIF), sleep disruption index (SDI), total 
daily steps (TDS), and baseline information regarding disease state and demographics will be 
studied. These data will be analyzed using both a univariate and multivariate approach, to 
determine which patterns best predict the subsequent development of a CE-COPD. Inspiratory 
flow values are obtained from the eMDPI, SDI is obtained for a subset of patients who agree to 
participate at specific investigational centers (n=100) from an accelerometer worn on the wrist, 
and TDS is obtained for a subset of patients who agree to participate at specific investigational 
centers (n=100) from an accelerometer worn on the ankle. Baseline disease state and 
demographic information will be obtained at screening. 
Another objective for this study is to evaluate the safety of ABS eMDPI use in patients with 
exacerbation-prone COPD. 
The safety endpoints for this study include the following: 
• adverse event data 
• physical examinations 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
13 
2. 
STUDY DESIGN 
2.1. 
General Design 
This is a 12-week, multicenter, open-label study to evaluate the relationship between as-needed 
usage of ABS eMDPI and CE-COPD in adult patients at least 40 years of age with exacerbation-
prone COPD. ABS eMDPI is a rescue/reliever agent that includes an eModule on top of the 
approved PROAIR® RESPICLICK inhaler. The on-board electronics and power source are fully 
integrated into the inhaler and are designed to operate for the life of the inhaler without 
intervention. The electronic module records timestamped, pre-defined events such as cap open 
and inhalation parameters. The inclusion of the eModule has been shown to have no impact on 
the dose delivery compared with the approved product without the eModule. 
The study will consist of a screening period of up to 2 weeks and a 12-week intervention period. 
After providing written informed consent, patients will complete a screening visit (visit 1) to 
determine eligibility for the study. Patients will provide medical history (including prior 
medications), complete a physical examination, pregnancy test, if applicable, and review COPD 
exacerbation history. Eligible patients will return to the investigational center within 2 weeks for 
the baseline visit (visit 2). Those meeting entry criteria will be trained on the use of the eMDPI 
device and, upon demonstrated competency, will receive ABS eMDPI devices for use as rescue 
bronchodilators during the study. The screening visit and baseline visit may be combined. 
Patients must use ABS eMDPI as their only rescue agent for the duration of their participation in 
this study and will be advised to place any current rescue pills, inhalers, or nebulizers, including 
SABA, short-acting muscarinic antagonists (SAMAs), or SABA/SAMA combination into 
storage. Patients may continue the use of other COPD and non-COPD medications as advised by 
their physician without changes unless deemed necessary by their physician. Patients will be 
managed according to routine clinical practice by their treating physician with no specific 
study-related instructions provided other than those on the proper use of ABS eMDPI. 
Patients will be contacted by phone on a monthly basis for the collection of information about 
COPD exacerbations and treatments, concomitant medications, and adverse events. A review of 
the instructions for the use of ABS eMDPI and the procedure for replacement and return of ABS 
eMDPI will also occur during the monthly call. 
Patients will receive initial eMDPI devices at visit 2 based on anticipated usage pattern. In the 
event that additional eMDPI devices are needed, patients will be required to visit the 
investigational center to receive them. Patients will be instructed to return all inhalers to the 
investigational center at the last study visit or earlier, including at the early termination visit, as 
well as at any other point if there is a problem with the inhaler. At the last study visit or early 
termination, patients will be queried for adverse events, concomitant medications, and COPD 
exacerbations; a physical examination will be completed; and the patient will subsequently be 
discharged from the trial. 
Two subsets of patients who agree to participate at specific investigational centers and wear an 
accelerometer either on the ankle to measure TDS (n=100) or on the wrist to measure SDI 
(n=100) will be instructed on the proper use of these devices at the baseline visit (visit 2). The 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
14 
devices will be worn throughout the 12-week intervention period and will be returned to the 
investigational center at the final visit or upon early termination (visit 5). 
The end of study is defined as the last visit of the last patient.  
The study duration will be approximately 9 months. 
Study procedures and assessments with their timing are summarized in Table 1 of the study 
protocol. 
Table 1: 
Study Procedures and Assessments 
Study period 
Pre-
intervention 
 
Intervention 
Visit number 
V1 
V2 
V3a 
V4a 
Vz 
V5 
Day and allowed time windows 
Day -14 to 
Day 1 
Day 1 
Day 28 
±7 days 
Day 56 
± 7 days 
Up to 14 days 
after CE-COPD 
start date 
Day 84 
±14 days 
Procedures and assessments 
Screening 
Baseline  Phone 
visit 
Phone 
visit 
Exacerbation visit Final/early 
termination 
visit 
Informed consent 
X 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
Assign patient number 
X 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
Prior medication and treatment history 
X 
 
 
 
 
 
Physical examination, including height 
and weightb  
X 
 
 
 
X 
X 
Vital signs measurementc  
X 
 
 
 
 
 
Urine pregnancy test for women of 
childbearing potential  
X 
 
 
 
 
X 
Inform patients of study compliance for 
eMDPI and accelerometer and 
requirement for provider visit in the 
event of CE-COPD 
X 
X 
X 
X 
 
 
Assess for COPD exacerbations 
X 
X 
X 
X 
 
X 
Adverse events inquiry 
 
X 
X 
X 
X 
X 
Wearable accelerometers: dispense, 
training, and collectiond  
 
X 
 
 
 
X 
ABS eMDPI: dispense, training, 
collection, and accountabilitye 
 
X 
 
 
X 
X 
Concomitant medication inquiry 
X 
X 
X 
X 
X 
X 
a Investigational centers must obtain source documentation for all COPD exacerbations that occur during the 
treatment period to confirm the accuracy of the information obtained from the patient. 
b Height will be measured at the screening visit only. 
c Vital signs measurements will include blood pressure, respiratory rate, and heart rate. 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
15 
d Wearable accelerometers for a subset of patients who agree to participate at specific investigational centers will be 
dispensed at visit 2, and SDI and TDS data will be collected continuously from visit 2 through visit 5 via the 
wearable accelerometer. Instructions for proper use of the devices will be provided to patients at visit 2. The 
devices will be collected at visit 5.  
e Patients will receive initial eMDPI devices at visit 2 based on anticipated usage pattern. In the event that additional 
eMDPI devices are needed, patients will be required to visit the investigational center to receive them. Patients 
will be instructed to return all inhalers to the investigational center at the last study visit or earlier, including at the 
early termination visit, as well as at any other point if there is a problem with the inhaler. Instructions for 
dispensing, proper clinical use, and collecting ABS eMDPI will be provided to patients at visit 2 and reviewed 
during the monthly calls. 
ABS = albuterol sulfate; CE-COPD = clinical exacerbation of chronic obstructive pulmonary disease; COPD= 
chronic obstructive pulmonary disease; eMDPI=multidose dry powder inhaler with an eModule; SDI = sleep 
disruption index; TDS=total daily step; V = visit. 
Note: Screening and baseline visits may be combined. 
2.1.1. 
Treatment 
2.1.1.1. 
Investigational Medicinal Products Used in the Study 
Patients will receive initial eMDPI devices at visit 2 based on anticipated usage pattern and 
return all inhalers to the investigational center at the last study visit or earlier, including at the 
early termination visit (visit 5), as well as at any other point if there is a problem with the inhaler.  
2.1.1.2. 
Test Investigational Medicinal Product 
ABS eMDPI is an inhalation-driven MDPI containing a blend of ABS and alpha-lactose 
monohydrate. The inhaler contains 200 actuations, each delivering 90 mcg of albuterol base 
ex-mouthpiece; the inhaler is equipped with a dose counter that shows only even numbers and 
counts down to “0”. 
Additional details may be found in Table 2 of the protocol. 
2.1.1.3. 
Starting Dose and Dose Levels 
The prescribed dose will be 90 mcg, 1 to 2 inhalations every 4 hours as needed. No dose 
escalations are planned.  
2.2. 
Randomization and Blinding 
This is a nonrandomized study. All patients will use the 1 Test investigational medicinal product 
(IMP), the ABS eMDPI. Blinding is not applicable. 
2.3. 
Sample Size and Power Considerations 
Assuming an expected dropout rate of 10%, it is recommended that 400 patients be enrolled so 
that 360 evaluable patients complete the study. These conclusions are based on a review of the 
relevant literature, as follows. 
Based on previous studies of an exacerbation-prone COPD cohort (Dransfield et al 2013, 
Vogelmeier et al 2011, Wedzicha et al 2013, Wedzicha et al 2016), it is expected that 91 (range, 
73 to 110) CE-COPD events will occur over the 12-week evaluation period in this study based 
on reported CE-COPD exacerbation rates of 1.05 and 1.14 events per year. Furthermore, it is 
expected that 14% (14) of total exacerbations will be severe. 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
16 
This sample size (ie, n=400 patients, 73 to 110 CE-COPD events) is considered adequate for the 
fulfillment of the study objectives to evaluate the relationship of albuterol use, inspiratory flow, 
SDI, and TDS data associated with a subsequent CE-COPD event. Per a previous study (Jenkins 
et al 2013), a statistically significant relationship was established between daily SABA usage and 
subsequent CE-COPD. 
In the present study, approximately 73 to 110 CE-COPD events are desired because the model’s 
fitting of the current study involves the analysis of multiple predictors as described in more detail 
below. Because the largest model considered has 7 covariates, it is desirable to have at least 
70 events. The probability to observe at least 70 CE-COPD events is higher than 0.99. 
Risk models published in the literature have typically included between 4 and 6 covariates/risk 
factors (Bateman et al 2015, Greenberg et al 2012, Quezada et al 2016) to examine the 
relationship between possible risk factors and a disease. When there is more than 1 covariate 
(risk factor) in the model, multiple logistic regression may be used to estimate the relationship of 
a specific covariate of interest (ie, albuterol use) to a primary outcome (ie, CE-COPD), adjusting 
for the other/remaining covariates (risk factors). In this case, the required sample size to estimate 
such a relationship is greater than that for univariate logistic regression.  
The number of events per variable has been suggested as a criterion for the size of a data set 
(Harrell et al 1984, Laupacis et al 1997, Peduzzi et al 1996,). The rule of thumb when building 
logistic regression models is 1 predictor variable for every 10 events (Peduzzi et al 1996, 
Vittinghoff and McCulloch 2007). Therefore, this sample size would be adequate for predicting 
the primary outcome (CE-COPD) using multiple logistic regression, including the covariate of 
primary interest (ie, albuterol use) and the remaining multiple predictors (inspiratory flow values, 
SDI, and TDS) as potential risk factors for CE-COPD in the model for this patient population. 
2.4. 
Sequence of Planned Analyses 
2.4.1. 
Planned Interim Analyses 
There will be no formal interim analysis for this study. 
2.4.2. 
Final Analyses and Reporting 
All analyses identified in this Statistical Analysis Plan will be performed after the end of the 
study as defined in the study protocol.  
Data used for final statistical analyses will be derived from various sources including eCRF, data 
from ABS eMDPI inhaler, wrist, and ankle accelerometers. 
This Statistical Analysis Plan and any corresponding amendments will be approved before 
database lock, in accordance with SOP GBP_RD_702 (Statistical Analysis Plan). 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
17 
3. 
ANALYSIS SETS 
3.1. 
Intent to Treat Analysis Set 
The intent-to-treat (ITT) analysis set will include all enrolled patients regardless of whether a 
patient took any IMP. A patient is considered enrolled according to the status reported in the 
database. This analysis set will be used for endpoint analysis and safety analysis.  
3.2. 
Modified Intent-to-Treat Analysis Set  
The modified intent-to-treat (mITT) analysis set is a subset of the ITT analysis set that will 
include patients who used the IMP at any time during the study and patients who did not use the 
IMP at any time during the study provided these patients complied with study requirements and 
the data from the ABS eMDPI inhalers were successfully downloaded at the end of the study.  
3.3. 
Safety Analysis Set 
The safety analysis set will include all enrolled patients who received at least 1 dose of the IMP.  
3.4. 
Wrist Accelerometry Analysis Set 
The wrist accelerometry analysis set is a subset of the mITT analysis set that will include patients 
who wore a wrist accelerometer with sufficient memory to capture 12 weeks of data during study 
participation and for whom data from the wrist accelerometer were successfully downloaded at 
the end of the study.  
3.5. 
Ankle Accelerometry Analysis Set 
The ankle accelerometry analysis set is a subset of the mITT analysis set that will include 
patients who wore an ankle accelerometer with sufficient memory to capture 12 weeks of data 
during study participation and for whom data from the ankle accelerometer were successfully 
downloaded at the end of the study.  


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
18 
4. 
GENERAL ISSUES FOR DATA ANALYSIS 
4.1. 
General 
Descriptive statistics for continuous variables include n (number), mean, standard deviation 
(SD), median, minimum, and maximum. Minimum and maximum will have the same number of 
decimal points as the original data. Mean and median will have 1 more decimal point than the 
original data. Reporting of SD will have 2 more decimal points than the original data. 
Descriptive statistics for categorical variables include patient counts and/or counts and 
percentages. Categories for missing data will be presented, if necessary. Confidence intervals 
(CIs) of means and/or proportions will be reported as specified. Summaries will be provided 
overall and by CE-COPD status (CE-COPD: No, CE-COPD: Yes, All) and by COPD severity 
(Yes: Moderate, Yes: Severe) where appropriate. 
4.2. 
Specification of Baseline Values 
4.2.1. 
Albuterol Use 
Baseline albuterol use is defined as the mean number of inhalations per day from day 1 to day 7. 
If no inhalations were taken during study day 1 through study day 7, the ‘baseline inhalation’ is 
the first available inhalation after study day 7. For analyses relative to baseline albuterol use, 
patients who had a CE-COPD during study day 1 through study day 7 will be excluded. 
4.2.2. 
Vital Signs, Physical Examination, Height, and Weight 
Baseline vital signs (systolic blood pressure, diastolic blood pressure, respiratory rate, and heart 
rate (pulse rate), physical examination, height, and weight are performed only at Screening. 
Given the screening and baseline visits can be combined, baseline vital signs, physical 
examination, height, and weight are those assessments performed during the Screening visit.  
4.2.3. 
Inhalational Flow Values 
The baseline inspiratory flow values are computed using the set of inhalations taken by the 
patient during study day 1 through day 7. Among these inhalations, the inhalation with the 
highest MIF value is considered the ‘baseline inhalation’. The baseline MIF, inhalational 
volume, inhalation duration, and time to MIF values are those of the identified ‘baseline 
inhalation’. If no inhalations were taken during study day 1 through study day 7, the ‘baseline 
inhalation’ is the first available inhalation after study day 7. 
4.2.4. 
Total Daily Steps 
Baseline TDS is the average number of daily steps a patient completes, computed using the daily 
steps recorded during the first 7 days of study participation (study day 1 through study day 7). 
The average will be calculated as the sum of the daily TDS divided by the number of days with 
nonmissing TDS. If no step data are available for study day 1 through study day 7, the ‘baseline 
TDS’ is the first available TDS after study day 7.  
Baseline TDS are computed for those patients in the ankle accelerometry analysis set. 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
19 
4.2.5. 
Sleep Parameters 
There are 8 measures of sleep disruption: (i) nighttime average total time in bed, (ii) nighttime 
average total sleep time, (iii) nighttime average sleep latency time, (iv) nighttime average 
wakening after sleep onset, (v) total time awake at night, (vi) daytime average minutes asleep, 
(vii) longest daytime sleep episode and (viii) longest nighttime wake episode. The first 7 sleep 
parameters are provided via Philips accelerometry and longest nighttime wake episode is derived 
from the accelerometry data as follows: 
The sleep interval data provided via Philips accelerometry includes the activity state 
("sleep"/"awake") every 30 seconds during the sleep interval. The number of successive 30 
second “awake” states occurring between “sleep” states within the sleep interval is summed 
to determine the duration of a given “awake” state. The longest nighttime wake episode is the 
summated “awake” state with the longest duration during the sleep interval. 
The baseline value of a given sleep parameter (eg, nighttime average total time in bed) is the 
average sleep parameter (eg, nighttime average total time in bed), computed using the sleep 
parameter (eg, nighttime average total time in bed) values captured by accelerometry during 
study day 1 through day 7. The average will be calculated as the sum of the average sleep 
parameter divided by the number of days with nonmissing values of the average sleep parameter. 
If no sleep parameter data are available for study day 1 through study day 7, the ‘baseline value 
of a given sleep parameter’ is the first available valid sleep parameter value after study day 7.  
Baseline sleep parameters are computed for those patients in the wrist accelerometry analysis set. 
4.3. 
Time on Study 
Time on study is the number of days from date of informed consent to date of completion or last 
contact date plus 1.  
4.4. 
eMDPI Time on Study 
The eMDPI time on study is the number of days (Demdpi) from the last device return date to the 
date the first ABS eMDPI device was dispensed. For instances where the last device return date 
is missing the patient’s last date of contact or study completion, date will be used, whichever 
comes first.  
4.5. 
Study Day and Study Week 
Study days will be numbered relative to the earliest date an ABS eMDPI device was dispensed 
(ie, ... –2, –1, 1, 2, ...). Day 1 is defined as the earliest date an ABS eMDPI device was dispensed 
and Day –1 is the day before the first ABS eMDPI device was dispensed. 
Week I is defined as study day (j + 1) to study day (j + 7), inclusive where I = 1 to 12 and j = 0, 
7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84, respectively. 
4.6. 
Handling Withdrawals and Missing Data 
Any data that was collected prior a patient’s withdrawal from the study will be used for analysis 
and presented in the data listings.  


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
20 
The following imputation rules will be used; 
• If the return date of the last ABS eMDPI device returned is missing the patient’s last 
date of contact if the patient withdrew from the study or the patient’s study 
completion date will be used as the return date (see Section 4.4 and Section 10.2).  
• Adverse events or serious adverse events with missing start dates will be considered 
treatment emergent (see Section 10.4). 
• If a patient never used the ABS eMDPI during the study or download of a given ABS 
eMDPI device was not successful, study day and weekly inhalational flow values will 
be missing. If download of a given wrist or ankle accelerometer was not successful, 
TDS and SDI indices will be missing. These missing data will not be imputed. 
• In the derivation of Study Day X Inhalation flow values, if there was no albuterol use 
on Study Day X, then the closest preceding nonmissing Study Day Inhalation is used 
as the ‘Study Day X Inhalation’ and the inhalational flow values for Study Day X are 
assigned accordingly (see Section 7.2.1). 
• For patients in the ankle accelerometry analysis set, if no step data are available for 
study day 1 through study day 7, the ‘baseline TDS’ is the first available TDS after 
study day 7 (see Section 4.2.4). 
• For patients in the wrist accelerometry analysis set, if no sleep parameter data are 
available for study day 1 through study day 7, the ‘baseline value of a given sleep 
parameter’ is the first available valid sleep parameter value after study day 7 (see 
Section 4.2.5).  
• In the derivation of Study Day X TDS if TDS are missing on Study Day X, then the 
average of the nonmissing TDS of the 7 days preceding Study Day X is computed and 
assigned to Study Day X TDS (see Section 7.3.1). 
• In the derivation of Study Day X nighttime average sleep latency time if nighttime 
average sleep latency time is missing on Study Day X, then the average of the 
nonmissing nighttime average sleep latency time of the 7 days preceding Study Day X 
is computed and assigned to Study Day X (see Section 7.4.1).  
• In the derivation of Study Day X longest nighttime wake episode if longest nighttime 
wake episode is missing on Study Day X, then the greatest nonmissing longest 
nighttime wake episode of the 7 days preceding Study Day X is computed and 
assigned to Study Day X (see Section 7.4.1). 
• In the derivation of Study Day X total time awake at night if total time awake at night 
is missing on Study Day X, then the average of the nonmissing total time awake at 
night of the 7 days preceding Study Day X is computed and assigned to Study Day X 
(see Section 7.4.1).  
 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
21 
5. 
STUDY POPULATION 
5.1. 
General 
The ITT analysis set will be used for all study population summaries unless otherwise specified. 
The data will be listed for all patients entered into the database. 
5.2. 
Patient Disposition 
Data from patients screened; patients who were screen failures; patients who re-screened; 
patients screened but not enrolled and reason for non-enrollment; patients who are enrolled; 
patients enrolled but who do not use ABS eMDPI at least once; patients in the ITT analysis set; 
patients in the ankle accelerometry cohort and patients in the wrist accelerometry cohort; patients 
who complete the study; and patients who withdraw from the study and the reason for 
withdrawal will be summarized using descriptive summary statistics (n, %) for all patients 
entered into the database.  
5.3. 
Demographics and Baseline Characteristics 
Patient demographic and baseline characteristics will be summarized for all patients in the ITT 
analysis set using descriptive statistics. Demographic and baseline characteristics will include: 
age, sex, race, ethnicity, weight, height, and body mass index (BMI), vital signs, TDS, 
inhalational flow values and SDIs.  
The formula for BMI is:
2
height
weight
BMI =
,  
where weight is in kilograms (kg), height in meters (m) and BMI is kg/m2.  
Baseline inhalational flow values include MIF, inhalational volume, inhalation duration, and 
time to MIF. Baseline SDIs include nighttime average total time in bed, nighttime average total 
sleep time, nighttime average sleep latency time, nighttime average wakening after sleep onset, 
total time awake at night, daytime average minutes asleep, longest daytime sleep episode and 
longest nighttime wake episode. 
Demographics and baseline characteristics will be summarized by analysis set (ITT analysis set 
and the ankle and wrist accelerometry analysis sets). 
5.4. 
Medical History 
All medical history will be coded using the most current version of the Medical Dictionary for 
Regulatory Activities (MedDRA) at the time of database lock. The incidence of medical history 
abnormalities will be summarized using descriptive statistics by system organ class (SOC) and 
preferred term (PT). Patients are counted only once in each PT and SOC category even if they 
have multiple applicable findings. 
Summaries will be provided for the ITT analysis set and the ankle and wrist accelerometry 
analysis sets. 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
22 
5.5. 
COPD History 
Patients’ COPD history data will be summarized. This will include duration of COPD. 
Summaries will be provided for the ITT analysis set and the ankle and wrist accelerometry 
analysis sets. 
5.6. 
Clinical COPD Exacerbations History 
Patients’ COPD exacerbations history data will be summarized. This will include COPD 
exacerbations in the past 12 months or previous year, hospitalizations, emergency room visits, 
urgent care, doctor visits for COPD exacerbations, ICU admissions, and systemic steroids 
administration for COPD.  
Summaries will be provided for the ITT analysis set and the ankle and wrist accelerometry 
analysis sets. 
5.7. 
Prior Therapy and Medication 
All prior medications will be coded using the most current version of the World Health 
Organization drug dictionary (WHO Drug) at the time of database lock. The incidence of prior 
medications will be summarized using descriptive statistics (count and percentages) by 
therapeutic class and PT term. In addition, a summary table of the incidence of prior COPD 
medications will be provided. Patients are counted only once in each therapeutic class category, 
and only once in each PT term category. Prior medications will include medications taken within 
30 days prior to the first day that IMP is dispensed. 
Summaries will be provided for the ITT analysis set and the ankle and wrist accelerometry 
analysis sets. 
5.8. 
Childbearing Potential and Methods of Contraception 
Information related to childbearing potential, contraception, and menopause will be collected at 
Screening and at the Final/Early Termination visit. All information for childbearing potential 
will be provided in a listing by patient. 
5.9. 
Study Protocol Violations 
Any deviation from the protocol that affects, to a significant degree, (a) the safety, physical, or 
mental integrity of the patients in the study and/or (b) the scientific value of the study will be 
considered a protocol violation. Protocol violations include non-adherence on the part of the 
patient, the investigator, or the sponsor to protocol-specific inclusion/exclusion criteria, primary 
outcome measure criteria, or good clinical practice (GCP) guidelines; noncompliance to study 
drug administration; use of prohibited medications; or any other deviations that may have an 
impact on the processes put in place for the care and safety of the patients.  
Protocol violations recorded in the Clinical Trial Management System during the study will be 
summarized overall and for each of the following categories using descriptive statistics: 
• Informed Consent Procedures 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
23 
• Inclusion/Exclusion Criteria 
• Concomitant Medications/Therapy 
• Lab Assessments/Procedures 
• Study Procedures 
• Serious Adverse Events 
• Randomization Procedures/Dosing 
• Visit Schedule/Interval 
Of note, any recorded ‘Randomization Procedures/Dosing’ violations related to medication 
errors, overdose, misuse, abuse, off-label use and occupational exposure will be summarized in 
the sub-category ‘Non-compliance to study medication’. 
Patients with at least 1 protocol violation will be summarized by the above categories (sub-
categories) using count and percentages, by analysis set (ITT analysis set, and the ankle and 
wrist accelerometry analysis sets). 
5.10. 
eMDPI Time on Study; Days and Weeks 
Summary statistics of the eMDPI time on study in days and weeks (days divided by 7) will be 
presented overall and by CE-COPD status and by CE-COPD severity (Yes: severe, moderate; 
No) for the ITT analysis set, ankle accelerometry analysis set and the wrist accelerometry 
analysis set.  


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
24 
6. 
EFFICACY ANALYSIS 
Efficacy will not be assessed in this study. Endpoint analyses are described in Section 7. 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
25 
7. 
ENDPOINT ANALYSES  
All endpoint analyses will be performed using the ITT analysis set. 
Data listings will be presented by patient. 
7.1. 
eMDPI: Albuterol Use 
7.1.1. 
Albuterol Use Definition 
Baseline albuterol use is defined as the mean number of inhalations per day from day 1 to day 7. 
If no inhalations were taken during study day 1 through study day 7, the ‘baseline inhalation’ is 
the first available inhalation after study day 7. For analyses relative to baseline albuterol use, 
patients who had a CE-COPD during study day 1 through study day 7 will be excluded. 
Week 1 Patient Albuterol Use: Week 1 patient albuterol use is each patient’s total number of 
albuterol inhalations taken and the number of days used during the first week (study day 1 
through study day 7) of study participation with an indicator of whether or not the most frequent 
daily usage of albuterol is in 1 of the following 3 categories: (a) 0 to 2 inhalations, (b) 3-6 
inhalations and (c) > 6 inhalations. It is presented as WK1:I#iD#dMTN#n, where “i” is the 
number of albuterol inhalations and “d” is the number of days used in the first 7 days of the 
study, and “n” is an indicator of whether or not the most frequent daily usage of albuterol falls 
into one of the 3 categories. If there is a tie in the most frequent daily usage, the category with 
the highest number of inhalations will be reported. For example, “I28D7MTN2” indicates a total 
of 28 inhalations were taken, albuterol use was used each of the 7 days and the highest most 
frequent usage per day falls into category 2 with 3-6 inhalations. 
Week 2 Patient Albuterol Use: Week 2 patient albuterol use is each patient’s total number of 
albuterol inhalations taken and the number of days used during the second week (study day 8 
through study day 14) of study participation with an indicator of whether or not the most 
frequent daily usage of albuterol is in one of the following 3 categories: (a) 0 to 2 inhalations, (b) 
3-6 inhalations and (c) > 6 inhalations. It is presented as “WK2:I#iD#dMTN#n”, where “i" is the 
number of albuterol inhalations and “d” is the number of days used in the second week of study, 
and “n” is an indicator of whether or not the most frequent daily usage of albuterol is in one of 
the 3 categories. If there is a tie in the most frequent daily usage, the category with the highest 
number of inhalations will be reported. 
14-Day Patient Albuterol Use: 14-day patient albuterol use is each patient’s total number of 
albuterol inhalations taken and the number of days used during the first 14 days (study day 1 
through study day 14) of study participation with an indicator of whether or not the most 
frequent daily usage of albuterol is in one of the following 3 categories: (1) 0 to 2 inhalations, (2) 
3-6 inhalations and (3) > 6 inhalations. It is presented as “D14:I#iD#dMTN#n”, where “i" is the 
number of albuterol inhalations and “d” is the number of days used in the first 14 days of study, 
and “n” is an indicator of whether or not the most frequent daily usage of albuterol is in one of 
the 3 categories. If there is a tie in the most frequent daily usage, the category with the highest 
number of inhalations will be reported. 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
26 
Albuterol use will be examined by the following 3 parameters; (i) total number of inhalations in 
the days preceding the peak of a CE-COPD, (ii) number of days prior to the peak of a CE-COPD 
when albuterol use increased, and (iii) number of albuterol uses in the day preceding a CE-
COPD. 
The maximum number of inhalations taken within a 24-hour period by each patient: The date 
and time stamp of the inhalations are taken into consideration when determining the maximum 
number of inhalations taken within a 24-hour period by each patient. For patients who 
experienced a CE-COPD, the maximum number of inhalations taken within a 24-hour period is 
determined among the days prior to the date of the symptom peak of the exacerbation. 
7.1.2. 
Analysis Methods for Albuterol Use 
7.1.2.1. 
Pattern of Baseline Daily and Weekly Albuterol Use 
A patient’s pattern of baseline albuterol use is exhibited if, on any given day, during a given 
week, they do not take more than their average number of inhalations computed from day 1 to 
day 7.  
Summary statistics including 95% CIs intervals of the proportion of patients exhibiting their 
individual weekly baseline albuterol use during each week of the 12 week study (Week 1, Week 
2,…, Week 12) will be presented overall and by CE-COPD status and by CE-COPD severity 
(Yes: severe, moderate; No).  
Summary statistics including 95% CIs intervals of the proportion of eMDPI time on study days 
when a patient did not take more than the average number of inhalations computed from day 1 to 
day 7 (number of days a given patient had no more than average baseline albuterol use) / total 
number of eMDPI study days for a given patient) will be summarized overall and by CE-COPD 
status and by CE-COPD severity (Yes: severe, moderate; No). 
Week 1 and Week 2 and the first 14 day patient albuterol use patterns, “WK1:I#iD#dMTN#n,” 
“WK2:I#iD#dMTN#n” and “D14:I#iD#dMTN#n” designation, will be summarized 
descriptively (counts and percent) overall and by CE-COPD status and by CE-COPD severity 
(Yes: severe, moderate; No).  
7.1.2.2. 
Total Number of Inhalations in the Days Preceding the Peak of a CE-COPD 
For patients who experienced a CE-COPD, summary descriptive statistics of the total number of 
inhalations taken in 1 day (eg, the 24-hour period on the day prior to the date of the CE-COPD 
symptom peak) and at 3, 5, 7, 10, 14, and 21 days preceding the date of the CE-COPD symptom 
peak, will be presented overall and by moderate CE-COPDs and severe CE-COPDs.  
In this analysis, among patients experiencing more than 1 CE-COPD, the subsequent CE-COPDs 
can be considered a separate CE-COPD, distinct from the first (preceding) CE-COPD, provided 
the patient exhibited at least 1 day of baseline albuterol use after the first (preceding) CE-
COPD’s end date, as captured on the adverse event page, and prior to the subsequent CE-
COPD’s start date, as captured on the adverse event page. For patients who experience multiple 
CE-COPDs, all distinct CE-COPDs will be considered in this descriptive analysis. Descriptive 
summaries of the number of inhalations on the days prior to a CE-COPD will only be reported if 
the event does not overlap with a preceding CE-COPD. For example, if the date of symptom 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
27 
peak for a patient’s second CE-COPD occurs 12 days after the end date of the patient’s first CE-
COPD and there is at least 1 day of baseline albuterol use between these dates, then only the data 
collected on 1, 3, 5, 7, and 10 days (not 14 and 21 days) prior to the second CE-COPD will be 
included when computing the summaries measures. 
Mean and 95% CIs of the total number of inhalations per day, for each eMDPI study day, will be 
summarized graphically. The number of patients contributing to the summary statistics at Day 7, 
14, 21, 28, 35, 42, 49, 56, 63, 70, 77, and 84 will also be presented. Three lines graphs will be 
presented in 1 figure: “Overall” and by “CE-COPD Status” (Yes, No). Three line graphs will be 
presented in a second figure; “CE-COPD Status No”, “CE-COPD Status Yes: Severe” and “CE-
COPD Status Yes: Moderate”. 
A figure summarizing the mean (+/- minimum and maximum) of the total number of inhalations 
per day, for each patient experiencing multiple CE-COPDs, will be presented for the time period 
of 21 days prior to the date of symptom peak of the first CE-COPD to 21 days after the date of 
symptom peak of the last CE-COPD. The x-axis will be labeled -21, -20, …., -1, 0, 1, 2, …D, 
where day 0 is the date of symptom peak of the first CE-COPD and D is the study day number 
21 days after the date of the symptom peak of the last CE-COPD. 
7.1.2.3. 
Hypothesis: Albuterol Use Will Increase Several Days Prior to a CE-COPD 
The hypothesis under consideration is that albuterol use will increase several days prior to a CE-
COPD. Several days will be defined as 7 days prior to the date of the CE-COPD symptom peak 
for this analysis.  
For each subject that experiences at least 1 CE-COPD, Y1, …, Y7 will represent the number of 
puffs of albuterol during the 7 days preceding the date of the CE-COPD symptom peak and  
Y8,…,Y14 will represent the number of puffs taken each day during days 8 through 14 preceding 
the date of the CE-COPD symptom peak. Under the hypothesis of no increased albuterol use 
preceding an exacerbation (ie, null hypothesis) assume for subject “xxx” that 
)
(
~
xxx
iid
i
Poisson
Y
λ
 
for all subjects i. Alternatively, if albuterol use does increase prior to an exacerbation, then 
)
(
~
xxx
iid
i
Poisson
Y
λ
 during day 8 through 14 preceding the date of the CE-COPD symptom peak 
and 
)
(
~
δ
λ
+
xxx
iid
i
Poisson
Y
 for the immediate 7 days preceding the CE-COPD(s). Also, for 
random subject effect, assume 
xxx
λ
 follows some distribution to account for subject to subject 
variability. Let dxxx will equal to the mean number of puffs during the 7 days immediately 
preceding the date of the CE-COPD symptom peak minus mean number of puffs during days 8 
through 14 preceding the date of the CE-COPD symptom peak. To assess if albuterol usage 
increases 7 days prior to a CE-COPD, H0: μD = 0, H1: μD > 0 will be tested using a t-test at the 
0.05 significance level.  


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
28 
7.1.2.4. 
Number of Days Prior to the Peak of a CE-COPD When Albuterol Use 
Increased 
Among patients who experienced a CE-COPD, summary statistics of the number of days prior to 
the peak of a CE-COPD when albuterol use increased, will be presented overall and by moderate 
CE-COPDs and severe CE-COPDs for 3 thresholds defining an increase in albuterol use;  
(i) 
First occurrence of a single day increase of 20% from baseline use prior to CE-
COPD 
(ii) 
First occurrence of a single day absolute increase of 2 inhalations from baseline 
use prior to CE-COPD 
(iii) 
First occurrence of a single day absolute increase of 4 inhalations from baseline 
use prior to CE-COPD 
Among patients who did not experience a CE-COPD, summary statistics, including 95% CIs 
intervals of the proportion of eMDPI time on study days when a patient exceeded a given 
threshold of albuterol use (number of days a given patient’s single day’s albuterol use exceeded 
4 inhalations/total number of eMDPI study days for a given patient), will be summarized for 3 
thresholds defining an increase in albuterol use; 
(i) 
First occurrence of a single day increase of 20% from baseline use 
(ii) 
First occurrence of a single day absolute increase of 2 inhalations from baseline 
use 
(iii) 
First occurrence of a single day absolute increase of 4 inhalations from baseline 
use 
7.1.2.5. 
Maximum Number of Inhalations Taken In a 24-Hour Period  
Summary descriptive statistics of the maximum number of inhalations taken in a 24-hour period 
will be presented overall and by CE-COPD status and by CE-COPD severity.  
Data listings for each parameter of albuterol use will be presented by patient. 
7.2. 
Inhalational Flow Values 
7.2.1. 
Inhalational Flow Values Definitions 
Study Day X and Week Y inhalational flow values are defined as follows: 
Study Day X Inhalational Flow Values: The inhalational flow values for study day X are 
computed using the set of inhalations taken by the patient on study day X. Among these 
inhalations, the inhalation with the highest maximal MIF value is considered the ‘Study Day X 
Inhalation’. The Study Day X MIF, inhalational volume, inhalation duration, and time to MIF 
values are those of the identified ‘Study Day X Inhalation’. If there was no albuterol use on 
Study Day X, then the closest preceding nonmissing Study Day Inhalation’ is used as the ‘Study 
Day X Inhalation’ and the inhalational flow values for Study Day X are assigned accordingly. 
Week Y Inhalational Flow Values: The inhalational flow values for Week Y are computed using 
the set of inhalations taken by the patient during a given week on the study. Among these 
inhalations, the inhalation with the highest MIF value is considered the ‘Weekly Y Inhalation’. 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
29 
The Weekly Y MIF, inhalational volume, inhalation duration, and time to MIF values are those 
of the identified ‘Weekly Y Inhalation’.  
Note, if a patient never used the ABS eMDPI during the study or download of a given ABS 
eMDPI device was not successful, study day and weekly inhalational flow values will be 
missing. 
7.2.2. 
Analysis Methods for Inhalational Flow Values 
7.2.2.1. 
Actual and Change from Baseline in Study Day X Inhalational Flow Values 
Prior to the Peak of a CE-COPD 
Among patients who experienced a CE-COPD, summary descriptive statistics of the actual 
inhalational flow values and change from baseline in daily inhalational flow values for MIF, 
inhalational volume, inhalation duration, and time to MIF at 1 day (eg, the 24-hour period on the 
day prior to the date of the CE-COPD symptom peak) and at 3, 5, 7, 10, 14, and 21 days 
preceding the peak of a CE-COPD, will be presented for all CE-COPDs and by moderate CE-
COPDs and severe CE-COPDs. 
In this analysis, among patients experiencing more than 1 CE-COPD, the subsequent CE-COPDs 
will be considered a separate CE-COPD distinct from the first (preceding) CE-COPD, provided 
the patient exhibited at least 1 day of baseline albuterol use after the first (preceding) CE-
COPD’s date of symptom peak and prior to the subsequent CE-COPD’s date of symptom peak. 
For patients who experience multiple CE-COPDs (eg, 3), for a given number of days preceding a 
CE-COPD (eg, 7 days), if the (eg, third) CE-COPD overlaps with the time period of the 
preceding (eg, second) CE-COPD, the CE-COPD (eg, third CE-COPD) should not be included in 
the analysis.  
Summary descriptive statistics of the actual inhalational flow values and change from baseline in 
daily inhalational flow values for MIF, inhalational volume, inhalation duration, and time to MIF 
will be presented for overall, by CE-COPD status, by CE-COPD severity (Yes: severe, moderate; 
No) and for the first occurrence of a single day increase of 20% from baseline use. For patients 
who experienced a CE-COPD, the single day increase of 20% from baseline use is the single day 
increase of 20% from baseline use prior to the exacerbation. 
In addition, summary descriptive statistics of the maximum change from baseline in daily 
inhalational flow values for MIF, inhalational volume, inhalation duration, and time to MIF, will 
be presented overall and by CE-COPD status and by CE-COPD severity (Yes: severe, moderate; 
No). For patients who experienced a CE-COPD, the maximum change from baseline is the 
maximum change prior to the exacerbation. 
7.2.2.2. 
Actual and Change from Baseline in Week Y Inhalational Flow Values 
Summary descriptive statistics of the actual inhalational flow values and change from baseline in 
MIF, inhalational volume, inhalation duration, and time to MIF for each study week (1 through 
12) will be presented overall, and by CE-COPD status and by CE-COPD severity.  


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
30 
7.3. 
Accelerometry: Total Daily Steps 
7.3.1. 
Total Daily Steps Definition 
Study Day X and Week Y TDS are defined as follows: 
Study Day X TDS: The TDS for study day X are the TDS recorded by accelerometry on study 
day X. If TDS are missing on Study Day X, then the average TDS of the 7 days preceding study 
day X is computed and assigned to Study Day X. 
Week Y TDS: The TDS for Week Y are computed using the set of TDS taken by the patient 
during a given week on study. The average will be calculated as the sum of the daily TDS 
divided by the number of days with nonmissing TDS.  
The TDS are computed for those patients in the ankle accelerometry analysis set. 
7.3.2. 
Analysis Methods for Total Daily Steps 
7.3.2.1. 
Actual and Change from Baseline in Study Day X Total Daily Steps Prior to the 
Peak of a CE-COPD 
Among patients in the ankle accelerometry cohort who experienced a CE-COPD, summary 
descriptive statistics of the actual TDS and change from baseline in TDS 1 day (eg, the 24-hour 
period on the day prior to the date of the CE-COPD symptom peak) and at 3, 5, 7, 10, 14, and 21 
days preceding the peak of a CE-COPD, will be presented for all CE-COPDs and by moderate 
CE-COPDs and severe CE-COPDs.  
In this analysis, among patients experiencing more than 1 CE-COPD, the subsequent CE-COPDs 
will be considered a separate CE-COPD distinct from the first (preceding) CE-COPD provided 
the patient exhibited at least 1 day of baseline albuterol use after the first (preceding) CE-
COPD’s date of symptom peak and prior to the subsequent CE-COPD’s date of symptom peak. 
For patients who experience multiple CE-COPDs (eg, 3), for a given number of days preceding a 
CE-COPD (eg, 7 days), if the (eg, third) CE-COPD overlaps with the time period of the 
preceding (eg, second) CE-COPD, the CE-COPD (eg, third CE-COPD) will not be included in 
the analysis. 
Among patients in the ankle accelerometry cohort, summary descriptive statistics of the actual 
TDS and change from baseline in TDS, will be presented for overall, by CE-COPD status, by 
CE-COPD severity (Yes: severe, moderate; No) and for the first occurrence of a single day 
increase of 20% from baseline use. For patients who experienced a CE-COPD, the single day 
increase of 20% from baseline use is defined as the single day increase of 20% from baseline use 
prior to the exacerbation. 
In addition, summary descriptive statistics of the maximum change from baseline in TDS will be 
presented overall and by CE-COPD status and by CE-COPD severity. For patients who 
experienced a CE-COPD, the maximum change from baseline in TDS is the maximum change 
from baseline in TDS during the days prior to the exacerbation. 


Statistical Analysis Plan with Amendment 01 
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7.3.2.2. 
Actual and Change from Baseline in Week Y Total Daily Steps 
Summary descriptive statistics of the actual Week Y TDS and change from baseline in TDS for 
each study week (1 through 12) will be presented overall, and by CE-COPD status and by CE-
COPD severity (Yes: severe, moderate; No) using the ankle accelerometry analysis set. 
7.4. 
Accelerometry: Sleep Disruption Index 
7.4.1. 
Sleep Disruption Index Definition 
The SDI for analysis in this study will consist of the following measures, which correlate 
significantly with SABA rescue use (Krouse et al. 2008) and the composite score derived from 
the summation of these 3 measures. 
(i) Nighttime Average Sleep Latency Time (r=0.78)  
(ii) Longest Nighttime Wake Episode (r=0.73) 
(iii)  Total Time Awake at Night (r=0.65) 
Study Day X and Week Y SDIs are defined as follows:  
Study Day X Nighttime Average Sleep Latency Time: The nighttime average sleep latency time 
for study day X is the nighttime average sleep latency time recorded by wrist accelerometry on 
study day X. If nighttime average sleep latency time is missing on Study Day X, then the average 
nighttime average sleep latency time of the 7 days preceding study day X is computed and 
assigned to Study Day X. 
Week Y Nighttime Average Sleep Latency Time: The nighttime average sleep latency time for 
Week Y is computed using the set of nighttime average sleep latency times recorded by wrist 
accelerometry during a given week on study. The average will be calculated as the sum of the 
daily nighttime average sleep latency times divided by the number of days with nonmissing 
nighttime average sleep latency times. 
Study Day X Longest Nighttime Wake Episode: The longest nighttime wake episode for study 
day X is the longest nighttime wake episode calculated as described in Section 4.2.5 on study day 
X. If longest nighttime wake episode is missing on Study Day X, then the greatest longest 
nighttime wake episode of the 7 days preceding study day X is computed and assigned to Study 
Day X 
Week Y Longest Nighttime Wake Episode: The longest nighttime wake episode for Week Y is 
the greatest longest nighttime wake episode calculated as described in Section 4.2.5 during a 
given week on study.  
Study Day X Total Time Awake at Night: The total time awake at night for study day X is the 
total time awake at night time recorded by wrist accelerometry on study day X. If total time 
awake at night is missing on Study Day X, then the average total time awake at night of the 7 
days preceding study day X is computed and assigned to Study Day X. 
Week Y Total Time Awake at Night: The total time awake at night for Week Y is computed using 
the set of total time awake at night times recorded by wrist accelerometry during a given week 
on study. The average will be calculated as the sum of the total time awake at night times divided 
by the number of days with nonmissing total time awake at night times. 


Statistical Analysis Plan with Amendment 01 
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Study Day X SDI Composite Score: The SDI composite score for study day X is sum of 
nighttime average sleep latency time, longest nighttime wake episode and total time awake at 
night on study day X.  
Week Y SDI Composite Score: The SDI composite score for Week Y is the sum of nighttime 
average sleep latency time, longest nighttime wake episode and total time awake at night for 
Week Y. 
The SDIs are computed for those patients in the wrist accelerometry analysis set. 
7.4.2. 
Analysis Methods for Sleep Disruption Indices 
7.4.2.1. 
Actual and Change from Baseline in Study Day X Sleep Disruption Indices Prior 
to the Peak of a CE-COPD 
Among patients in the wrist accelerometry cohort who experienced a CE-COPD, summary 
descriptive statistics of nighttime average sleep latency time, longest nighttime wake episode, 
and total time awake at night and change from baseline in these 3 measures of SDI at 1 day (eg, 
the 24-hour period on the day prior to the date of the CE-COPD symptom peak) and at 3, 5, 7, 
10, 14 and 21 days preceding the peak of a CE-COPD, will be presented for all CE-COPDs and 
by moderate CE-COPDs and severe CE-COPDs.  
Summary descriptive statistics of nighttime average sleep latency time, longest nighttime wake 
episode, and total time awake at night and change from baseline in these 3 measures of SDI will 
be presented for overall, by CE-COPD status, by CE-COPD severity (Yes: severe, moderate; No) 
and for the first occurrence of a single day increase of 20% from baseline use. For patients who 
experienced a CE-COPD, the single day increase of 20% from baseline use is defined as the 
increase prior to the exacerbation. 
In addition, summary descriptive statistics of the maximum daily change from baseline nighttime 
average sleep latency time, longest nighttime wake episode, and total time awake at night, will 
be presented overall and by CE-COPD status and by CE-COPD severity. For patients who 
experienced a CE-COPD, the maximum daily change from baseline is the change prior to the 
exacerbation. 
7.4.2.2. 
Actual and Change from Baseline in Week Y Sleep Disruption Indices 
Summary descriptive statistics of the absolute Week Y nighttime average sleep latency time, 
longest nighttime wake episode, total time awake at night, and SDI composite score and change 
from baseline in these 4 SDIs for each study week (1 through 12), will be presented overall, and 
by CE-COPD status and by CE-COPD severity. 
7.5. 
Clinical Exacerbation of COPD  
7.5.1. 
Definition of Clinical Exacerbation of COPD 
A CE-COPD is the primary outcome measure of this study. In this study, a CE-COPD is an 
occurrence of either a “severe CE-COPD” or a “moderate CE-COPD.” “Mild CE-COPD” is 
defined below for investigator information but is not used either for entry criteria or as a measure 
in this study. 


Statistical Analysis Plan with Amendment 01 
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• Severe CE-COPD is defined as an event that involves worsening respiratory 
symptoms for at least 2 consecutive days requiring treatment with systemic 
corticosteroids (SCS; at least 10 mg prednisone equivalent above baseline [Table 2]) 
and/or systemic antibiotics and a hospitalization for CE-COPD. 
• Moderate CE-COPD is defined as an event that involves worsening respiratory 
symptoms for at least 2 consecutive days requiring treatment with SCS (at least 
10 mg prednisone equivalent above baseline [Table 2]), and/or systemic antibiotics, 
and an unscheduled encounter (such as a phone call, an office visit, an urgent care 
visit, or an emergency care visit) for a CE-COPD, but not a hospitalization. 
• Mild CE-COPD is defined as a worsening of respiratory symptoms for at least 
2 consecutive days requiring self-management by the patient, such as increased 
inhaler use, but not requiring treatment with SCS and/or antibiotics, nor an 
unscheduled visit of any kind. 
Table 2: 
Systemic Glucocorticoid Treatment Equivalent to 10 mg of Prednisone 
Glucocorticoid 
Treatment 
Dose (mg) Equivalent to 
10 mg of Prednisone 
Comment 
Cortisone  
50 
Includes parenteral 
Hydrocortisone 
40 
Cortisol 
Prednisolone 
10 
- 
Methylprednisolone 
8 
Medrol: includes parenteral SOLU-MEDROL® 
Triamcinolone 
8 
- 
Betamethasone 
0.4 
- 
Dexamethasone 
0.4 
Oral or parenteral DECADRON® 
The designation of a CE-COPD as moderate or severe is denoted by the response to the CRF 
question “Severity” on the Clinical Exacerbation of COPD CRF page regardless of whether the 
following CRF questions are answered in the negative or missing: 
• “The treating physician elects to administer prednisone (or equivalent glucocorticoid 
treatment) at least 10 mg prednisone equivalent above baseline, for at least 3 days” 
• An unscheduled provider visit such as an office visit, telephone call, urgent care visit, 
emergency care visit, or hospitalization  
A patient may experience more than 1 CE-COPD during the study period. 
Clinical Exacerbation of COPD Status: Clinical exacerbation of COPD status is an indicator of 
whether or not a patient experienced a CE-COPD during study follow-up (Yes, No).  
Clinical Exacerbation of COPD Rate: The percentage of patients who experience at least 1 
moderate of severe CE-COPD at the end of study follow-up. 
Recurrent Clinical Exacerbation of COPD Rate: The percentage of patients who experience more 
than 1 moderate of severe CE-COPD at the end of study follow-up. 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
34 
Time to Clinical Exacerbation of COPD: Time, in days, from Study Day 1 to the Date of 
Symptom Peak plus 1.  
7.5.2. 
Analysis Methods for Clinical (COPD) Exacerbation 
As specified in the protocol, because the device-use-measures will be collected continuously over time, 
these measures could be used to derive many potential predictors of risk. Several analyses are proposed 
to study correlations between CE-COPD and device-use-measures. 
7.5.2.1. 
Within Patient CE-COPD Analyses 
For each CE-COPD event occurring at least 2 weeks after baseline, device-use measures 
(albuterol use, inhalational flow [MIF], inhalational volume, and time to MIF) will be 
summarized for each of 2 weeks of interest: first- 'CE-COPD-adjacent week', the week 
immediately preceding the onset of CE-COPD symptom (ie, day 1 through 7 preceding the date 
of the CE-COPD symptom onset), and second – 'CE-COPD-Prior Adjacent week', the week 
preceding that week (ie, during day 8 through 14 preceding the date of the CE-COPD symptom 
onset). Summary measures of daily and or weekly use will be compared between the two weeks, 
as proposed below: 
Albuterol use measures: 
• total number of inhalations in that week 
• the maximal daily number of inhalations in that week 
• the mean number of daily inhalations (ie, total number of inhalations divided by number 
of days with number>0) 
• occurrence of a single day’s albuterol use exceeding 4 inhalations 
• occurrence of a single day’s albuterol use exceeding 8 inhalations  
• occurrence  of a single day’s albuterol use exceeding 12 inhalations 
• number of days when albuterol use exceeding 4 inhalations 
• number of days when albuterol use exceeding 8 inhalations  
• number of days when albuterol use exceeding 12 inhalations 
To note, in this analysis, no inhalation in any day will be taken as a 0 count. 
Inhalation flow values parameters: 
• maximal daily MIF during the week 
• minimal daily time to MIF within a week 
• maximal total daily inhalational volume within a week  
To note, if no inhalation was taken at a specific day, flow value parameters will be missing and 
will not be imputed. 
Analysis will be based on all patients CE-COPDs for which there are 14 days (or more) prior to 
the CE-COPD onset, where patient has been on study and CE-COPD free. 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
35 
Descriptive statistics of use measures in the 'CE-COPD-adjacent week' and 'CE-COPD-Prior 
Adjacent week' will be presented.  
Continuous measures will be compared between the 2 weeks using paired t-test (and Wilcoxon 
Signed Ranks test) whereas binary patterns will be compared using Mc-Nemar test. 
7.5.2.2. 
Time to Clinical  (COPD) Exacerbations Short-term Exacerbation Risk (7 days) 
For each patient, the following 3 landmark use events will be identified: 
• first time in study when had >4 inhalations per day ("low use group") 
• first time in study when had >8 inhalations per day ("medium use group") 
• first time in study when had >12 inhalations per day ("high use group") 
A patient may be included in more than 1 landmark use group (for example, if had >12 
inhalations a day any time during study, then on that time or already before he/she also had >8 
and >4 a day). 
For each landmark use groups, time to CE-COPD within 7 days since the landmark event will be 
estimated and plotted using Kaplan-Meier plot. The 3 groups will be presented in the same plot, 
to assess a possible 'dose-response' association, if higher use is associated with shorter time to 
CE-COPD.  
If a CE-COPD has not occurred within 7 days, then that observation will be censored at 7 days or 
earlier if follow-up had completed/terminated before 7 days elapsed. Note, if CE-COPD occurred 
on the same date where landmark use happened, then time to CE-COPD will be calculated as 0. 
7.5.2.3. 
All Days Analysis (Only CE-COPD-free Days) 
This analysis will be performed by the data analytics group. Additional details may be specified 
in a separate report.  One possible analysis is presented below: 
For each patient, all study days where the patient was CE-COPD free will be the unit of this 
analysis. There are various ways to summarize albuterol use on this, for example by looking at: 
• daily number of inhalations 
• albuterol use exceeding 4 inhalations (Yes/No) 
• albuterol use exceeding 12 inhalations (Yes/No)  
Exploratory analyses using all these patient days can be performed to predict occurrence of 
CE-COPD event in the next day (for example, using logistic regression). Exploratory predictive 
analyses will be reported separately. 
7.5.2.4. 
Summary Descriptive Statistics of Initial and Recurrent Clinical COPD 
Exacerbation Rates 
Proportion of patients with at least 1 CE-COPD and proportion of patients with recurrent events 
will be presented. 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
36 
7.5.3. 
Predicting Severe CE-COPD/Moderate CE-COPD from Multiple Device-Use-
Measures 
Predictive analysis will be performed by the data analytics group. Additional details may be 
specified in a separate report. Exploratory predictive analyses will be reported separately. 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
37 
8. 
SENSITIVITY ANALYSIS 
There will be no sensitivity analysis performed in this study. 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
38 
9. 
MULTIPLE COMPARISONS AND MULTIPLICITY 
No adjustment for multiplicity will be applied. 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
39 
10. 
SAFETY ANALYSIS 
10.1. 
General 
The ITT analysis set will be used for all safety analyses.  
10.2. 
Duration of Exposure to ABS eMDPI  
Duration of exposure to ABS eMDPI (days and weeks) for the individual patient is the number 
of days the patient took at least 1 inhalation from the ABS eMDPI. Patients receive the ABS 
eMDPI devices at Baseline and subsequently by courier on Day 21. Duration of exposure is 
determined from all eMDPIs used by a patient and it is the total number of unique dates recorded 
by the eMDPIs from the dispense date and return date of a given device, inclusive. Note, if a 
patient uses more than 1 eMDPI device on a given day, it is still only 1 day of exposure for that 
given day. The patient’s last date of contact or study completion date will be used as the device 
return date if the device return date is missing. 
Duration of exposure (days and weeks) will be summarized using descriptive statistics overall, 
and by CE-COPD status and by CE-COPD severity. 
Exposure to IMP, expressed in mcg units, will also be summarized using descriptive statistics. 
Average daily exposure, average weekly exposure, and the maximum exposure in a single day 
will be summarized overall, and by CE-COPD status and CE-COPD severity. One inhalation 
recorded by the ABS eMDPI is equivalent to 90 mcg.  
10.3. 
 Time on Study  
Duration of time on study (days and weeks) will be summarized using descriptive statistics 
overall, and by CE-COPD status and by CE-COPD severity. 
10.4. 
Adverse Events 
All treatment emergent adverse events will be coded using the MedDRA (Medical Dictionary for 
Regulatory Activities). Adverse events will be included as treatment emergent based on the date 
of the baseline (ie, the earliest date an ABS eMDPI device was dispensed). Each patient will be 
counted only once in each PT or SOC category for the analyses of safety. Summaries will be 
presented for all adverse events (overall and by severity), adverse events determined by the 
investigator to be related to test IMP (ie, reasonable possibility [Table 5 in Section 7.1.4 of the 
protocol], defined as related or with missing relationship; overall and by severity), serious 
adverse events, CE-COPD related adverse events, and adverse events leading to withdrawal from 
the study, COPD exacerbations by severity, and COPD exacerbations by deterioration.  
Patient listings for all adverse events, serious adverse events, and adverse events leading to 
withdrawal will be presented. 
If any patient dies during the study, a listing of deaths will be provided, and all relevant 
information will be discussed in the patient narrative included in the CSR. 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
40 
Any adverse event or serious adverse event with a missing start date will be considered treatment 
emergent. 
10.5. 
Deaths 
A listing of deaths by patient and narratives will be provided, if any patient dies during the study. 
10.6. 
Clinical Laboratory Tests 
Any patient who experiences menarche following screening will be required to have a negative 
urine pregnancy test prior to dosing with IMP. If a patient has a positive urine pregnancy test, 
then she will be discontinued from the study. A urine pregnancy test for women of childbearing 
potential will be performed at the Screening and Final/Early Termination visit. 
A listing of urine pregnancy test by patient will be provided. 
10.7. 
Physical Examinations 
Physical examinations will be performed at the Screening, exacerbation visits, and Final/Early 
Termination visit.  
A physical examination that includes, at a minimum, skin, lungs, cardiovascular, respiratory, 
gastrointestinal, and neurological assessments are completed at the Screening visit (eg, baseline 
values], exacerbation visits, and Final/Early Termination visit. Height (to be obtained at the 
Screening visit only) and weight will also be measured and recorded. Any pre-existing 
abnormality will be reported as a part of medical history and any ongoing abnormality identified 
at screening and any new findings or clinically significant change (worsening) identified at an 
exacerbation visit or the Final/Early Termination visit will be reported as an adverse event. 
10.8. 
Concomitant Medications or Therapies  
Concomitant therapies and medications, including medications that are taken on an as needed 
basis and occasional therapies, will be monitored during the study. Details of prohibited 
medications may be found in Section 5.6 of the study protocol. All concomitant medications will 
be coded using the WHO Drug Dictionary. 
The incidence of concomitant therapies and medications will be summarized using descriptive 
statistics by therapeutic class category and PT term. Patients are counted only once in each 
therapeutic class, and only once in each PT category. Concomitant therapies and medications for 
a given patient will include all medications up to the end of the patient’s participation in the 
study (date of completion, withdrawal, lost to follow-up, or death). 
A listing of all concomitant therapies and medications by patient and the study day the therapy or 
medication was started will be provided. 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
41 
11. 
TOLERABILITY VARIABLES AND ANALYSIS 
Tolerability was not specifically defined for this study. 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
42 
12. 
PHARMACOKINETIC ANALYSIS 
Not applicable. 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
43 
13. 
PHARMACODYNAMIC ANALYSIS 
Not applicable. 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
44 
14. 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS 
Not applicable. 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
45 
15. 
BIOMARKER ANALYSIS 
Not applicable. 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
46 
16. 
IMMUNOGENICITY ANALYSIS 
Not applicable. 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
47 
17. 
ANCILLARY STUDIES ANALYSIS 
Not applicable. 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
48 
18. 
PLANNED INTERIM ANALYSIS 
Not applicable. 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
49 
19. 
STATISTICAL SOFTWARE 
All data listings, summaries, and statistical analyses will be generated using SAS® version 9.1.3 
or higher. 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
50 
20. 
CHANGES TO ANALYSES SPECIFIED IN THE STUDY 
PROTOCOL 
20.1. 
Intent-To-Treat Analysis Set 
Statistical 
Analysis Plan 
Section 
Protocol 
Section 
Protocol 
Description 
Statistical Analysis 
Plan Change 
Rationale 
3.1 
9.2.1 
The intent-to-treat 
(ITT) analysis set 
will include all 
enrolled patients 
regardless of 
whether or not a 
patient took any 
IMP. A patient is 
considered 
enrolled according 
to the status 
reported in the 
database. This 
analysis 
population will be 
used for 
summarization of 
patient disposition. 
The intent-to-treat 
(ITT) analysis set 
will include all 
enrolled patients 
regardless of 
whether a patient 
took any 
investigational 
medicinal product 
(IMP). A patient is 
considered enrolled 
according to the 
status reported in 
the database. This 
analysis set will be 
used for endpoint 
analysis and safety 
analysis.  
 
Patient disposition 
will be summarized 
using all patients 
entered into the 
database not just 
enrolled patients, 
since all patients are 
needed to 
descriptively 
summarize patients 
screened, patients 
screened but not 
enrolled and reason 
for non-enrollment. 
All endpoint and 
safety analyses will 
use the ITT analysis 
set. 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
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20.2. 
Modified Intent-To-Treat Analysis Set 
Statistical 
Analysis Plan 
Section 
Protocol 
Section 
Protocol 
Description 
Statistical Analysis Plan 
Change 
Rationale 
3.2 
9.2.2 
The modified 
intent-to-treat 
(mITT) analysis 
set is a subset of 
the ITT analysis 
set that will 
include only the 
patients who 
used the IMP at 
any time during 
the study. This 
analysis 
population will 
be used for 
endpoint 
analysis”.  
The modified intent-to-
treat (mITT) analysis set 
is a subset of the ITT 
analysis set that will 
include patients who 
used the IMP at any time 
during the study and 
patients who did not use 
the IMP at any time 
during the study 
provided these patients 
complied with study 
requirements and the 
ABS eMDPI inhalers 
were available for data 
download at the end of 
the study.  
This study is to 
evaluate the 
relationship 
between as-
needed usage of 
ABS eMDPI and 
CE-COPD/severe 
CE-COPD. As-
needed usage 
may include no 
usage if patients’ 
health did not 
require ABS 
eMDPI use. 
Endpoint 
analyses will be 
summarized 
using the ITT 
analysis set.  


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
52 
20.3. 
Safety Analysis Set 
Statistical 
Analysis Plan 
Section 
Protocol 
Section 
Protocol 
Description 
Statistical Analysis 
Plan Change 
Rationale 
3.3 
9.2.3 
The safety analysis 
set will include all 
enrolled patients 
who receive at 
least 1 dose of the 
test IMP. In this 
analysis 
population, 
treatment will be 
assigned based on 
the treatment 
patients actually 
received unless 
otherwise 
specified. This 
analysis population 
will be used for 
analysis and 
summarization of 
safety data. 
The safety analysis 
set will include all 
enrolled patients 
who receive at 
least 1 dose of the 
IMP.  
There is only one 
IMP in this study. 
The sentence 
regarding how 
treatment will be 
assigned was 
deleted for clarity. 
Safety analyses 
will be 
summarized using 
the ITT analysis 
set. 


Statistical Analysis Plan with Amendment 01 
Study ABS-COPD-30065 
53 
20.4. 
Predicting Severe CE-COPD/Moderate CE-COPD from Multiple 
Device-Use-Measures 
Statistical 
Analysis Plan 
Section 
Protocol 
Section 
Protocol Description Statistical 
Analysis Plan 
Change 
Rationale 
7.5.3 
9.5.2.1 
The multiple 
device-use-measures 
will be used as 
predictors of CE-
COPD in stepwise 
selection logistic 
regression models to 
select significant 
predictors in a 
forward manner. 
Predicative 
analysis will be 
performed by the 
data analytics 
group. Additional 
details may be 
specified in a 
separate report. 
Exploratory 
predictive analyses 
will be reported 
separately.  
Clarification. 
Analysis was 
removed from the 
SAP as this 
analysis will be 
performed 
separately by the 
data analytics 
group. 


Statistical Analysis Plan with Amendment 01 
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54 
21. 
REFERENCES 
Bateman ED, Buhl R, O’Byrne PM, Humbert M, Reddel HK, Sears MR, et al. Development and 
validation of a novel risk score for asthma exacerbations: the risk score for exacerbations. 
J Allergy Clin Immunol 2015;135:1457-64. 
Dransfield MT, Bourbeau J, Jones PW, Hanania, NA, Mahler DA, Vestbo J, et al. Once-daily 
inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations 
of COPD: two replicate double-blind, parallel-group, randomised controlled trials. Lancet Respir 
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Greenberg S, Liu N, Kaur A, Lakshminarayanan M, Zhou Y, Nelsen L, et al. The asthma disease 
activity score: a discriminating, responsive measure predicts future asthma attacks. J Allerg Clin 
Immunol 2012;130:1071-7. 
Harrell FE, Lee K, Califf RM, Pryor DB, Rosati RA. Regression modeling strategies for 
improved prognostic prediction. Stat Med 1984;3:143-52. 
Jenkins CR, Postma DS, Anzueto AR, Make BJ, Peterson S, Eriksson G, et al. Reliever 
salbutamol use as a measure of exacerbation risk in chronic obstructive pulmonary disease. BMC 
Pulm Med 2015;15:97. 
Krouse HJ, Yarandi H, McIntosh J, Cowen C, Selim V. Assessing sleep quality and daytime 
wakefulness in asthma using wrist actigraphy, J Asthma 2008;45(5):389-95. 
Laupacis A, Sekar N, Stiell IG. Clinical prediction rules: a review and suggested modifications 
of methodological standards. JAMA 1997;277:488-94. 
Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein AR. A simulation study of the number 
of events per variable in logistic regression analysis. J Clin Epidemiol 1996;49(12):1373-9. 
Quezada W, Kwak ES, Reibman J, Rogers L, Mastronarde J, Teague WG, et al. Predictors of 
asthma exacerbation among patients with poorly controlled asthma despite inhaled corticosteroid 
treatment. Ann Allergy Asthma Immunol 2016;116:112-7.  
Vittinghoff E, McCulloch CE. Relaxing the rule of ten events per variable in logistic and Cox 
regression. Am J Epidemiol 2007;165:710-8. 
Vogelmeier C, Hederer B, Glaab T, Schmidt H, et al. Tiotropium versus Salmeterol for the 
prevention of exacerbations of COPD. N Engl J Med 2016;364:1093-103. 
Wedzicha JA, Banerji D, Chapman KR, Vestbo J, et al. Indacaterol-Glycopyrronium versus 
Salmeterol-Fluticasone for COPD. N Engl J Med 2016;374:2222-34. 
Wedzicha JA, Decramer M, Ficker JH, Niewoehner DE, et al. Analysis of chronic obstructive 
pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with 
glycopyrronium and tiotropium (SPARK): a randomized, double-blind, parallel-group study. 
Lancet Respir Med 2013;1:199-209.