Clinical trial NCT02969408
Conditions: Asthma
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Start date: 2017-02-13; Completion date: 2018-02-02
Enrollment: 397 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 albuterol sulfate (ABS) eMDPI and clinical asthma exacerbation (CAE) in adult participants at least 18 years of age with exacerbation-prone asthma. The ABS eMDPI dose will be 90 micrograms (mcg), 1 to 2 inhalations every 4 hours as needed, but participant dosing will not be limited to this dosing regimen. The purpose of this study is to evaluate the relationship between albuterol dosing and CAE.

Detailed description:

Arms: arm 1: Participants will receive 90 mcg of ABS via an 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.
Interventions: intervention 1: Albuterol Sulfate
Intervention descriptions: intervention 1: Albuterol sulfate will be administered as per the dose and schedule specified in the arm.

Protocol documents:
Prot_000.pdf: 
 
 
 
 
Clinical Study Protocol with Amendment 02 
 
 
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 (18 Years of Age or Older) with Asthma 
 
 
Study Number ABS-AS-30064 
 
NCT02969408 
 
Protocol with Amendment 02 Approval Date: 22 February 2017  
 


 
Uncontrolled Study–Asthma 
Clinical Study Protocol with Amendment 02 
Study ABS-AS-30064 
1 
 
 
Clinical Study Protocol with Amendment 02 
Study Number ABS-AS-30064 
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 (18 Years of Age or Older) with Asthma 
(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: 26 July 2016 
Protocol with Amendment 01 Approval Date: 08 September 2016 
Protocol with Amendment 02 Approval Date: 22 February 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. 


 
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AMENDMENT HISTORY 
The protocol for study ABS-AS-30064 (original protocol dated 26 July 2016) 
Amendment 01 
08 September 2016 
no patients enrolled to date 
Amendment 02 
22 February 2017 
3 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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INVESTIGATOR AGREEMENT 
Clinical Study Protocol with Amendment 02 
Original Protocol Dated 26 July 2016 
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 (18 Years of Age or Older) with Asthma 
 
Principal Investigator: __________________________________________ 
Title: _________________________________________________ 
Address of Investigational Center: __________________________________ 
 
__________________________________ 
 
__________________________________ 
Tel: ______________ 
I have read the protocol with Amendment 02 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, investigational medicinal products (IMP) 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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CLINICAL STUDY PROTOCOL SYNOPSIS 
Study ABS-AS-30064 
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 (18 Years of Age or Older) with Asthma   
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 asthma 
Is This Study Conducted to Investigate the New Use of an Approved, Marketed Product? 
No 
Number of Investigational Centers Planned: Approximately 45 
Countries Planned: United States 
Planned Study Period: Approximately 9 months 
Number of Patients Planned (Total): Approximately 500 patients will be screened to achieve 
approximately 400 enrolled patients. A subset of patients (n=100) who agree to participate at 
specific sites 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 will wear an 
accelerometer on the ankle to measure total daily steps (TDS). 
Study Population: The cohort will consist of patients 18 years of age or older with 
exacerbation-prone asthma, defined as at least 1 documented “severe” clinical asthma 
exacerbation (CAE; defined in Section 6.1.1 of the protocol) in the past 12 months, currently on 
moderate- to high-dose inhaled corticosteroid (ICS) with or without a long-acting beta agonist 
(LABA) and with uncontrolled asthma quantified as an Asthma Control Questionnaire-5 (ACQ-
5) score ≥1.5.  
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 CAE and in 
particular, a severe CAE (as diagnosed by the investigators per the protocol). The hypothesis is 
that albuterol use will increase several days prior to a severe CAE and can serve as a marker of 
asthma deterioration. 


 
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The endpoints of the trial are the primary outcome measure (ie, CAE/severe CAE) and the 
primary outcome predictor (ie, albuterol use) alone or in combination with secondary predictors 
(ie, other study data). Multiple correlates of CAE/severe CAE focused on albuterol use, alone or 
in combination with other study data, will be modeled to determine which patterns best predict 
the subsequent development of CAE/severe CAE. 
For albuterol use, parameters of interest will include (1) the total number of inhalations in the 
days preceding the peak of a severe CAE, (2) the number of days prior to the peak of a severe 
CAE when albuterol use increased, (3) the number of albuterol uses in the 24 hours preceding a 
severe CAE. 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 moderate CAE or severe CAE. Inspiratory flow values are obtained from the 
eMDPI, SDI is obtained for a subset of patients who agree to participate at specific sites (n=100) 
from an accelerometer worn on the wrist, and TDS is obtained for a subset of patients who agree 
to participate at specific sites (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 asthma. 
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 CAE/severe CAE in adult patients at least 18 years 
of age with exacerbation-prone asthma. 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 2-week screening period 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, and review asthma 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, 


 
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including short-acting beta2 agonists (SABA), short-acting muscarinic antagonists (SAMA), or 
SABA/SAMA combination, into storage. Patients may continue the use of other asthma and 
non-asthma medications as advised by their physician without changes unless a change is 
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 
asthma 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 and subsequently by courier on Day 21. 
Patients will be instructed to return all inhalers to the site at the last study visit or early 
termination. At the last study visit or early termination, 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. 
Two subsets of patients who agree to participate at specific sites 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 (visit 5). 
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 CAE in adult patients at least 18 years of age with exacerbation-prone asthma. 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 CAE.  
Method of Randomization and Blinding: This is an open-label study and there will be no 
blinding. 
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 14 weeks (2 weeks screening period and 
12 weeks intervention period). 
Study Duration: Approximately 9 months 
End of Study: End of study is defined as the last visit of the last patient. 


 
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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. 
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, 18 years of age or older, with a physician diagnosis of 
asthma.  
b. The patient has had at least 1 episode of a severe CAE (as described in Section 6.1.1 
of the protocol) over the past 12 months before screening. If on a biologic (eg, 
omalizumab, mepolizumab, or reslizumab) and/or post-bronchial thermoplasty, 
exacerbation has occurred after these interventions. 
c. The patient’s ACQ-5 score at the time of screening is ≥1.5. 
d. The patient is using a moderate-dose ICS, equivalent to at least 440 mcg daily of 
fluticasone propionate) (see Table 1). 
Table 1:  Moderate-Dose Inhaled Corticosteroid Treatment Equivalent to at Least 
440  mcg Daily of Fluticasone Propionate 
 
e. All asthma controller treatments are at a stable dose for 3 months prior to the 
screening visit.  
f. The patient’s baseline asthma therapy regimen, including oral corticosteroids, 
leukotriene antagonists, 5-lipoxygenase inhibitors, LABA, long-acting muscarinic 
agent, or cromolyn, biologicals, theophylline, or mepolizumab, is allowed. 
g. The patient must be able to demonstrate appropriate use of albuterol from the ABS 
eMDPI. 
h. The patient is able to provide written informed consent. 
i. 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. 
ICS Treatment 
Total Daily Dose (mcg) Equivalent to at Least 
440 mcg Daily of  Fluticasone Propionate  
Beclomethasone dipropionate  
≥ 320 mcg 
Budesonide  
≥ 720 mcg 
Flunisolide  
≥ 640 mcg 
Mometasone  
≥ 400 mcg 
Ciclesonide  
≥ 320 mcg 
Fluticasone furoate 
≥ 100 mcg 
ICS=inhaled corticosteroid 
 


 
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j. The patient is willing to discontinue all other rescue or maintenance SABA or anti-
muscarinic agents and replace them with the study-provided ABS eMDPI for the 
duration of the trial. 
k. Women of childbearing potential (not surgically sterile or ≥2 years postmenopausal) 
must have exclusively same-sex partners or use a highly effective 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. 
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 asthma. 
c. The patient has used an investigational drug within 5 half-lives of it being 
discontinued, or 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). 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 or presence of “silent” infections, including 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. A member of the patient’s household is participating in the study at the same time. 


 
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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 a poorly-controlled, exacerbating asthma cohort, it is expected that 
between 20% and 25% of patients at risk in this patient population will experience a CAE (event) 
over 3 months, resulting in 72 to 90 expected CAE events in this study. In addition, it is expected 
that approximately 6.7% and 15% of subjects at risk in this patient population will experience 
moderate and severe events, respectively, resulting in approximately 78 events (24 moderate 
events and 54 severe events) in the study. 
This sample size (n=400 patients; 72 to 90 CAE events) is considered adequate for 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 CAE or severe CAE. Per the study by Patel et al 2013b, a statistically 
significant relationship was established between prior mean daily SABA usage at baseline and 
subsequent CAE, studying 45 exacerbations (p<0.006).  
In the present study, approximately 72 to 90 CAE events are desired for this trial because the 
model’s fitting of the current study involves the analysis of multiple predictors as described in 
more detail below. 
Risk models published in the literature have typically included between 4 and 6 covariates/risk 
factors 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, CAE), 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. The rule of thumb when building logistic regression models is 1 predictor variable for 
every 10 events. Therefore, this sample size would be adequate for predicting the primary 
outcome (CAE) 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 CAE in the model for this patient population. 
Analysis of Endpoints: The multiple device-use-measures will be used as predictors of CAE 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 


 
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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 CAE, 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. The primary hypothesis under 
consideration is that >12 inhalations of SABA dosing will have higher odds of CAE 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. 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 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 CAE. 
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 
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 ...........................................................................................................20 
1.2.2.1. 
Clinical Safety and Efficacy Studies ..........................................................................21 
1.3. 
Known and Potential Benefits and Risks to Patients ..................................................21 
1.3.1. 
Known and Potential Benefits and Risks of the Test Investigational 
Medicinal Product .......................................................................................................21 
1.3.2. 
Overall Benefit and Risk Assessment for This Study ................................................22 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................23 
2.1. 
Study Objectives and Endpoints .................................................................................23 
2.1.1. 
Justification of the Endpoints .....................................................................................23 
3. 
STUDY DESIGN .......................................................................................................25 
3.1. 
General Design ...........................................................................................................25 
3.2. 
Planned Number of Patients and Countries ................................................................26 
3.3. 
Justification for Study Design and Selection of Population .......................................26 
3.4. 
Stopping Rules for the Study ......................................................................................27 
3.5. 
Schedule of Study Procedures and Assessments ........................................................27 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................29 
4.1. 
Patient Inclusion Criteria ............................................................................................29 
4.2. 
Patient Exclusion Criteria ...........................................................................................30 
4.3. 
Withdrawal Criteria and Procedures for the Patient ...................................................31 
4.4. 
Replacement of Patients .............................................................................................32 
4.5. 
Rescreening .................................................................................................................32 
4.6. 
Screening Failure ........................................................................................................32 
5. 
TREATMENTS ..........................................................................................................33 


 
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5.1. 
Investigational Medicinal Products Used in the Study ...............................................33 
5.1.1. 
Test Investigational Medicinal Product ......................................................................33 
5.1.1.1. 
Starting Dose and Dose Levels ...................................................................................33 
5.1.1.2. 
Dose Modification and Dose Stratification ................................................................33 
5.1.2. 
Reference Investigational Medicinal Product .............................................................33 
5.1.3. 
Placebo Investigational Medicinal Product ................................................................33 
5.2. 
Preparation, Handling, Labeling, Storage, and Accountability for 
Investigational Medicinal Products ............................................................................34 
5.2.1. 
Storage and Security ...................................................................................................34 
5.2.2. 
Labeling ......................................................................................................................34 
5.2.3. 
Accountability .............................................................................................................34 
5.3. 
Justification for Investigational Medicinal Products ..................................................35 
5.3.1. 
Justification for Dose of Test Investigational Medicinal Product ..............................35 
5.4. 
Treatment After the End of the Study .........................................................................35 
5.5. 
Restrictions .................................................................................................................35 
5.6. 
Prior and Concomitant Medication or Therapy ..........................................................35 
5.7. 
Procedures for Monitoring Patient Compliance .........................................................36 
5.8. 
Randomization and Blinding ......................................................................................36 
5.9. 
Total Blood Volume ...................................................................................................36 
6. 
ASSESSMENT OF EFFICACY ................................................................................37 
6.1. 
Assessments ................................................................................................................37 
6.1.1. 
Clinical Asthma Exacerbation ....................................................................................37 
6.1.2. 
Albuterol Use ..............................................................................................................38 
6.1.3. 
Inhalational Flow Values Upon Albuterol Dosing .....................................................38 
6.1.4. 
Accelerometry .............................................................................................................38 
7. 
ASSESSMENT OF SAFETY .....................................................................................39 
7.1. 
Adverse Events ...........................................................................................................39 
7.1.1. 
Definition of an Adverse Event ..................................................................................39 
7.1.2. 
Recording and Reporting of Adverse Events .............................................................39 
7.1.3. 
Severity of an Adverse Event .....................................................................................40 
7.1.4. 
Relationship of an Adverse Event to the Test Investigational Medicinal 
Product ........................................................................................................................41 
7.1.5. 
Serious Adverse Events ..............................................................................................41 


 
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7.1.5.1. 
Definition of a Serious Adverse Event .......................................................................41 
7.1.5.2. 
Expectedness ...............................................................................................................42 
7.1.5.3. 
Reporting a Serious Adverse Event ............................................................................42 
7.1.6. 
Protocol-Defined Adverse Events not for Expedited Reporting ................................44 
7.1.7. 
Protocol-Defined Adverse Events of Special Interest ................................................44 
7.1.8. 
Protocol Deviations Because of an Adverse Event ....................................................44 
7.2. 
Pregnancy ...................................................................................................................45 
7.3. 
Medication Error and Special Situations Related to the Investigational 
Medicinal Products .....................................................................................................45 
7.4. 
Clinical Laboratory Tests ...........................................................................................46 
7.5. 
Physical Examinations ................................................................................................46 
7.6. 
Vital Signs ..................................................................................................................46 
7.7. 
Electrocardiography ....................................................................................................46 
8. 
ASSESSMENT OF PHARMACOKINETICS / PHARMACODYNAMICS / 
BIOMARKERS / PHARMACOGENOMICS / IMMUNOGENICITY / 
ANCILLARY STUDIES ............................................................................................47 
9. 
STATISTICS ..............................................................................................................48 
9.1. 
Sample Size and Power Considerations .....................................................................48 
9.2. 
Analysis Sets ...............................................................................................................49 
9.2.1. 
Intent-to-Treat Analysis Set ........................................................................................49 
9.2.2. 
Modified Intent-to-Treat Analysis Set ........................................................................49 
9.2.3. 
Safety Analysis Set .....................................................................................................49 
9.3. 
Data Handling Conventions ........................................................................................49 
9.3.1. 
Handling Withdrawals and Missing Data ...................................................................49 
9.4. 
Study Population .........................................................................................................49 
9.4.1. 
Patient Disposition ......................................................................................................49 
9.4.2. 
Demographic and Baseline Characteristics ................................................................49 
9.5. 
Endpoint Analysis .......................................................................................................50 
9.5.1. 
Endpoints ....................................................................................................................50 
9.5.2. 
Planned Method of Analysis .......................................................................................50 
9.5.2.1. 
Endpoint Analysis .......................................................................................................50 
9.5.2.2. 
Sensitivity Analysis ....................................................................................................51 
9.6. 
Multiple Comparisons and Multiplicity......................................................................51 


 
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9.7. 
Safety Analysis ...........................................................................................................51 
9.8. 
Tolerability Analysis ..................................................................................................52 
9.9. 
Planned Interim Analysis ............................................................................................52 
9.10. 
Reporting Deviations from the Statistical Analysis Plan ...........................................52 
10. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................53 
11. 
COMPLIANCE STATEMENT ..................................................................................53 
12. 
DATA MANAGEMENT AND RECORD KEEPING ..............................................53 
13. 
FINANCING AND INSURANCE .............................................................................54 
14. 
PUBLICATION POLICY ..........................................................................................54 
15. 
REFERENCES ...........................................................................................................55 
16. 
SUMMARY OF CHANGES TO PROTOCOL .........................................................57 
16.1. 
Amendment 02 Dated 22 February 2017 ....................................................................57 
16.2. 
Amendment 01 Dated 08 September 2016 .................................................................66 
APPENDIX A. CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND 
INSTITUTIONS .........................................................................................................75 
APPENDIX B. STUDY PROCEDURES AND ASSESSMENTS BY VISIT ...........................76 
APPENDIX C. QUALITY CONTROL AND QUALITY ASSURANCE ................................78 
APPENDIX D. ETHICS .............................................................................................................80 
APPENDIX E. WOMEN OF CHILDBEARING POTENTIAL AND BIRTH 
CONTROL METHODS .............................................................................................82 
APPENDIX F. LOST TO FOLLOW-UP ...................................................................................85 
APPENDIX G. PRODUCT COMPLAINTS ..............................................................................86 
APPENDIX H. DATA MANAGEMENT AND RECORD KEEPING .....................................88 
APPENDIX I. PUBLICATION POLICY ...................................................................................91 


 
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LIST OF TABLES 
Table 1: 
Study Procedures and Assessments ............................................................................28 
Table 2: 
Moderate-Dose Inhaled Corticosteroid Treatment Equivalent to at Least 440 
mcg Daily of Fluticasone Propionate .........................................................................29 
Table 3: 
Investigational Medicinal Products Used in the Study ...............................................34 
Table 4: 
Systemic Glucocorticoid Treatment Equivalent to 10 mg of Prednisone...................38 
Table 5: 
The Relationship of an Adverse Event to the Test IMP .............................................41 
 


 
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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
ABS 
albuterol sulfate 
ACQ-5 
Asthma Control Questionnaire-5 
CAE 
clinical asthma exacerbation 
CDMS 
clinical data management system 
CFR 
Code of Federal Regulations (USA) 
CRF 
case report form (refers to any media used to collect study data [ie, paper or 
electronic]) 
CRO 
contract research organization 
CSR 
clinical study report 
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 
HFA 
hydrofluoroalkane 
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 
LSO 
local safety officer 
MDI 
metered dose inhaler 
MDPI 
multidose dry powder inhaler 
MIF 
maximal inhalational flow 


 
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Abbreviation 
Term 
mITT 
modified intent-to-treat 
OCS 
oral corticosteroid 
PEF 
peak expiratory flow 
RSI 
reference safety information 
SABA 
short-acting beta2 agonist 
SAMA 
short-acting muscarinic antagonist 
SDI 
sleep disruption index 
SmPC 
Summary of Product Characteristics 
SUSAR 
suspected unexpected serious adverse reaction 
TDS 
total daily steps 
ULN 
upper limit of normal 
USA 
United States of America 


 
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1. 
INTRODUCTION AND BACKGROUND INFORMATION 
1.1. 
Introduction 
Asthma is one of the most common chronic diseases (NAEPP 1997). This condition affects the 
airway passages of the lungs and is characterized by airway inflammation and bronchial 
hyper-responsiveness (MMWR Surveillance Summaries 2002, NAEPP 1997). During acute 
asthmatic episodes, the airway passages become narrower and more obstructed, resulting in 
coughing, wheezing, tightness of the chest, shortness of breath, and increased mucus production 
(NAEPP 1997, US Dept of HHS 1998). It is believed that these asthma symptoms may be 
associated with chronic changes in airway structure and function, increasing the morbidity and 
mortality of those affected (MMWR Surveillance Summaries 2002). 
As the recommended drug for relief of acute asthmatic symptoms and as the prophylaxis for 
exercise-induced bronchoconstriction, short-acting beta2 agonists (SABA), such as albuterol, are 
a mainstay of asthma management. The use of inhaled aerosol medications for asthma 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 Inhalation Aerosol is available in the United States of America 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 
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 USA 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 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. Information from eMDPI and wearable devices will be used to determine 


 
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if they can help predict the subsequent development of a clinical asthma exacerbation (CAE) or 
severe CAE.  
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 
beta-agonists and methylxanthines were administered concurrently. The clinical significance of 
these findings is unknown.  
1.2.2. 
Clinical Studies 
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 forced expiratory 
volume in 1 second (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® 


 
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RESPICLICK and PROAIR® HFA 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 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 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 CAE or severe 
CAE event. In addition to ABS eMDPI use, inhalation flow values and sleep disruption index 
(SDI) and total daily steps (TDS) data will be used to determine if changes in these measures can 
further improve the prediction of risk for severe CAE.  
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 


 
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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 is an open-label study in patients 18 years of age or older with exacerbation-prone asthma 
being conducted for assessment of relationship of the use of ABS eMDPI and other 
electronically collected data with a severe CAE 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 CAE and in particular, a 
severe CAE (as diagnosed by the 
investigators per the protocol). The 
hypothesis is that albuterol use will 
increase several days prior to a severe 
CAE and can serve as a marker of asthma 
deterioration. 
The endpoints of the trial are the primary outcome measure 
(ie, CAE/severe CAE) and the primary outcome predictor (ie, 
albuterol use) alone or in combination with secondary 
predictors (ie, other study data). Multiple correlates of 
CAE/severe CAE focused on albuterol use, alone or in 
combination with other study data, will be modeled to 
determine which patterns best predict the subsequent 
development of CAE/severe CAE.  
For albuterol use, parameters of interest will include (1) the 
total number of inhalations in the days preceding the peak of a 
severe CAE, (2) the number of days prior to the peak of a 
severe CAE when albuterol use increased, (3) the number of 
albuterol uses in the 24 hours preceding a severe CAE. 
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 moderate CAE or 
severe CAE. Inspiratory flow values are obtained from the 
eMDPI, SDI is obtained for a subset of patients who agree to 
participate at specific sites (n=100) from an accelerometer 
worn on the wrist, and TDS is obtained for a subset of patients 
who agree to participate at specific sites (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 asthma. 
The safety endpoints for this study include the following: 
• 
adverse event data 
• 
physical examinations 
2.1.1. 
Justification of the Endpoints  
The endpoints of the trial are the primary outcome measure (ie, CAE/severe CAE) and the 
primary outcome predictor (ie, albuterol use) alone or in combination with secondary predictors 
(ie, other study data). Multiple correlates of CAE focused on albuterol use, alone or in 
combination with other study data, will be modeled to determine which patterns best predict the 
subsequent development of CAE/severe CAE.  


 
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The increased use of SABA, deterioration in peak expiratory flow, and worsening of symptoms 
are associated with CAE in previously reported studies (Tattersfield et al 1999, Patel et al 
2013b).  
In the present trial, SABA use will be monitored electronically concomitant with the CAE 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 asthma symptom complex. Furthermore, 
TDS is an effortless, digital concomitant correlate of dyspnea on exertion, which is also a key 
symptom of asthma deterioration. These parameters therefore are likely to help predict the 
subsequent development of a moderate CAE or severe CAE. 


 
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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 CAE/severe CAE in adult patients at least 18 years of age with 
exacerbation-prone asthma. 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 2-week screening period 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, and review asthma 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 (SAMA), or SABA/SAMA combination 
into storage. Patients may continue use of other asthma and non-asthma 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 
asthma 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 and subsequently by courier on Day 21. 
Patients will be instructed to return all inhalers to the site at the last study visit or early 
termination. At the last study visit or early termination, 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. 
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 (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). 
The end of study is defined as the last visit of the last patient.  


 
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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 sites will wear an accelerometer on the wrist 
to measure SDI. A second subset of patients (n=100) who agree to participate at specific sites 
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 45 investigational 
centers. 
3.3. 
Justification for Study Design and Selection of Population 
The current study is designed to capture the natural history of CAE 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 a wearable accelerometer are added to routine care). 
Prior work has documented a relationship between SABA usage rates and the subsequent 
occurrence of CAE. The relationship between (1) 3 different metrics of baseline albuterol use 
over 2 weeks of monitoring with an electronic module and (2) future severe CAE was explored 
in a nested cohort study (Patel et al 2013b). The study was undertaken in real-world asthma 
patients (16 to 65 years of age) at risk of severe asthma exacerbations, receiving 
budesonide/formoterol twice a day as maintenance therapy for 24 weeks, with albuterol as-
needed for relief of symptoms. The nested cohort comprised 147 patients out of a total number of 
303 patients for the parent trial (Patel et al 2013a). Severe CAE was defined as either the use of 
systemic corticosteroids for at least 3 days or a hospitalization or emergency visit due to asthma 
that required the use of systemic corticosteroids. Exacerbations were quantified over the 24-week 
observation period. 
Average daily albuterol use (quantified over the 2-week monitoring period at the baseline of the 
study) was the metric that performed best as a predictor of risk of future severe CAE. The 
45 participants in the group with subsequent severe asthma (exacerbation group) had 
1 exacerbation each using 5.5±9.7 actuations per day of albuterol, compared to 
1.83±3.3 actuations per day in the non-exacerbating group (102 patients). For average daily 
albuterol use, univariate logistic regression for the risk of a future severe asthma exacerbation 
showed that higher baseline mean daily albuterol use was a significant predictor of severe asthma 
exacerbations (odds ratio=1.24 [95% confidence interval, 1.06-1.46]; p<0.006). 
In a less recent study, change in peak expiratory flow (PEF), symptoms, and use of rescue SABA 
were quantified during the 425 severe CAE events that occurred during a 12-month parallel 
group study (FACET) in which low and high doses of budesonide with and without formoterol 
were compared in patients with asthma (Tattersfield et al 1999). Oral corticosteroids (OCS) were 
prescribed for severe CAE, the main study endpoint, defined as the need for a course of OCS 
(n=311) or a reduction in morning PEF of >30% on 2 consecutive days. PEF, symptoms, and 
bronchodilator use over the 14 days before and after the CAE were obtained from diary cards.  


 
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CAEs were characterized by a gradual fall in PEF over several days, followed by more rapid 
changes over 2 to 3 days. An increase in symptoms and rescue SABA use occurred in parallel, 
and both the severity and time course of the changes were similar in all treatment groups. CAE 
identified by the need for OCS were associated with more symptoms and smaller changes in PEF 
than those identified on the basis of PEF criteria. Female sex was the main patient characteristic 
associated with an increased risk of having a severe CAE. CAE were characterized 
predominantly by a change in symptoms or a change in PEF, but the pattern was not affected by 
the dose of ICS or by formoterol use. Thus, in the study of Tattersfield et al, multiple physiologic 
changes preceeded CAE. These changes were noted as early as 10 days before a CAE event, and 
were well-established 5 days before a CAE event. These results suggest that patients who 
develop severe CAEs 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 
accelerometer will be used to determine if changes in these measures can predict the 
development of severe CAE. 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 investigational medicinal product (IMP) 
• the number of severe CAEs collected. 
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 to14 days 
After CAE 
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 
 
Vital signs measurementc  
X 
 
 
 
 
 
Urine pregnancy test for women of 
childbearing potential  
X 
 
 
 
 
X 
Complete ACQ-5  
X 
 
 
 
 
 
Inform patients of study 
compliance for eMDPI and 
accelerometer, and requirement for 
provider visit in the event of CAE 
X 
X 
X 
X 
 
 
Assess for asthma 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 of all asthma 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 consent to participate at specific sites 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 ABS eMDPI devices at visit 2 and subsequently by courier on Day 21. Patients will be 
instructed to return all inhalers to the site at the last study visit or early termination. 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; CAE=clinical asthma exacerbation; SDI=sleep disruption index; TDS=total daily steps; 
eMDPI=multidose dry powder inhaler with an eModule; IMP=investigational medicinal product; V=visit. 
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, 18 years of age or older, with a physician diagnosis of 
asthma.  
b. The patient has had at least 1 episode of severe CAE as described in Section 6.1.1 
over the past 12 months before screening. If on a biologic (eg, omalizumab, 
mepolizumab, or reslizumab) and/or post-bronchial thermoplasty, exacerbation has 
occurred after these interventions. 
c. The patient’s Asthma Control Questionnaire-5 (ACQ-5) score at the time of screening 
is ≥1.5 (Juniper et al 2005). 
d. The patient is using a moderate-dose ICS, equivalent to at least 440 mcg daily of 
fluticasone propionate (see Table 2).  
Table 2: Moderate-Dose Inhaled Corticosteroid Treatment Equivalent to at Least 
440 mcg Daily of Fluticasone Propionate 
  
e. All asthma controller treatments are at a stable dose for 3 months prior to the 
screening visit. 
f. The patient’s baseline asthma therapy regimen, including oral corticosteroids, 
leukotriene antagonists, 5-lipoxygenase inhibitors, LABA, long-acting muscarinic 
agent, or cromolyn, biologicals, theophylline, or mepolizumab, is allowed. 
g. The patient must be able to demonstrate appropriate use of albuterol from the ABS 
eMDPI.  
ICS Treatment 
Total Daily Dose (mcg) Equivalent to at Least 
440 mcg Daily of  Fluticasone Propionate  
Beclomethasone dipropionate  
≥ 320 mcg 
Budesonide  
≥ 720 mcg 
Flunisolide  
≥ 640 mcg 
Mometasone  
≥ 400 mcg 
Ciclesonide  
≥ 320 mcg 
Fluticasone furoate 
≥ 100 mcg 
ICS=inhaled corticosteroid 
 


 
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h. The patient is able to provide written informed consent. 
i. 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. 
j. The patient is willing to discontinue all other rescue or maintenance SABA or anti-
muscarinic agents and replace them with the study-provided ABS eMDPI for the 
duration of the trial. 
k. Women of childbearing potential (not surgically sterile or ≥2 years postmenopausal) 
must have exclusively same-sex partners or use a highly effective 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. Additional details can be found in 
Appendix E.  
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 asthma. 
c. The patient has used an investigational drug within 5 half-lives of it being 
discontinued, or 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). 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 or presence of “silent” infections, including 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 


 
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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. 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. 
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 case report form 
(CRF) 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 CRF; both the adverse 
events page and termination page of the CRF will be completed at that time. 
All assessments should be performed according to the protocol for the final visit or upon early 
termination (visit 5) if possible. Patients are required to return the ABS eMDPI (used and 
unused) upon withdrawal from the study.  


 
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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 resigned. 
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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5. 
TREATMENTS 
5.1. 
Investigational Medicinal Products Used in the Study 
Patients will receive initial ABS eMDPI devices at visit 2 and subsequently by courier on 
Day 21. 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 to return all inhalers to the 
site at the last study visit or early termination (visit 5). 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 3 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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Table 3: 
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 be by courier direct to 
the patient as needed.  


 
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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 
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. 
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 for the management of asthma and relief of acute 
symptoms of asthma in adults and children 4 years and older, and for the prevention of exercise-
induced bronchoconstriction. For the relief of acute asthma 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 the 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 CRF. Trade name and international nonproprietary 


 
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name (if available), indication, dose, and start and end dates of the administered medication will 
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 albuterol nebulizer outside of a CAE 
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 an open-label study and there will be no blinding. 
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, CAE/severe CAE) and the 
primary outcome predictor (ie, albuterol use) alone or in combination with secondary predictors 
(ie, other study data). Multiple correlates of CAE/severe CAE focused on albuterol use, alone or 
in combination with other study data, will be modeled to determine which patterns best predict 
the subsequent development of CAE/severe CAE. 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 Asthma Exacerbation 
The diagnosis of CAE will be determined by the investigator using the definitions shown below, 
which are based on the official American Thoracic Society/European Respiratory Society 
statement (Reddel et al 2009).  
In this study, “CAE” is an occurrence of either “severe CAE” or “moderate CAE.” 
• Severe CAE is defined as a CAE that involves worsening asthma such that  
− the treating physician elects to administer prednisone (or equivalent 
glucocorticoid treatment) at least 10 mg prednisone equivalent above baseline 
(Table 4), for at least 3 days  
AND  
− an unscheduled provider visit such as an office visit, urgent care visit, emergency 
care visit, or hospitalization  
• Moderate CAE is defined as a CAE that involves worsening asthma such that  
− the treating physician elects to administer prednisone (or equivalent 
glucocorticoid treatment) at least 10 mg prednisone equivalent above baseline 
(Table 4), for at least 3 days 
 OR  
− an unscheduled provider visit such as an office visit, urgent care visit, emergency 
care visit, or hospitalization associated with an increase in asthma therapy that 
does not qualify for “severe CAE” as defined above 


 
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Table 4: 
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 severe CAE, (2) the number of days prior to the peak of a severe 
CAE when albuterol use increased, (3) the number of albuterol uses in the 24 hours preceding a 
severe CAE. 
6.1.3. 
Inhalational Flow Values Upon Albuterol Dosing 
Inhalational flow values will include (1) 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 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 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 medication1 
• drug interactions 
All CAE events require documentation by the Investigator in the CAE Exacerbation Page in the 
CRF. All evaluations entered into the CAE Exacerbation Page require an in-person visit (Vz 
“Exacerbation Visit”, see Table 1). This visit can co-incide 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 asthma exacerbations 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 event, 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 the CRF, regardless of the severity of the event or judged relationship 
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 (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 CRF and, if it is a serious adverse event, on the 
serious adverse event form. 
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 the CRF. 
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 


 
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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: 
Table 5: 
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 


 
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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. 
• 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: 
• 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. 
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 


 
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sponsor by the investigator. The event must be reported within 24 hours of when the investigator 
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 the last administration of IMP of that patient 
has ended should be reported to the sponsor if the investigator becomes aware of them. 
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. 
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) 
− autopsy findings (if available) 


 
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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. 
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/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. 
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. 


 
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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 (LSO/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 
pregnancy form (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. 
• For an elective abortion due to developmental anomalies, report as a serious adverse 
event. 
• 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 
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 patients 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 CRF as “Non-Compliance to 
investigational medicinal product (IMP).” 
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 


 
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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.  
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. The rationale is based on a review of the relevant 
literature, as follows. 
Based on previous studies of a poorly-controlled, exacerbating asthma cohort (Bateman et al 
2015, Ko et al 2012, McCarren et al 1998, Quezada et al 2016), it is expected that between 
20% and 25% of subjects at risk in this patient population will experience a CAE (event) over 
3 months resulting in 72 to 90 expected CAE events in this study. In addition, it is expected that 
approximately 6.7% and 15% (Bousquet et al 2007, Ko et al 2012, Kuna et al 2007, and Rabe et 
al 2006) of subjects at risk in this patient population will experience moderate and severe events, 
respectively, resulting in approximately 78 events (24 moderate events and 54 severe events) in 
this study.   
This sample size (n=400 patients; 72 to 90 CAE events) is considered adequate for 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 CAE or severe CAE. Per the study by Patel (Patel et al 2013b), a 
statistically significant relationship was established between prior mean daily SABA usage at 
baseline and subsequent CAE, studying 45 exacerbations (p<0.006).  
In the present study, approximately 72 to 90 CAE events are desired for this trial because the 
model’s fitting of the current study involves the analysis of multiple predictors as described in 
more detail below. 
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, CAE), 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 (Peduzzi et al 1996, 
Harrell et al 1984, Laupacis et al 1997). 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 (CAE) 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 CAE 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 any time during the study. This analysis 
population will be used for endpoint analysis. 
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.  
9.3. 
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. 
9.4. 
Study Population 
The cohort will consist of patients 18 years of age or older with exacerbation-prone asthma, 
defined as at least 1 documented “severe” CAE; (Section 6.1.1) in the past 12 months, currently 
on medium- to high-dose ICS with or without LABA and with uncontrolled asthma quantified as 
an ACQ-5 score ≥1.5).   
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 and the 
reason for withdrawal will be summarized using descriptive summary statistics (n, %).  
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 


 
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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. 
9.5. 
Endpoint Analysis 
9.5.1. 
Endpoints 
The endpoints of the trial are the primary outcome measure (CAE) and the primary predictor (ie, 
albuterol use) alone or in combination with secondary predictors (ie, other study data) of CAE. 
Several parameters of CAE focused on albuterol use, alone or in combination with other study 
data (inspiratory flow, SDI, TDS, disease state at baseline, and demographics at baseline), will 
be modeled to determine which patterns best predict the subsequent development of CAE/severe 
CAE. For albuterol use, examples of correlates of CAE of interest include (1) the total number of 
inhalations in the days preceding the peak of a severe CAE, (2) the number of days prior to the 
peak of a severe CAE when albuterol use increased, (3) the number of albuterol uses in the 
24◦hours preceding a severe CAE. Therefore, endpoints are not designated as either primary or 
secondary.  
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 multiple device-use-measures will be used as predictors of CAE 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 


 
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4. albuterol usage + TDS 
5. albuterol usage + inspiratory flow values + SDI 
6. albuterol usage + inspiratory flow values + TDS 
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 CAE, 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. The primary hypothesis under 
consideration is that >12 inhalations of SABA dosing will have higher odds of CAE 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. Goodness-of-fit tests may be applied to make sure that the finally selected 
model fits the data closely. The C-statistic 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 CAE (Hosmer et al 2013). 
9.5.2.2. 
Sensitivity Analysis 
There will be no sensitivity analysis performed in this study. 
9.6. 
Multiple Comparisons and Multiplicity 
Since the goal of this analysis is to build 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. 


 
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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 
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. 
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 IECand IRB, confidentiality regarding study patients, and requirements for registration of 
the clinical study. 
12. 
DATA MANAGEMENT AND RECORD KEEPING 
See Appendix G 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 
CRFs and source documents.  
Investigational centers must obtain source documentation of all asthma 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. 
14. 
PUBLICATION POLICY 
See Appendix I for information regarding the publication policy. 


 
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15. 
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Bousquet J, et al. Budesonide/formoterol for maintenance and relief in uncontrolled asthma vs. 
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Greenberg S, Liu N, Kaur A, Lakshminarayanan M, Zhou Y, Nelsen L, et al. The asthma disease 
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Harrell FE, Lee K, Califf RM, Pryor DB, Rosati RA. Regression modeling strategies for 
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Hosmer DW, Lemeshow S, Sturdivant RX. Applied Logistic Regression (3rd Edition). John 
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Juniper EF, Svensson K, Mörk A-C, Ståhl E. Measurement properties and interpretation of three 
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Krouse HJ, Yarandi H, McIntosh J, Cowen C, Selim V. Assessing sleep quality and daytime 
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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 
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Lenney J, Innes JA, Crompton GK. Inappropriate inhaler use: assessment of use and patient 
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McCarren M, McDermott MF, Zalenski RJ, Jovanovic B, Marder D, Murphy DG, et al. 
Prediction of relapse within eight weeks after an acute asthma exacerbation in adults. J Clin 
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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 
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Patel M, Pilcher J, Pritchard A, Perrin K, Travers J, Shaw D, et al. Efficacy and safety of 
maintenance and reliever combination budesonide-formoterol inhaler in patients with asthma at 
risk of severe exacerbations: a randomised controlled trial. Lancet Respir Med 2013a;1(1):32-42.  
Patel M, Pilcher J, Reddel HK, Pritchard A, Corin A, Helm C, et al. Metrics of salbutamol use as 
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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 
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Rabe KF, Atienza T, Magyar P, Larsson P, Jorup C, Lalloo UG. Effect of budesonide in 
combination with formoterol for reliever therapy in asthma exacerbations: a randomised 
controlled, double-blind study. Lancet 2006;368:744-53. 
Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, et al. An official 
American Thoracic Society/European Respiratory Society statement: asthma control and 
exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J 
Respir Crit Care Med 2009;180:59-99. 
Surveillance for Asthma – United States, 1998-1999. MMWR Surveillance Summaries. 
March 29, 2002;51:1-13. 
Tattersfield A, Postma DS, Barnes PJ, Svensson K, Bauer CA, O’Byrne PM, et al. Exacerbations 
of asthma: a descriptive study of 425 severe exacerbations. The FACET International Study 
Group. Am J Respir Crit Care Med 1999;160:594-9. 
US Department of Health and Human Services. Centers for Disease Control and Prevention. 
National Center for Health Statistics, Division of Data Services 1998. Available at 
http://www.cdc.gov/nchs/fastats/asthma.html. 
Vittinghoff E, McCulloch CE. Relaxing the rule of ten events per variable in logistic and Cox 
regression. Am J Epidemiol 2007;165:710-8. 


 
Uncontrolled Study–Asthma 
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Study ABS-AS-30064 
57 
16. 
SUMMARY OF CHANGES TO PROTOCOL 
16.1. 
Amendment 02 Dated 22 February 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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Clinical Study Protocol with Amendment 02 
Study ABS-AS-30064 
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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 this change: Section 3.2) 
Number of Investigational Centers Planned: 
Approximately 50 45 
Number of Investigational Centers Planned: 
Approximately 45 
The word “Approximately” added to 
match text in the body of the protocol and 
reduced to 45 sites 
Clinical Study Protocol Synopsis (Other sections affected by this change: Section 3.2 and Section 9.1) 
Number of Patients Planned (Total): Approximately 
6500 patients will be screened to achieve approximately 
5400 enrolled patients. 
Number of Patients Planned (Total): Approximately 
500 patients will be screened to achieve approximately 
400 enrolled patients. 
Re-evaluation of sample size to meet study 
endpoints 
Clinical Study Protocol Synopsis (Other section affected by this change: Section 9.4) 
Study Population: The cohort will consist of patients 
18 years of age or older with exacerbation-prone 
asthma, defined as at least 1 documented “severe” 
clinical asthma exacerbation (CAE; defined in 
Section 6.1.1 of the protocol) in the past 12 months, 
currently on moderate- to high-dose inhaled 
corticosteroid (ICS) with or without a long-acting beta 
agonist (LABA) and with uncontrolled asthma 
quantified as an Asthma Control Questionnaire-5 
(ACQ-5) score ≥1.5.  
Study Population: The cohort will consist of patients 
18 years of age or older with exacerbation-prone 
asthma, defined as at least 1 documented “severe” 
clinical asthma exacerbation (CAE; defined in 
Section 6.1.1 of the protocol) in the past 12 months, 
currently on moderate- to high-dose inhaled 
corticosteroid (ICS) with or without a long-acting beta 
agonist (LABA) and with uncontrolled asthma 
quantified as an Asthma Control Questionnaire-5 
(ACQ-5) score ≥1.5. 
Asthma Control Questionnaire-5 (ACQ-5) 
added to quantify uncontrolled asthma. 
 
 


 
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Original text with changes shown 
New wording 
Reason/Justification for change 
Clinical Study Protocol Synopsis (Other section affected by this change: Section 3.1) 
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. 
Number of devices removed from the 
sentence to allow for change in the 
number of devices, if necessary.  
Clinical Study Protocol Synopsis (Other sections affected by this change: Section 3.1, Table 1 V4 and footnote e, Section 5.1, and Appendix B, Section 
2,b) 
Patients will receive initial eMDPI devices at visit 2 and 
subsequently by courier on Days 21 and 56. 
Patients will receive initial eMDPI devices at visit 2 and 
subsequently by courier on Day 21. 
The change was made to reduce the 
number of Direct to Patient shipments 
from 2 shipments to 1 shipment. 
Clinical Study Protocol Synopsis (Other section affected by this change: Section 4.1) 
Inclusion Criteria 
b. The patient has had at least 1 episode of severe CAE 
as described in Section 6.1.1 over the past 12 months 
before screening. If on a biologic (eg, omalizumab, 
mepolizumab, or reslizumab) and/or post-bronchial 
thermoplasty, exacerbation has occurred after these 
interventions. 
c. The patient’s  Asthma Control Questionnaire-5 
(ACQ-5) score at the time of screening is ≥1.5. (Juniper 
et al 2005) .must be able to demonstrate appropriate use 
of albuterol from the ABS eMDPI. 
d. The patient must be abe to demonstrate appropriate 
use of albuterol from the ABS eMDPI is using at least a 
moderate-dose ICS, (equivalent to at least 440 mcg 
daily of fluticasone propionate) (see Table 1). and any 
additional asthma controller at a stable dose for 3 
months prior to the screening visit.  
e. and any additional  All asthma controller treatments 
Inclusion Criteria 
b. The patient has had at least 1 episode of severe CAE 
as described in Section 6.1.1 over the past 12 months 
before screening. If on a biologic (eg, omalizumab, 
mepolizumab, or reslizumab) and/or post-bronchial 
thermoplasty, exacerbation has occurred after these 
interventions. 
c. The patient’s Asthma Control Questionnaire-5 (ACQ-
5) score at the time of screening is ≥1.5 (Juniper et al 
2005).  
d. The patient is using a moderate-dose ICS, equivalent 
to at least 440 mcg daily of fluticasone propionate 
(Table 1). 
 e. All asthma controller treatments are at a stable dose 
for 3 months prior to the screening visit. 
Moderate-Dose Inhaled Corticosteroid Treatment 
Equivalent to at Least 440  mcg Daily of Fluticasone 
Propionate 
Inclusion criteria “b” modified to include 
instructions for a patient on a biologic 
and/or post-bronchial thermoplasty. ACQ-
5 inclusion criteria added as inclusion 
criteria” c” with reference in body of 
protocol.  Old inclusion criteria “c” moved 
to inclusion criteria “f”. Inclusion criteria 
“d” revised and split into “d” and “e” and 
table added to clarify equivalent doses of 
moderate-dose ICS to at least 440 mcg 
daily of fluticasone propionate. 


 
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Original text with changes shown 
New wording 
Reason/Justification for change 
are at a stable dose for 3 months prior to the screening 
visit.  
Moderate-Dose Inhaled Corticosteroid Treatment 
Equivalent to at Least 440  mcg Daily of Fluticasone 
Propionate 
f. The patient must be able to demonstrate appropriate 
use of albuterol from the ABS eMDPI. 
ICS Treatment 
Total Daily Dose (mcg) 
Equivalent to at Least 
440 mcg Daily 
of  Fluticasone 
Propionate  
Beclomethasone 
dipropionate  
≥ 320 mcg 
Budesonide  
≥ 720 mcg 
Flunisolide  
≥ 640 mcg 
Mometasone  
≥ 400 mcg 
Ciclesonide  
≥ 320 mcg 
Fluticasone furoate 
≥ 100 mcg 
ICS=inhaled 
corticosteroid 
 
f. The patient must be able to demonstrate appropriate 
use of albuterol from the ABS eMDPI. 
ICS Treatment 
Total Daily Dose (mcg) 
Equivalent to at Least 
440 mcg Daily 
of  Fluticasone 
Propionate  
Beclomethasone 
dipropionate  
≥ 320 mcg 
Budesonide  
≥ 720 mcg 
Flunisolide  
≥ 640 mcg 
Mometasone  
≥ 400 mcg 
Ciclesonide  
≥ 320 mcg 
Fluticasone furoate 
≥ 100 mcg 
ICS=inhaled 
corticosteroid 
 


 
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61 
Original text with changes shown 
New wording 
Reason/Justification for change 
Clinical Study Protocol Synopsis (Other section affected by this change: Section 4.2) 
Exclusion Criteria 
c. The patient has used an investigational drug within 5 
half-lives of it being discontinued, or 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). Dietary lactose intolerance 
does not exclude the patient from inclusion in the study 
or as per the investigator’s medical discretion. 
Exclusion Criteria 
c. The patient has used an investigational drug within 5 
half-lives of it being discontinued, or 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). Dietary lactose intolerance 
does not exclude the patient from inclusion in the study 
or as per the investigator’s medical discretion. 
 
Visit 2 added to exclusion criteria “c” for 
clarity. Revised exclusion criteria “f” to 
include allergy to excipients of the IMP or 
rescue medication formulation.  
Clinical Study Protocol Synopsis (Other sections affected by this change: Section 3.2 and Section 9.1) 
Sample Size Rationale: 
Assuming an expected dropout rate of 10%, it is 
recommended that 5400 patients be enrolled so that 
43560 evaluable patients complete the study. 
Based on previous studies of a poorly-controlled, 
exacerbating asthma cohort, it is expected that between 
20% and 25% of patients at risk in this patient 
population will experience a CAE (event) over 
3 months, resulting in 9072 to 11390 expected CAE 
events in this study. In addition, it is expected that 
approximately 6.7% and 15% of subjects at risk in this 
patient population will experience moderate and severe 
events, respectively, resulting in approximately 78 
events (24 moderate events and 54 severe events) in the 
study. 
This sample size (n=4500 patients; 9072 to 11390 CAE 
events) is considered adequate for fulfillment of the 
study objectives using univariate and multivariate 
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. 
Based on previous studies of a poorly-controlled, 
exacerbating asthma cohort, it is expected that between 
20% and 25% of patients at risk in this patient 
population will experience a CAE (event) over 
3 months, resulting in 72 to 90 expected CAE events in 
this study. In addition, it is expected that  approximately 
6.7% and 15% of subjects at risk in this patient 
population will experience moderate and severe events, 
respectively, resulting in approximately 78 events (24 
moderate events and 54 severe events) in the study. 
This sample size (n=400 patients; 72 to 90 CAE events) 
is considered adequate for fulfillment of the study 
objectives using univariate and multivariate analyses to 
evaluate the relationship of the pattern of albuterol use, 
Re-evaluation of sample size to meet study 
endpoints 


 
Uncontrolled Study–Asthma 
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Study ABS-AS-30064 
62 
Original text with changes shown 
New wording 
Reason/Justification for change 
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 CAE or severe CAE. Per the study by Patel et 
al 2013b, a statistically significant relationship was 
established between prior mean daily SABA usage at 
baseline and subsequent CAE, studying 45 
exacerbations (p<0.006).  
In the present study, approximately 9072 to 11390 CAE 
events are desired for this trial because the model’s 
fitting of the current study involves the analysis of 
multiple predictors as described in more detail below. 
inspiratory flow, SDI, and TDS data associated with the 
subsequent development of a moderate CAE or severe 
CAE. Per the study by Patel et al 2013b, a statistically 
significant relationship was established between prior 
mean daily SABA usage at baseline and subsequent 
CAE, studying 45 exacerbations (p<0.006).  
In the present study, approximately 72 to 90 CAE 
events are desired for this trial because the model’s 
fitting of the current study involves the analysis of 
multiple predictors as described in more detail below. 
List of Abbreviations 
ACQ-5    Asthma Control Questionnaire-5 
ACQ-5    Asthma Control Questionnaire-5 
ACQ-5 added to List of Abbreviations 
Section 3.5, Table 1 Study Procedures and Assessments (Other section affected by this change: Appendix B, Study Procedures and Assessments by Visit, 
Section 1,2, and 3) 
Visit number                               V1 
Day and allowed time windows Day -14 to Day 01 
Visit number                               V2 
Day and allowed time windows ±7 days 
Visit number                               Vz                               
Day and allowed time windows ±Up to 14 days After 
CAE Start Date 
 
Complete ACQ-5    X in Screening column 
Visit number                               V1 
Day and allowed time windows Day -14 to Day 1 
Visit number                               V2 
Day and allowed time windows  
Visit number                               Vz                               
Day and allowed time windows  Up to 14 days After 
CAE Start Date 
 
Complete ACQ-5    X in Screening column 
Day and allowed time windows corrected 
for accuracy.  
 
Complete ACQ-5 added to Screening visit 
in Appendix B, Section 1 
Sentence added to Appendix B, Section 3, 
for clarity 
Section 6.1.1 Clinical Asthma Exacerbation 
Table 4: Systemic Glucocorticoid Treatment Equivalent 
to 10 mg of Prednisone 
Table 4: Systemic Glucocorticoid Treatment Equivalent 
to 10 mg of Prednisone 
Added Table 4 to clarify systemic 
glucocorticoid treatment equivalent to 10 
mg of prednisone. 


 
Uncontrolled Study–Asthma 
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Original text with changes shown 
New wording 
Reason/Justification for change 
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® 
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® 
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 is the Actigraph GT9XLink.This accelerometer 
has been cleared by falls into a product classification 
that the Food and Drug Administration (FDA) has 
deemed 510(k) exempt. through a 50110(k) (K089545) 
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 falls into a product 
classification that the Food and Drug Administration 
(FDA) has deemed 510(k) exempt. 
The location of the description of the 
analysis has been added for completeness. 
Teva does not want to include the device 
model should the device need to be 
changed for any reason. 
Typographical error corrected and update 
of product classification 


 
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64 
Original text with changes shown 
New wording 
Reason/Justification for change 
with the intended use of documenting physical 
movement associated with physiological monitoring, 
including sleep. 
See the Study Reference Manual User Guide for a 
detailed description of care and use of wearable devices. 
 
See the User Guide for a description of care and use of 
wearable devices. 
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). 
SDI endpoints added for clarity. 
Section 15  References (Other section affected by this change: Section 9.1) 
Bousquet J, et al. Budesonide/formoterol for 
maintenance and relief in uncontrolled asthma vs. high-
dose salmeterol/fluticasone. Respiratory Medicine 
2007;101:2437-46. 
Juniper EF, Svensson K, Mörk A-C, Ståhl E. 
Measurement properties and interpretation of three 
shortened versions of the asthma control questionnaire. 
Respiratory Medicine (2005) 99, 553-8. 
Bousquet J, et al. Budesonide/formoterol for 
maintenance and relief in uncontrolled asthma vs. high-
dose salmeterol/fluticasone. Respiratory Medicine 
2007;101:2437-46. 
Juniper EF, Svensson K, Mörk A-C, Ståhl E. 
Measurement properties and interpretation of three 
shortened versions of the asthma control questionnaire. 
Respiratory Medicine (2005) 99, 553-8. 
New references were added to the text and 
therefore, to the reference list. 


 
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Clinical Study Protocol with Amendment 02 
Study ABS-AS-30064 
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Original text with changes shown 
New wording 
Reason/Justification for change 
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. 
Kuna P, et al. Effect of budesonide/formoterol 
maintenance and reliever therapy on asthma 
exacerbations. Int J Clin Pract 2007;61(5):725-36. 
Rabe KF, Atienza T, Magyar P, Larsson P, Jorup C, 
Lalloo UG. Effect of budesonide in combination with 
formoterol for reliever therapy in asthma exacerbations: 
a randomised controlled, double-blind study. Lancet 
2006;68:744-53. 
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. 
Kuna P, et al. Effect of budesonide/formoterol 
maintenance and reliever therapy on asthma 
exacerbations. Int J Clin Pract 2007;61(5):725-36. 
Rabe KF, Atienza T, Magyar P, Larsson P, Jorup C, 
Lalloo UG. Effect of budesonide in combination with 
formoterol for reliever therapy in asthma exacerbations: 
a randomised controlled, double-blind study. Lancet 
2006;368:744-53. 
Appendix A. Clinical Laboratories and Other Departments and Institutions 
Contract Research Organization     PPDPRA 
Contract Research Organization     PRA 
Change in Contract Research Organization 
Appendix B, Study Procedures and Assessments by Visit, Section 2.c, 4th bullet 
• 
collect wearable accelerometer, if 
applicable 
• 
collect wearable accelerometer, if 
applicable 
“if applicable” added for clarity  
 
 


 
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Study ABS-AS-30064 
66 
16.2. 
Amendment 01 Dated 08 September 2016 
The primary reason for this amendment is to clarify the definition, collection, and recording of 
CAEs. 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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Study ABS-AS-30064 
67 
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 selected 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 selected 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. 
This change was made because sites are 
not selected in a statistical sense but are 
identified as having agreed to participate in 
the substudy. 
 
Clarification: “nighttime awakening” was 
changed to “sleep disruption” and 
“physical” was added to daily activity to 
better describe these measurements.  
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 CAE, (2) the number of days prior to 
the peak of a severe CAE when albuterol use increased,  
For albuterol use, parameters of interest will include 
(1) the total number of inhalations in the days 
preceding the peak of a severe CAE, (2) the number of 
days prior to the peak of a severe CAE when albuterol 
use increased 
This change was made to further define the 
parameters that will be assessed as 
endpoints in this study.  
Section 2.1 Study Objectives and Endpoints (Other sections affected by these changes: Sections 2.1.1 and 9.1) 
These data will be analyzed using both a univariate and 
multivariate approach, to determine which patterns best 
predict the subsequent development of a moderate CAE 
or severe CAE.  
These data will be analyzed using both a univariate 
and multivariate approach, to determine which 
patterns best predict the subsequent development of a 
moderate CAE or severe CAE. 
This language was updated to reflect that 
the data will be used to predict only 
moderate or severe CAEs and not all 
CAEs. 
Section 3.1 General Design (Other sections affected by this change: Sections 3.5 [Table 1, Footnote e] and 5.1)  
Patients will receive initial eMDPI devices at visit 2 and 
subsequently in the mail by courier as needed, based on 
usage pattern on Days 21 and 56. 
Patients will receive initial eMDPI devices at visit 2 
and subsequently by courier on Days 21 and 56. 
Clarification: “in the mail” was changed to 
“by courier on Days 21 and 56” to indicate 
they will not be mailed through the US 
Postal Service on specific days.  


 
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Original text with changes shown 
New wording 
Reason/justification for change 
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 this change: 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.  
Section 3.1 General Design (Other sections affected by this change: Sections 3.2 and 9.4) 
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 
The text was moved from Section 9.4 to 
Section 3.2 and 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 CAE. 
Prior work has documented a relationship between 
SABA usage rates and the subsequent occurrence of 
CAE. 
This change was made because the 
language was superfluous.  
Section 3.5 Study Procedures and Assessments, Table 1 (Other sections affected by these changes: Sections 3.1, 5.1, 5.6, 7.1.2, 12, and Appendix B) 
Day and allowed time windows: 
V1: Up to 2 weeks Day -14 to Day 0 
V2: Day 1±7 days 1 week 
Vz: ±14 days 2 weeks 
V35: Day 84±14 days 2 weeks 
Day and allowed time windows: 
V1: Day -14 to Day 0 
V2: Day 1±7 days  
Vz: ±14 days  
V5: Day 84±14 days  
This change was made to include the days 
of the study visits. visit 3 was updated to 
visit 5 because 2 phone visits were added 
(see below).  


 
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a 
A total of 2 monthly calls will occur between Visit 1 
and Visit 3 to collect information about asthma 
exacerbations and treatments, use of concomitant 
medications, adverse event information, and to review the 
instructions for use of ABS eMDPI and the procedure for 
replacement and return of ABS eMDPI. Investigational 
centers must obtain source documentation of all asthma 
exacerbations that occur during the treatment period to 
confirm the accuracy of the information obtained from 
the patient. 
V3: Day 28±7 days 
V4: Day 56±7 days 
Procedures to be done on these visits as indicated by 
an X in Table 1:  
Inform patients of study compliance for eMDPI and 
accelerometer, and requirement for provider visit in 
the event of CAE 
ABS eMDPI dispense, training, collection and 
accountability 
Assess for asthma exacerbations 
Adverse events inquiry 
Concomitant medication inquiry 
These visits were originally included in 
Footnote a of Table 1 and were moved to 
the table itself. The footnote was updated 
to reflect this change and new text was 
added for clarification. 
e 
Patients will receive initial ABS eMDPI devices at 
visit 2 and subsequently in the mail by courier as needed 
on Days 21 and 56.  
e 
Patients will receive initial ABS eMDPI devices 
at visit 2 and subsequently by courier on Days 21 and 
56.  
Footnote e was updated to reflect new 
information on the delivery of replacement 
IMP. 
Section 4.1 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, 18 years of age or 
older, with a physician diagnosis of uncontrolled asthma.  
b. The patient has had at least 1 episode of severe CAE 
(requiring an emergency department visit or 
hospitalization) as described in Section 6.1.1 over the 
past 12 months before screening. 
Patients may be enrolled in this study only if they 
meet all of the following criteria: 
a. 
The patient is male or female, 18 years of age or 
older, with a physician diagnosis of asthma.  
b. The patient has had at least 1 episode of severe 
CAE as described in Section 6.1.1 over the past 
12 months before screening. 
Inclusion Criterion a was changed because 
the original intent was to include the entire 
asthma population. 
Inclusion Criterion b was changed to 
reflect the change made to the definition of 
CAE.  
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 CAE is highest in the 30-day 
period following an exacerbation, and their 
pattern of albuterol use is of great interest 
from the research and clinical perspective. 


 
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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. 
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 Clinical Asthma Exacerbation (Other sections affected by these changes: Section 7.1.1) 
Investigator determined The diagnosis of CAE will be 
defined determined by the investigator using the 
definitions shown below, which were adapted from the 
official American Thoracic Society/European Respiratory 
Society statement (Reddel et al 2009). This statement 
defines asthma exacerbation as a worsening of asthma 
such that the treating physician elected to administer 
systemic glucocorticoids for at least 3 days, or the patient 
visited an urgent care clinic or emergency department or 
The diagnosis of CAE will be determined by the 
investigator using the definitions shown below, which 
were adapted from the official American Thoracic 
Society/European Respiratory Society statement 
(Reddel et al 2009). 
In this study, “CAE” is an occurrence of either 
“severe CAE” or “moderate CAE.” 
• Severe CAE is defined for the purpose of this 
The definitions of serious and moderate 
CAEs were updated to reflect new 
information. 
The final statement was moved to 
Section 7.1.1 because it is the more 
appropriate section for discussing adverse 
events.  


 
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was hospitalized. 
In this study, “CAE” is an occurrence of either “severe 
CAE” or “moderate CAE.” 
• Severe CAE is defined for the purpose of this study as 
a CAE that involves worsening asthma respiratory 
symptoms requiring treament with systemic 
corticosteroids (with or without antibiotics) such that 
− 
the treating physician elects to add prednisone (or 
equivalent glucocorticoid treatment) at least 10 
mg prednisone equivalent above baseline, for at 
least 3 days 
AND  
− 
an unscheduled provider visit such as, an office 
visit, urgent care visit, emergency care visit, or 
hospitalization. Note that a CAE required 
hospitalization should not be considered an SAE 
unless it meets other SAE criteria.  
• Moderate CAE is defined as a CAE that involves 
worsening asthma respiratory symptoms requiring 
treatment with systemic corticosteroids (with or 
without antibiotics) such that  
 
the treating physician elects to add prednisone (or 
equivalent glucocorticoid treatment) at least 10 
mg prednisone equivalent above baseline, for at 
least 3 days 
 
OR 
 
an unscheduled provider visit such as, an office 
visit, urgent care visit, emergency care visit, or 
hospitalization associated with an increase in 
asthma therapy that does not qualify for “severe 
study as a CAE that involves worsening asthma 
such that 
− 
the treating physician elects to add prednisone 
(or equivalent glucocorticoid treatment) at 
least 10 mg prednisone equivalent above 
baseline, for at least 3 days 
AND  
− 
an unscheduled provider visit such as, an 
office visit, urgent care visit, emergency care 
visit, or hospitalization.  
• Moderate CAE is defined as a CAE that involves 
worsening asthma such that  
 
the treating physician elects to add prednisone 
(or equivalent glucocorticoid treatment) at 
least 10 mg prednisone equivalent above 
baselin, for at least 3 days 
 
OR 
 
an unscheduled provider visit such as, an 
office visit, urgent care visit, emergency care 
visit, or hospitalization associated with an 
increase in asthmas therapy that does not 
qualify for “severe CAE” as defined above. 
 


 
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CAE” as defined above. 
All CAE events will be documented by the investigator in 
the CAE Exacerbation Page in the CRF. Investigational 
centers must obtain source documentation of all asthma 
exacerbations to confirm the accuracy of the information 
obtained from the patient. 
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 is the 
ActiGraph GT9X Link. This accelerometer has been 
cleared by the (Food and Drug Administration) FDA 
through a 501(k) (K080545) with the intended use of 
documenting physical movement associated with 
physiological monitoring, including sleep. 
The wearable accelerometer used in this study is the 
ActiGraph GT9X Link. This accelerometer has been 
cleared by the Food and Drug Administration (FDA) 
through a 501(k) (K080545) with the intended use of 
documenting physical movement associated with 
physiological monitoring, including sleep. 
This language was added to provide 
information on the accelerometer used in 
the study.  
Section 7.1.1 Definition of an Adverse Event 
Asthma exacerbations will not be considered adverse 
events unless they are severe enough to require 
hospitalization of the patient, in which case they will be 
recorded as serious adverse events. All CAE events 
require documentation by the Investigator in the CAE 
Exacerbation Page in the CRF. All evaluations entered 
into the CAE Exacerbation Page require an in-person 
visit (Vz “Exacerbation Visit”, see Table 1). This visit 
can co-incide 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 asthma 
exacerbations that occur during the treatment period to 
confirm the accuracy of the information obtained from 
the patient.  
All CAE events require documentation by the 
Investigator in the CAE Exacerbation Page in the 
CRF. All evaluations entered into the CAE 
Exacerbation Page require an in-person visit (Vz 
“Exacerbation Visit”, see Table 1). This visit can co-
incide 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 asthma exacerbations that occur 
during the treatment period to confirm the accuracy of 
the information obtained from the patient.  
This change was made because of the 
requirement for patients to return to the 
center in the event of an asthma 
exacerbation and to denote the requirement 
to record all asthma exacerbations as 
adverse events.  


 
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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.  
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 
CAE 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 CAE 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.  
Section 15 References (Other sections affected by these changes: Section 2.1.1, 3.3, 9.1) 
International Committee of Medical Journal Editors 
(ICMJE). Recommendations for the conduct, reporting, 
editing, and publication of scholarly work in medical 
journals. Available at 
http://www.icmje.org/recommendations/. 
Patel M, Pilcher J, Pritchard A, Perrin K, Travers J, Shaw 
D, et al2. Efficacy and safety of maintenance and reliever 
combination budesonide-formoterol inhaler in patients 
with asthma at risk of severe exacerbations: a randomised 
controlled trial. Lancet Respir Med 2013a;1(1):32-42. 
Patel M, Pilcher J, Reddel HK, Pritchard A, Corin A, 
Patel M, Pilcher J, Pritchard A, Perrin K, Travers J, 
Shaw D, et al2. Efficacy and safety of maintenance 
and reliever combination budesonide-formoterol 
inhaler in patients with asthma at risk of severe 
exacerbations: a randomised controlled trial. Lancet 
Respir Med 2013a;1(1):32-42. 
Patel M, Pilcher J, Reddel HK, Pritchard A, Corin A, 
Helm C, et al. Metrics of salbutamol use as predictors 
of future adverse outcomes in asthma. Clin Exp 
Allergy 2013b;43:1144-51. 
These changes were made because of new 
references added to the text and the 
inadvertent inclusion of a reference that is 
not cited in the text.  


 
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Original text with changes shown 
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Reason/justification for change 
Helm C, et al. Metrics of salbutamol use as predictors of 
future adverse outcomes in asthma. Clin Exp Allergy 
2013b;43:1144-51. 
Appendix G Product Complaints 
 
 
 
Added the entire Appendix G - Product Complaints 
This appendix was added because of an 
oversight from the original protocol that 
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 
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. 
 
Teva Pharmaceuticals 
 
 
Contract Research Organization 
PRA 
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 
• complete ACQ-5 
• 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 asthma exacerbation (CAE) 
• assess for asthma 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 CAE 
• assess for asthma 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 


 
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• concomitant medication inquiry 
b. Phone Visit (Visits 3 and 4, Days 28±7 days and 56±7 days, respectively) 
Patients will be contacted by phone on a monthly basis between visit 2 and visit 3. 
The following information will be discussed during the phone call: 
• assess for asthma exacerbations and treatments 
• inquire about adverse events 
• concomitant medication inquiry 
• ABS eMDPI dispense, training, collection, and accountability (only Visit 3) 
• inform patients of study compliance for eMDPI and accelerometer, and requirement 
for a provider visit in the event of CAE 
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: 
• urine pregnancy test for women of childbearing potential 
• assess for asthma exacerbations 
• inquire about adverse events 
• collect wearable accelerometer, if applicable 
• collect ABS eMDPI 
• concomitant medication inquiry 
3. Exacerbation Visit (Vz [+14 days]) 
In the case of a CAE (defined in Section 6.1.1 of the protocol), the patient will be required to 
return to the clinic.The exacerbation visit should be conducted up to 14 days after the clinical 
asthma exacerbation start date. The date and reason for the unscheduled visit will be recorded 
on the CRF 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 


 
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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 in the case 
report form (CRF). 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 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 (CRFs 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 informed consent form 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 


 
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center before the IEC/IRB and competent authority (as applicable) for the investigational center 
give written approval or a favorable opinion. 
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 CRFs 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 CRF. 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. 
Contraception for female partners of male study participants: 
Female partners of male study participants must use contraception for non-pregnant woman of 
childbearing potential partner until the end of relevant systemic exposure in case of IMPs with 
genotoxicity or IMPs with no genotoxicity but demonstrated or suspected human 
teratogenicity/fetotoxicity. 
Pregnancy tests in women of childbearing potential: 
For IMPs with unlikely risk of human teratogenicity/fetotoxicity, additional pregnancy testing is 
generally not necessary. This refers to IMPs 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. 


 
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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 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 


 
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• description or nature of complaint 
• 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. 
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 beyond the scope of the complaint may be a reason to unblind the clinical 
supplies for an affected patient. 
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 case report form (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. 
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 CRF, 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, 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 CRFs that are specifically designed for this study. The data collected 
on the CRFs will be captured in a clinical data management system (CDMS) that meets the 
technical requirements described in 21CFR Part 11 (USA) 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 CRFs must be completed for each patient who provided informed consent. Patient 
identity should not be discernible from the data provided on the CRF. 
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 CRF, 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. 
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 CRF. 


 
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89 
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 SOPs for clinical studies. Day to day data management tasks for this study are 
delegated to a contract organization, and these functions may be carried out as described in the 
Standard Operating Procedures (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 CRFs will be archived by the sponsor. Investigational center-specific CRFs 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 
• patient identification lists 
• case report forms for each patient on a per-visit basis 
• data from other sources (eg, central laboratory, bioanalytical laboratory, 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 


 
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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 
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” (ICMJE). 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 (18 Years of Age or Older) with Asthma 
 
 
Study Number ABS-AS-30064 
 
NCT02969408 
 
Statistical Analysis Plan with Amendment 01 Approval Date: 09 April 2018  
 


Statistical Analysis Plan with Amendment 01 
Study ABS-AS-30064 
1 
 
 
 
Statistical Analysis Plan with Amendment 01 
Study ABS-AS-30064 
 
 
 
 
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 (18 Years of Age or Older) with Asthma 
 
Phase 3B 
 
 
 
IND Number: 104532 
NDA Number: NA   
EudraCT Number: NA 
 
 
Approval Date: 9 April 2018 
 
 
Sponsor 
Teva Branded Pharmaceutical  
Products R&D, Inc. 
41 Moores Road 
Frazer, Pennsylvania 19355 
United States 
 
 
Prepared by: 
 
 Teva Branded Pharmaceutical Products R&D, Inc. 
 
 
 


Statistical Analysis Plan with Amendment 01 
Study ABS-AS-30064 
2 
STATISTICAL ANALYSIS PLAN APPROVAL 
 
 
TABLE OF CONTENTS 


Statistical Analysis Plan with Amendment 01 
Study ABS-AS-30064 
3 
TITLE PAGE ...................................................................................................................................1 
STATISTICAL ANALYSIS PLAN APPROVAL ..........................................................................2 
AMENDMENT HISTORY .............................................................................................................8 
INTRODUCTION .........................................................................................................................10 
1. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................11 
1.1. 
Objectives and Endpoints ...........................................................................................11 
2. 
STUDY DESIGN .......................................................................................................12 
2.1. 
General Design ...........................................................................................................12 
2.2. 
Randomization and Blinding ......................................................................................14 
2.3. 
Sample Size and Power Considerations .....................................................................14 
2.4. 
Sequence of Planned Analyses ...................................................................................14 
2.4.1. 
Planned Interim Analyses ...........................................................................................14 
2.4.2. 
Final Analyses and Reporting .....................................................................................15 
3. 
ANALYSIS SETS ......................................................................................................16 
3.1. 
Intent to Treat Analysis Set ........................................................................................16 
3.2. 
Modified Intent-to-Treat Analysis Set ........................................................................16 
3.3. 
Safety Analysis Set .....................................................................................................16 
3.4. 
Wrist Accelerometry Analysis Set..............................................................................16 
3.5. 
Ankle Accelerometry Analysis Set .............................................................................16 
4. 
GENERAL ISSUES FOR DATA ANALYSIS ..........................................................17 
4.1. 
General ........................................................................................................................17 
4.2. 
Specification of Baseline Values ................................................................................17 
4.2.1. 
Albuterol Use ..............................................................................................................17 
4.2.2. 
Vital Signs, Physical Examination, Height, and Weight ............................................17 
4.2.3. 
Inhalational Flow Values ............................................................................................17 
4.2.4. 
Total Daily Steps ........................................................................................................17 
4.2.5. 
Sleep Parameters .........................................................................................................18 
4.3. 
Time on Study .............................................................................................................18 
4.4. 
eMDPI Time on Study ................................................................................................18 
4.5. 
Study Day and Study Week ........................................................................................18 
4.6. 
Handling Withdrawals and Missing Data ...................................................................18 
5. 
STUDY POPULATION .............................................................................................20 
5.1. 
General ........................................................................................................................20 


Statistical Analysis Plan with Amendment 01 
Study ABS-AS-30064 
4 
5.2. 
Patient Disposition ......................................................................................................20 
5.3. 
Demographics and Baseline Characteristics ...............................................................20 
5.4. 
Medical History ..........................................................................................................20 
5.5. 
Asthma History ...........................................................................................................21 
5.6. 
Asthma Exacerbations History ...................................................................................21 
5.7. 
Prior Therapy and Medication ....................................................................................21 
5.8. 
Childbearing Potential and Methods of Contraception ..............................................21 
5.9. 
Study Protocol Violations ...........................................................................................21 
5.10. 
eMDPI Time on Study; Days and Weeks ...................................................................22 
6. 
EFFICACY ANALYSIS ............................................................................................23 
7. 
ENDPOINT ANALYSES ..........................................................................................24 
7.1. 
eMDPI: Albuterol Use ................................................................................................24 
7.1.1. 
Albuterol Use Definition ............................................................................................24 
7.1.2. 
Analysis Methods for Albuterol Use ..........................................................................24 
7.1.2.1. 
Pattern of Baseline Daily and Weekly Albuterol Use ................................................24 
7.1.2.2. 
Total Number of Inhalations in the Days Preceding the Peak of a CAE ....................25 
7.1.2.3. 
Hypothesis: Albuterol Use Will Increase Several Days Prior to a CAE ....................25 
7.1.2.4. 
Number of Days Prior to the Peak of a CAE When Albuterol Use Increased ...........26 
7.1.2.5. 
Maximum Number of Inhalations Taken In a 24-Hour Period ..................................26 
7.2. 
Inhalational Flow Values ............................................................................................26 
7.2.1. 
Inhalational Flow Values Definitions .........................................................................26 
7.2.2. 
Analysis Methods for Inhalational Flow Values ........................................................27 
7.2.2.1. 
Actual and Change from Baseline in Study Day X Inhalational Flow Values 
Prior to the Peak of a CAE .........................................................................................27 
7.2.2.2. 
Actual and Change from Baseline in Week Y Inhalational Flow Values ...................27 
7.3. 
Accelerometry: Total Daily Steps ..............................................................................28 
7.3.1. 
Total Daily Steps Definition .......................................................................................28 
7.3.2. 
Analysis Methods for Total Daily Steps .....................................................................28 
7.3.2.1. 
Actual and Change from Baseline in Study Day X Total Daily Steps Prior to 
the Peak of a CAE .......................................................................................................28 
7.3.2.2. 
Actual and Change from Baseline in Week Y Total Daily Steps ...............................28 
7.4. 
Accelerometry: Sleep Disruption Index .....................................................................29 
7.4.1. 
Sleep Disruption Index Definition ..............................................................................29 


Statistical Analysis Plan with Amendment 01 
Study ABS-AS-30064 
5 
7.4.2. 
Analysis Methods for Sleep Disruption Indices .........................................................30 
7.4.2.1. 
Actual and Change from Baseline in Study Day X Sleep Disruption Indices 
Prior to the Peak of a CAE .........................................................................................30 
7.4.2.2. 
Actual and Change from Baseline in Week Y Sleep Disruption Indices ....................30 
7.5. 
Clinical Asthma Exacerbation ....................................................................................30 
7.5.1. 
Clinical Asthma Exacerbation Definition ...................................................................30 
7.5.2. 
Analysis Methods for Clinical Asthma Exacerbation ................................................31 
7.5.2.1. 
Within Patient CAE Analyses ....................................................................................32 
7.5.2.2. 
Time to Clinical Asthma Exacerbations Short-term Exacerbation Risk (7 
days) ............................................................................................................................32 
7.5.2.3. 
All Days Analysis (Only CAE-free Days)..................................................................33 
7.5.2.4. 
Summary Descriptive Statistics of Initial and Recurrent Clinical Asthma 
Exacerbation Rates .....................................................................................................33 
7.5.3. 
Predicting Severe CAE/Moderate CAE from Multiple Device-Use-Measures .........33 
8. 
SENSITIVITY ANALYSIS .......................................................................................34 
9. 
MULTIPLE COMPARISONS AND MULTIPLICITY ............................................35 
10. 
SAFETY ANALYSIS ................................................................................................36 
10.1. 
General ........................................................................................................................36 
10.2. 
Duration of Exposure to IMP .....................................................................................36 
10.3. 
Time on Study .............................................................................................................36 
10.4. 
Adverse Events ...........................................................................................................36 
10.5. 
Deaths .........................................................................................................................37 
10.6. 
Clinical Laboratory Tests ...........................................................................................37 
10.7. 
Physical Examinations ................................................................................................37 
10.8. 
Concomitant Medications or Therapies ......................................................................37 
11. 
TOLERABILITY VARIABLES AND ANALYSIS..................................................38 
12. 
PHARMACOKINETIC ANALYSIS .........................................................................39 
13. 
PHARMACODYNAMIC ANALYSIS ......................................................................39 
14. 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS ..............................39 
15. 
BIOMARKER ANALYSIS........................................................................................39 
16. 
IMMUNOGENICITY ANALYSIS ............................................................................39 
17. 
ANCILLARY STUDIES ANALYSIS .......................................................................39 
18. 
PLANNED INTERIM ANALYSIS ...........................................................................39 


Statistical Analysis Plan with Amendment 01 
Study ABS-AS-30064 
6 
19. 
STATISTICAL SOFTWARE ....................................................................................40 
20. 
CHANGES TO ANALYSES SPECIFIED IN THE STUDY PROTOCOL ..............41 
20.1. 
Intent-To-Treat Analysis Set ......................................................................................41 
20.2. 
Modified Intent-To-Treat Analysis Set ......................................................................42 
20.3. 
Safety Analysis Set .....................................................................................................43 
20.4. 
Predicting Severe CAE/Moderate CAE from Multiple Device-Use-Measures .........44 
21. 
REFERENCES ...........................................................................................................45 


Statistical Analysis Plan with Amendment 01 
Study ABS-AS-30064 
7 
LIST OF TABLES 
Table 1: 
Study Procedures and Assessments ............................................................................13 
Table 2: 
Systemic Glucocorticoid Treatment Equivalent to 10 mg of Prednisone...................31 
 
 
 


Statistical Analysis Plan with Amendment 01 
Study ABS-AS-30064 
8 
AMENDMENT HISTORY 
The Statistical Analysis Plan for study ABS-AS-30064 (study protocol with amendment 02 dated 
22 February 2017) has been amended and reissued as follows: 
Amendment 
number 
Date 
Author(s) 
Summary of Changes 
Reason for 
Amendment 
01  
9 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 4.6 updated to remove the 
bullets regarding the derivation of 
Study Day X TDS, Study Day X 
nighttime average sleep latency 
time, Study Day X longest nighttime 
wake episode, and Study Day X 
total time awake at night. 
Clarification as this will 
not be done 
Sections 7.3.1 and 7.4.1 updated to 
remove the statements regarding the 
missing data handling for Study X 
TDS, Study Day X nighttime 
average sleep latency time, Study 
Day X longest nighttime wake 
episode, and Study Day X total time 
awake at night. 
Clarification as this will 
not be done 
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-AS-30064 
9 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
Abbreviation 
Term 
ABS 
albuterol sulfate 
ACQ-5 
Asthma Control Questionnaire-5 
BMI 
body mass index 
CAE 
clinical asthma exacerbation 
CI 
confidence interval 
CRF 
case report form (refers to any media used to collect study data [ie, paper or electronic]) 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DPI 
dry powder inhaler  
eMDPI 
multidose dry powder inhaler with an eModule 
ICH 
International Council for Harmonisation 
IMP 
investigational medicinal product 
ITT 
intent-to-treat 
KM 
Kaplan Meier 
MDI 
metered dose inhaler 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIF 
maximal inhalational flow 
mITT 
modified intent-to-treat 
PT 
preferred term 
R&D 
Research and Development 
SABA 
short-acting beta agonist 
SAMA 
short-acting muscarinic antagonist 
SD 
standard deviation 
SDI 
sleep disruption index 
SOC 
system organ class 
SOP 
standard operating procedure 
TDS 
total daily steps 
ULN 
upper limit of normal 
WHO Drug 
World Health Organization Drug Dictionary 


Statistical Analysis Plan with Amendment 01 
Study ABS-AS-30064 
10 
INTRODUCTION 
This Statistical Analysis Plan describes the planned analysis and reporting for Teva Branded 
Pharmaceutical Products R&D, Inc. Study ABS-AS-30064 (A 12-Week, Open-Label Study to 
Evaluate the Relationship Between Use of Albuterol Multidose Dry Powder Inhaler with an 
eModule (eMDPI), an Inhaled Short-Acting Beta Agonist (SABA) “Rescue” Agent with an 
eModule, and Exacerbations in Patients (18 Years of Age or Older) with Asthma), 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. 


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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 ABS eMDPI), alone or in combination with other study data, preceding a clinical asthma 
exacerbation (CAE) and in particular, a severe CAE (as diagnosed by the investigators per the 
protocol). The hypothesis is that albuterol use will increase several days prior to a severe CAE 
and can serve as a marker of asthma deterioration. 
The endpoints of the trial are the primary outcome measure (ie, CAE/severe CAE) and the 
primary outcome predictor (ie, albuterol use) alone or in combination with secondary predictors 
(ie, other study data). Multiple correlates of CAE/severe CAE focused on albuterol use, alone or 
in combination with other study data, will be modeled to determine which patterns best predict 
the subsequent development of CAE/severe CAE. 
For albuterol use, parameters of interest will include (1) the total number of inhalations in the 
days preceding the peak of a severe CAE, (2) the number of days prior to the peak of a severe 
CAE when albuterol use increased, and (3) the number of albuterol uses in the day preceding a 
severe CAE. 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 moderate CAE or severe 
CAE. Inspiratory flow values are obtained from the eMDPI, SDI is obtained for a subset of 
patients who agree to participate at specific sites (n=100) from an accelerometer worn on the 
wrist, and TDS is obtained for a subset of patients who agree to participate at specific sites 
(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 asthma. 
The safety endpoints for this study include: 
• adverse event data and  
• physical examinations 


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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 CAE/severe CAE in adult patients at least 18 years of age with 
exacerbation-prone asthma. 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 2-week screening period 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, and review asthma 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 (SAMA), or SABA/SAMA combination 
into storage. Patients may continue use of other asthma and non-asthma 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 
asthma 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 and subsequently by courier on Day 21. 
Patients will be instructed to return all inhalers to the site at the last study visit or early 
termination. At the last study visit or early termination, 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. 
Two subsets of patients who agree to participate at specific sites and wear an accelerometer 
either on the wrist to measure SDI (n=100) or on the ankle to measure TDS (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). 
The end of study is defined as the last visit of the last patient.  
Study procedures and assessments with their timing are summarized in Table 1 . 


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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 to14 days 
After CAE 
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 
 
Vital signs measurementc  
X 
 
 
 
 
 
Urine pregnancy test for women of 
childbearing potential  
X 
 
 
 
 
X 
Complete ACQ-5  
X 
 
 
 
 
 
Inform patients of study 
compliance for eMDPI and 
accelerometer, and requirement for 
provider visit in the event of CAE 
X 
X 
X 
X 
 
 
Assess for asthma 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 of all asthma 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 (pulse rate). 
d  Wearable accelerometers for a subset of patients who consent to participate at specific sites 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 ABS eMDPI devices at visit 2 and subsequently by courier on Day 21. Patients will be 
instructed to return all inhalers to the site at the last study visit or early termination. 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; CAE=clinical asthma exacerbation; SDI=sleep disruption index; TDS=total daily steps; 
eMDPI=multidose dry powder inhaler with an eModule; IMP=investigational medicinal product; V=visit. 
Screening and baseline visits may be combined.  


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2.2. 
Randomization and Blinding 
This is an open-label study and there will be no blinding and no randomization. 
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. The rationale is based on a review of the relevant 
literature, as follows. 
Based on previous studies of a poorly-controlled exacerbating asthma cohort (Bateman et al 
2015, Ko et al 2012, McCarren et al 1998, Quezada et al 2016), it is expected that between 20% 
and 25% of subjects at risk in this patient population will experience a CAE (event) over 3 
months, resulting in 72 to 90 expected CAE events in this study. In addition, it is expected that 
approximately 6.7% and 15% (Bousquet et al 2007, Ko et al 2012, Kuna et al 2007, and Rabe et 
al 2006) of subjects at risk in this patient population will experience moderate and severe events, 
respectively, resulting in approximately 78 events (24 moderate events and 54 severe events) in 
this study.   
This sample size (n=400 patients; 72 to 90 CAE events) is considered adequate for 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 CAE or severe CAE. Per the study by Patel (Patel et al 2013), a 
statistically significant relationship was established between prior mean daily SABA usage at 
baseline and subsequent CAE, studying 45 exacerbations (p<0.006).  
In the present study, approximately 72 to 90 CAE events are desired for this trial because the 
model’s fitting of the current study involves the analysis of multiple predictors as described in 
more detail below. 
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, CAE), 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 (Peduzzi et al 1996, 
Harrell et al 1984, Laupacis et al 1997). 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 (CAE) 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 CAE 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. 


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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.    
This Statistical Analysis Plan and any corresponding amendments will be approved before 
database lock, in accordance with SOP GBP_RD_702 (Statistical Analysis Plan). 
 


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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 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. 
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 receive 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.    


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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 CAE status (CAE: No, CAE: Yes, All) and by CAE severity (Yes: Moderate, Yes: 
Severe) where appropriate. 
4.2. 
Specification of Baseline Values 
4.2.1. 
Albuterol Use 
For the purpose of the analysis described in Section 7.1.2.1 , baseline albuterol use is defined as 
no more than 4 inhalations (eg, 0 to 4 inhalations) per day of use regardless of the number of 
days albuterol is used in a 7-day period. Of note, the term ‘baseline’ does not refer to study days 
-14 to 1 of study, but rather to the expected daily albuterol use of asthma symptoms that is 
controlled. 
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 14. Among these inhalations, the inhalation with the 
highest maximal inhalation flow (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 14, the ‘baseline inhalation’ is the first available inhalation after study day 14. 
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 14 days of study participation (study day 1 through study day 14). 
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 14, the ‘baseline 
TDS’ is the first available TDS after study day 14.  
Baseline TDS are computed for those patients in the ankle accelerometry analysis set. 


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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 14. 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 14, the ‘baseline value 
of a given sleep parameter’ is the first available valid sleep parameter value after study day 14.  
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.   


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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 or 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 14, the ‘baseline TDS’ is the first available TDS after 
study day 14 (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 14, the ‘baseline value of a given sleep 
parameter’ is the first available valid sleep parameter value after study day 14 (see 
Section 4.2.5).  


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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 enrolled 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 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 sleep disruption 
indices.   
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 sleep disruption indices 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 preferred term 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. 


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5.5. 
Asthma History 
Asthma history data will be summarized. This will include duration of asthma, history of positive 
methacholine challenge within the past 5 years, greater than 20% variability in FEV1 between 2 
prior measurements, and diurnal variation in peak flow measurement reversibility and/or with an 
Asthma Control Questionnaire (ASQ) score of at least 1.5.  
Summaries will be provided for the ITT analysis set and the ankle and wrist accelerometry 
analysis sets. 
5.6. 
Asthma Exacerbations History 
Asthma exacerbations history data will be summarized. This will include asthma exacerbations 
in the past 12 months, hospitalizations, emergency room visits, urgent care, doctor visits for 
asthma exacerbations, and systemic steroids administration for asthma.   
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. In addition, a summary table of the incidence of prior asthma 
medications will be provided. Patients are counted only once in each therapeutic class category, 
and only once in each PT 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 
Data from patients with any protocol violation during the study will be summarized overall and 
for each category using descriptive statistics. Of note, medication errors, overdose, misuse, 
abuse, off-label use, and occupational exposure will be summarized in category. Protocol 
violations also include nonadherence on the part of the patient, the investigator, or the sponsor to 
protocol-specific inclusion/exclusion criteria, primary outcome measure criteria, or GCP 
guidelines; 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 will be reviewed 
and major protocol violations will be identified and confirmed by the clinical and statistical 
personnel prior to database lock. Major violations are violations that could have an effect on the 
primary outcome. 


Statistical Analysis Plan with Amendment 01 
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Patient with at least 1 protocol violation for each category will be summarized 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 study in days and weeks (days divided by 7) 
will be presented overall and by CAE status and by CAE severity for the ITT analysis set, ankle 
accelerometry analysis set and the wrist accelerometry analysis set.   
 
 


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


Statistical Analysis Plan with Amendment 01 
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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 no more than 4 inhalations (eg, 0 to 4 inhalations) per day of 
use regardless of the number of days albuterol is used in a 7-day period. 
Daily baseline albuterol use is defined as no more than 4 inhalations (eg, 0 to 4 inhalations) per 
day. 
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 any daily usage of 
albuterol exceeded 4 inhalations. It is presented as WK1:I#iD#dMT4Y/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 “MT4Y/N” is an indicator of whether or not any of the days albuterol was used 
exceeded 4 inhalations. For example, “I28D7MT4N” indicates a total of 28 inhalations were 
taken, albuterol use was used each day and none of the daily number of inhalations exceeded 4 
(No More Than 4 inhalations per day Yes/ No). 
Week 2 Patient Albuterol Use:  Week 2 patient albuterol use is each patient’s total number of 
albuterol inhalations taken and the number days used during the second week (study day 8 
through study day 14) of study participation with an indicator of whether or not any daily usage 
of albuterol exceeded 4 inhalations. It is presented as “WK2:I#iD#dMT4Y/N”, where “i" is the 
number of albuterol inhalations and “d” is the number of days used in the second week of study. 
Albuterol use will be examined by the following 3 parameters; (i) total number of inhalations in 
the days preceding the peak of a CAE, (ii) number of days prior to the peak of a CAE when 
albuterol use increased, and (iii) number of albuterol uses in the day preceding a CAE. 
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 CAE, 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 
Summary statistics including 95% CIs of the proportion of eMDPI time on study days when a 
patient took 0 to 4 inhalations a day (number of days a given patient took 0 to 4 inhalations a day 
divided by the total number of eMDPI study days for a given patient) will be summarized overall 
and by CAE status and by CAE severity. In addition, the proportion of patients exhibiting 


Statistical Analysis Plan with Amendment 01 
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weekly baseline albuterol use (Week 1, Week 2,…, Week 12) will be summarized overall and by 
CAE status and by CAE severity.   
Week 1 and Week 2 patient albuterol use patterns, “WK1:I#iD#dMT4Y/N” and 
“WK2:I#iD#dMT4Y/N” designation, will be summarized descriptively (counts and percent) 
overall and by CAE status and by CAE severity.  
7.1.2.2. 
Total Number of Inhalations in the Days Preceding the Peak of a CAE 
For patients who experienced a CAE, 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 CAE 
symptom peak) and at 3, 5, 7, 10, 14, and 21 days preceding the date of the CAE symptom peak 
will be presented overall and by moderate CAEs and severe CAEs.  
In this analysis, among patients experiencing more than 1 CAE, the subsequent CAEs can be 
considered a separate CAE distinct from the first (preceding) CAE provided the patient exhibited 
at least 1 day of baseline albuterol use after the first (preceding) CAE’s date of symptom peak 
and prior to the subsequent CAE’s date of symptom peak. For patients who experience multiple 
CAEs (eg, 3), for a given number of days preceding a CAE (eg, 21 days), if the (eg, third) CAE 
overlaps with the time period of the preceding (eg, second) CAE, the CAE (eg, third CAE) 
should not be included in the analysis.   
Mean and 95% CI 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 statistic at study 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 “CAE Status” (Yes, No). Three line graphs will 
be presented in a second figure; “CAE Status No”, “CAE Status Yes: Severe” and “CAE Status 
Yes: Moderate”. 
A figure summarizing the mean (+/- minimum and maximum) of the total number of inhalations 
per day for each patient experiencing multiple CAEs will be presented for the time period of 21 
days prior to the date of symptom peak of the first CAE to 21 days after the date of symptom 
peak of the last CAE. 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 CAE and D is the study day number 21 days after the date of 
the symptom peak of the last CAE. 
7.1.2.3. 
Hypothesis: Albuterol Use Will Increase Several Days Prior to a CAE 
The hypothesis under consideration is that albuterol use will increase several days prior to a 
CAE. Several days will be defined as 7 days prior to the date of the CAE symptom peak for this 
analysis.  
For each subject that experiences at least 1 CAE, Y1, …, Y7 will represent the number of puffs 
of albuterol during the 7 days preceding the date of the CAE symptom peak and let Y8,…,Y14  
will represent the number of puffs taken each day during day 8 through 14 preceding the date of 
the CAE 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 


Statistical Analysis Plan with Amendment 01 
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)
(
~
xxx
iid
i
Poisson
Y
λ
 during day 8 through 14 preceding the date of the CAE symptom peak and 
)
(
~
δ
λ
+
xxx
iid
i
Poisson
Y
 for the immediate 7 days preceding the CAE(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 CAE symptom peak minus mean number of puffs during days 8 through 14 preceding the 
date of the CAE symptom peak. To assess if albuterol usage increases 7 days prior to a CAE, H0: 
µD = 0, H1: µD > 0 will be tested using a t-test at the 0.05 significance level.  
7.1.2.4. 
Number of Days Prior to the Peak of a CAE When Albuterol Use Increased 
Among patients who experienced a CAE, summary statistics of the number of days prior to the 
peak of a CAE when albuterol use increased will be presented overall and by moderate CAEs 
and severe CAEs for 3 thresholds defining an increase in albuterol use;  
(i) 
First occurrence of a single day’s albuterol use exceeding 4 inhalations; 
(ii) 
First occurrence of a single day’s albuterol use exceeding 12 inhalations; 
(iii) 
First occurrence of a single day’s albuterol use exceeding 20 inhalations. 
Among patients who did not experience a CAE, summary statistics, including 95% CIs, 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) 
a single day’s albuterol use exceeding 4 inhalations; 
(ii) 
a single day’s albuterol use exceeding 12 inhalations; 
(iii) 
a single day’s albuterol use exceeding 20 inhalations. 
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 CAE status and by CAE 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 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, 


Statistical Analysis Plan with Amendment 01 
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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 inhalation flow value is considered the ‘Weekly 
Y Inhalation’. 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 CAE 
Among patients who experienced a CAE, 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 CAE symptom peak) and at 3, 5, 7, 10, 14, and 21 days preceding the 
peak of a CAE will be presented for all CAEs and by moderate CAEs and severe CAEs.   
In this analysis, among patients experiencing more than 1 CAE, the subsequent CAEs can be 
considered a separate CAE distinct from the first (preceding) CAE provided the patient exhibited 
at least 1 day of baseline albuterol use after the first (preceding) CAE’s date of symptom peak 
and prior to the subsequent CAE’s date of symptom peak. For patients who experience multiple 
CAEs (eg, 3), for a given number of days preceding a CAE (eg, 7 days), if the (eg, third) CAE 
overlaps with the time period of the preceding (eg, second) CAE, the CAE (eg, third CAE) 
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 the first occurrence of a single day’s albuterol use exceeding (i) 4 
inhalations, (ii) 12 inhalations, and (iii) 20 inhalations, overall and by CAE status and by CAE 
severity.  
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 CAE status and by CAE severity.  
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 CAE status and by CAE severity.  


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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.  
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 CAE 
Among patients in the ankle accelerometry cohort who experienced a CAE, 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 CAE symptom peak) and at 3, 5, 7, 10, 14, and 21 days preceding 
the peak of a CAE will be presented for all CAEs and by moderate CAEs and severe CAEs.   
In this analysis, among patients experiencing more than 1 CAE, the subsequent CAEs can be 
considered a separate CAE distinct from the first (preceding) CAE provided the patient exhibited 
at least 1 day of baseline albuterol use after the first (preceding) CAE’s date of symptom peak 
and prior to the subsequent CAE’s date of symptom peak. For patients who experience multiple 
CAEs (eg, 3), for a given number of days preceding a CAE (eg, 7 days), if the (eg, third) CAE 
overlaps with the time period of the preceding (eg, second) CAE, the CAE (eg, third CAE) 
should 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 the first occurrence of a single day’s 
albuterol use exceeding (i) 4 inhalations, (ii) 12 inhalations, and (iii) 20 inhalations, overall and 
by CAE status and by CAE severity.  
In addition, summary descriptive statistics of the maximum change from baseline in TDS will be 
presented overall and by CAE status and by CAE severity. For patients who experienced a CAE, 
the maximum change from baseline in TDS is the maximum change from baseline in TDS 
among the days prior to the exacerbation. 
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 CAE status and by CAE 
severity (Yes: severe, moderate; No) using the ankle accelerometry analysis set. 
 


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7.4. 
Accelerometry: Sleep Disruption Index 
7.4.1. 
Sleep Disruption Index Definition 
The sleep disruption index (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 SDI 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.  
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.  
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  
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. 
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 SDI are computed for those patients in the wrist accelerometry analysis set. 


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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 CAE 
Among patients in the wrist accelerometry cohort who experienced a CAE, 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 three measures of SDI at 1 day (eg, the 24-hour 
period on the day prior to the date of the CAE symptom peak) and at 3, 5, 7, 10, 14 and 21 days 
preceding the peak of a CAE will be presented for all CAEs and by moderate CAEs and severe 
CAEs.   
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 three measures of SDI 
will be presented for the first occurrence of a single day’s albuterol use exceeding (i) 4 
inhalations, (ii) 12 inhalations, and (iii) 20 inhalations overall, and by CAE status and by CAE 
severity. 
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 CAE status and by CAE severity.  
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 four sleep disruption indices for each study week (1 through 12) will be 
presented overall, and by CAE status and by CAE severity. 
7.5. 
Clinical Asthma Exacerbation     
7.5.1. 
Clinical Asthma Exacerbation Definition 
A CAE is the primary outcome measure of this study. In this study, a CAE is an occurrence of 
either a “severe CAE” or a “moderate CAE.” defined as the following: 
• A severe CAE is defined as a CAE that involves worsening asthma such that  
− the treating physician elects to administer prednisone (or equivalent 
glucocorticoid treatment) at least 10 mg prednisone equivalent above baseline 
(Table 2), for at least 3 days  
AND  
− an unscheduled provider visit such as an office visit, urgent care visit, emergency 
care visit, or hospitalization  
• A moderate CAE is defined as a CAE that involves worsening asthma such that  
− the treating physician elects to administer prednisone (or equivalent 
glucocorticoid treatment) at least 10 mg prednisone equivalent above baseline 
(Table 2), for at least 3 days 


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 OR  
− an unscheduled provider visit such as an office visit, urgent care visit, emergency 
care visit, or hospitalization associated with an increase in asthma therapy that 
does not qualify for “severe CAE” as defined above 
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 CAE as moderate or severe is denoted by the response to the CRF question 
“Severity” on the Clinical Asthma Exacerbation 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, urgent care visit, emergency 
care visit, or hospitalization  
A patient may experience more than 1 CAE during the study period. 
Clinical Asthma Exacerbation Status: Clinical asthma exacerbation status is an indicator of 
whether or not a patient experienced a CAE during study follow-up (Yes, No).  
Clinical Asthma Exacerbation Rate: The percentage of patients who experience at least 1 
moderate of severe CAE at the end of study follow-up. 
Recurrent Clinical Asthma Exacerbation Rate: The percentage of patients who experience more 
than 1 moderate of severe CAE at the end of study follow-up. 
Time to Clinical Asthma Exacerbation: Time, in days, from Study Day 1 to the Date of Symptom 
Peak plus 1.  
7.5.2. 
Analysis Methods for Clinical Asthma 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 CAE and device-use-measures. 


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7.5.2.1. 
Within Patient CAE Analyses  
For each CAE 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- 'CAE-adjacent week', the week immediately preceding the onset of 
CAE symptom (ie, day 1 through 7 preceding the date of the CAE symptom onset), and second – 
'CAE-Prior Adjacent week', the week preceding that week (ie, during day 8 through 14 preceding 
the date of the CAE 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 CAEs for which there are 14 days (or more) prior to the 
CAE onset, where patient has been on study and CAE free. 
Descriptive statistics of use measures in the 'CAE-adjacent week' and 'CAE-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 Asthma Exacerbations Short-term Exacerbation Risk (7 days) 
For each patient, the following 3 landmark use events will be identified: 


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• 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 CAE 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 
CAE.  
If a CAE 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 CAE occurred on 
the same date where landmark use happened, then time to CAE will be calculated as 0. 
7.5.2.3. 
All Days Analysis (Only CAE-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 CAE 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 CAE 
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 Asthma 
Exacerbation Rates 
Proportion of patients with at least 1 CAE and proportion of patients with recurrent events will 
be presented. 
7.5.3. 
Predicting Severe CAE/Moderate CAE 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. 


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8. 
SENSITIVITY ANALYSIS 
There will be no sensitivity analysis performed in this study. 


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9. 
MULTIPLE COMPARISONS AND MULTIPLICITY 
No adjustment for multiplicity will be applied. 
 


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10. 
SAFETY ANALYSIS 
10.1. 
General 
The ITT analysis set will be used for all safety analyses.  
10.2. 
Duration of Exposure to IMP  
Duration of exposure to IMP (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 CAE status and by CAE 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 CAE status and CAE 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 CAE status and by CAE severity. 
10.4. 
Adverse Events 
All treatment emergent adverse events will be coded using the MedDRA. 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 Term 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, CAE related adverse 
events, and adverse events leading to withdrawal from the study, asthma exacerbations by 
severity, and asthma exacerbations by deterioration.    
Patient listings for all adverse events, of 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. 
Any adverse event or serious adverse event with a missing start date will be considered treatment 
emergent. 


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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 screening and exacerbation visits.  
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] and exacerbation visits. 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 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. 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. 


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11. 
TOLERABILITY VARIABLES AND ANALYSIS 
Tolerability was not specifically defined for this study. 
 


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12. 
PHARMACOKINETIC ANALYSIS 
Not applicable. 
13. 
PHARMACODYNAMIC ANALYSIS 
Not applicable. 
14. 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS 
Not applicable. 
15. 
BIOMARKER ANALYSIS 
Not applicable. 
16. 
IMMUNOGENICITY ANALYSIS 
Not applicable. 
17. 
ANCILLARY STUDIES ANALYSIS 
Not applicable. 
18. 
PLANNED INTERIM ANALYSIS 
Not applicable. 
 


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19. 
STATISTICAL SOFTWARE 
All data listings, summaries, and statistical analyses will be generated using SAS® version 9.1.3 
or higher. 
 


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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-AS-30064 
42 
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 
CAE/severe 
CAE. 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-AS-30064 
43 
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-AS-30064 
44 
20.4. 
Predicting Severe CAE/Moderate CAE 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 CAE 
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 
Study ABS-AS-30064 
45 
21. 
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