Conditions: Asthma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 333
Healthy volunteers: no

Brief summary:
This is a 12-week treatment, multicenter, open-label, randomized, parallel group comparison feasibility study to evaluate the effectiveness of the Albuterol eMDPI Digital System (DS), including inhaler, App, digital health platform (DHP) (Cloud solution), and dashboard, to optimize outcomes in participants at least 13 years of age or older with asthma.

The study will consist of a screening visit, a 12-week open-label treatment period, and a follow-up telephone call (2 weeks following treatment completion).

Participants with suboptimal asthma control will be enrolled in the study and randomized in a 1:1 ratio to 1 of 2 parallel groups stratified by investigational center: DS group participants utilizing the Albuterol eMDPI DS, including inhaler, App, DHP (Cloud solution), and dashboard, and CC group participants who will be treated with their standard of care albuterol-administering rescue inhalers and will not use the DS during the treatment period.

Detailed description:

Arms:
arm 1: Participants will be trained on the use of the albuterol eMDPI DS (including instructions on how to use both the eMDPI and the App) and, upon demonstrating competency, will receive 2 albuterol eMDPI devices for use as reliever bronchodilators to replace their reliever treatment during the study. The eMDPI Digital System consists of 4 devices: Device 1: albuterol eMDPI (the test investigational medicinal product \[IMP\]); Device 2: Patient-facing App; Device 3: Digital health platform (DHP) (Cloud solution); and Device 4: Provider-facing Dashboard. Participants will receive 90 micrograms (mcg) albuterol, 1 to 2 oral inhalations every 4 to 6 hours, as needed for 12 weeks. arm 2: Participants will be treated with their standard of care albuterol-administering reliever inhalers and will use the digital system during the treatment period. Participants will be reimbursed or given a voucher to use to purchase their existing reliever medications.

Interventions: intervention 1: Albuterol eMDPI DS intervention 2: albuterol
Intervention descriptions: intervention 1: Albuterol sulfate electronic multidose dry powder inhaler (Albuterol eMDPI) DS with 4 component devices:

* Device 1: Albuterol eMDPI
* Device 2: Albuterol eMDPI Patient-facing smart device application (App)
* Device 3: DHP Cloud solution)
* Device 4: Provider-facing dashboard (dashboard) intervention 2: Standard of care albuterol-administering rescue inhaler

Protocol document:
Prot_000.pdf: 
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
1
 
Clinical Study Protocol with Amendment 04
Study Number ABS-AS-40138
CONNected Electronic Inhalers Asthma Control Trial 1 (“CONNECT 1”), a 12-Week Treatment, 
Multicenter, Open-Label, Randomized, Parallel Group Comparison, Feasibility Study to Evaluate 
the Effectiveness of the Albuterol eMDPI Digital System, to Optimize Outcomes in Patients at 
Least 13 Years of Age or Older with Asthma
Short title: A 12-Week Treatment Study to Evaluate the Effectiveness of Albuterol eMDPI DS in 
Patients 13 Years or Older with Asthma
Lay person title: A Study to Test if Using the Albuterol eMDPI System is Effective in Getting 
Better Control of Asthma in Patients at Least 13 Years of Age Compared to Usual Care 
Feasibility Study
IND number: 104532;
NDA number: Not applicable;
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
Original Protocol Approval Date: 12 October 2018
Protocol with Amendment 04 Approval Date: 12 March 2021
Sponsor
Teva Branded Pharmaceutical
Products R&D, Inc.
145 Brandywine Parkway
West Chester, PA 19380
United States of America
Information regarding clinical laboratories and other departments and institutions is 
found in Appendix A
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 and Regulations (as applicable in the 
region of the study); national country legislation; and the sponsor’s Standard Operating Procedures 
(SOPs).
Confidentiality Statement
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 and/or its affiliates. The recipient agrees that no information 
contained herein may be published or disclosed without written approval from the sponsor.
© 2021 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved.
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
2
AMENDMENT HISTORY
The protocol for Study ABS-AS-40138 (original protocol dated 12 October 2018) has been 
amended and reissued as follows:
Amendment 04
12 March 2021
163 patients randomized/enrolled to date
Amendment 03
30 July 2020
0 patients randomized/enrolled to date
Amendment 02
26 February 2019
0 patients randomized/enrolled to date
Amendment 01
13 December 2018
0 patients randomized/enrolled to date
The Summary of Changes to the Protocol includes the corresponding reason/justification for 
each change and is provided in Section 16.
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
3
INVESTIGATOR AGREEMENT
Original Protocol Dated 12 October 2018
Protocol with Amendment 04 Approval Date: 12 March 2021
IND number: 104532;
NDA number: Not applicable; 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
CONNected Electronic Inhalers Asthma Control Trial 1 (“CONNECT 1”), a 12-Week 
Treatment, Multicenter, Open-Label, Randomized, Parallel Group Comparison, Feasibility Study 
to Evaluate the Effectiveness of the Albuterol eMDPI Digital System, to Optimize Outcomes in 
Patients at Least 13 Years of Age or Older with Asthma
Principal Investigator: 
Title:
Address of Investigational Center:
Tel:
I have read the protocol with Amendment 04 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 agreement with 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 
reporting 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, IMP shipment and return forms, and all other information 
collected during the study, in accordance with national and local Good Clinical Practice (GCP) 
regulations as well as all other national and international laws and regulations.
Principal Investigator
Signature
Date
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
4
SPONSOR PROTOCOL APPROVAL
Sponsor’s Authorized 
Representative
Global Medical Affairs
Signature
Date
Executed signature pages are maintained separately within the Trial Master File.
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
5
COORDINATING INVESTIGATOR AGREEMENT
Original Protocol Dated 12 October 2018
Protocol with Amendment 04 Approval Date: 12 March 2021
IND number: 104532;
NDA number: Not applicable; 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
CONNected Electronic Inhalers Asthma Control Trial 1 (“CONNECT 1”), a 12-Week 
Treatment, Multicenter, Open-Label, Randomized, Parallel Group Comparison, Feasibility Study 
to Evaluate the Effectiveness of the Albuterol eMDPI Digital System, to Optimize Outcomes in 
Patients at Least 13 Years of Age or Older with Asthma
I have read the protocol with Amendment 04 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 agreement with 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 and 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 
reporting 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 patient information, IMPs shipment and return forms, and other information collected 
during the study, in accordance with my responsibilities under the function of the coordinating 
investigator and in accordance with national and local Good Clinical Practice (GCP) regulations
as well as all other national and international laws and regulations. In addition I will assume the 
responsibility of the coordinating investigator according to a separate contract.
Coordinating Investigator
Title:
Address of Investigational Center:
Tel:
Coordinating Investigator
Signature  
Date
Executed signature pages are maintained separately within the Investigator Site File and Trial Master File.
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
6
CLINICAL STUDY PROTOCOL SYNOPSIS WITH AMENDMENT 04
Study Number ABS-AS-40138
Title of Study: CONNected Electronic Inhalers Asthma Control Trial 1 (“CONNECT 1”), a 12-
Week Treatment, Multicenter, Open-Label, Randomized, Parallel Group Comparison, Feasibility 
Study to Evaluate the Effectiveness of the Albuterol eMDPI Digital System, to Optimize 
Outcomes in Patients at Least 13 Years of Age or Older with Asthma
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
145 Brandywine Parkway
West Chester, PA 19380
United States of America (USA)
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 electronic 
multidose dry powder inhaler (Albuterol eMDPI) Digital System (DS) with 4 component 
devices:
!
Device 1: Albuterol eMDPI
!
Device 2: Albuterol eMDPI Patient-facing smart device application (App)
!
Device 3: Digital Health Platform (DHP, Cloud solution)
!
Device 4: Provider-facing dashboard (dashboard)
Type of Study: Feasibility study to measure the effectiveness of the Albuterol eMDPI DS.
Is this study conducted to investigate the New Use of an approved, marketed product? No
Indications: 1) Treatment or prevention of bronchospasm in patients 4 years of age and older 
with reversible obstructive airways disease. 2) Prevention of exercise induced bronchospasm in 
patients 4 years of age and older.
Number of Investigational Centers Planned: The study is planned to be conducted in 
approximately 30 investigational centers.
Countries Planned: The study is planned to be conducted in 1 country (USA)
Planned Study Period: The study is expected to start in Q4 2020 and last until approximately 
Q4 2021.
Number of Patients Planned (total): A total of 330 patients will be enrolled in the study 
(accounting for 10% early dropouts) and the number of evaluable patients is planned to be 150 in 
each group. 
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
7
Study Population: The study population will consist of patients 13 years of age or older with a 
diagnosis of asthma, currently on an inhaled corticosteroid (ICS) with a long-acting beta2 agonist 
(LABA), using an albuterol rescue inhaler as part of their existing asthma treatment regimen. 
Additionally, patients will have uncontrolled or partly controlled asthma quantified as an Asthma 
Control Test (ACT) score of less than 19 at the screening or baseline visit.
Primary and Secondary Objectives and Endpoints: The primary and secondary study 
objectives and endpoints are presented in Table 1.
Table 1:
Primary and Secondary Study Objectives and Endpoints
Objectives
Endpoints
The primary objective of 
this study is to demonstrate 
the effectiveness of the DS 
compared to a concurrent 
control (CC) group. 
The primary endpoint is the proportion of patients for the DS 
and CC groups achieving meaningful improvement, which is 
defined as an ACT score greater than or equal to 20 at the end 
of the 12-week treatment period or an increase of at least 3 
units on the ACT score from baseline at the end of the 12-week 
treatment period.
The secondary objective 
(#1) is to describe the 
asthma management actions 
by investigational center 
health care providers 
(iHCPs) for all patients in 
both groups. 
This secondary endpoint is the frequency and types of 
interventions done to improve asthma control including:
!
number of discussions between patient and iHCP 
regarding inhaler technique or adherence
!
number of adjustments of therapy including:
o
increased or decreased doses of inhaled 
medication
o
change to different inhaled medication
o
additional inhaled medication
o
addition of a systemic corticosteroid medication 
for asthma or another controller, including a 
long-acting muscarinic antagonist (LAMA) or 
biologics
!
frequency of intervention to manage comorbid 
conditions associated with poor asthma control 
(gastroesophageal reflux disease [GERD], sinusitis, 
etc.)
The secondary objective 
(#2) is to evaluate short-
acting beta2 agonist (SABA) 
usage and the number of 
SABA-free days in the DS 
group.
This secondary endpoint is the change from baseline in the 
mean weekly SABA usage and the change from baseline in the 
number of SABA-free days over the 12-week treatment period 
for the DS group.
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
8
Objectives
Endpoints
The secondary objective 
(#3) is to assess the usability 
and acceptability of the DS 
by patients in the DS group 
and the investigational 
center personnel.
This secondary endpoint is the assessment of the DS (eMDPI, 
App and dashboard) acceptability and usability, utilizing the 
System Usability Scale (SUS), completed by the patients in the 
DS group, 18 years of age or older, and the investigational 
center personnel at the end of the study.
The secondary objective 
(#4) is to assess behavioral 
correlates of responsiveness 
to digital health technology 
among patients for all 
patients in both groups.
This secondary endpoint is the assessment of patients’ beliefs 
and perceptions about their disease and treatment, utilizing the 
Beliefs about Medicines Questionnaire (BMQ) and the Brief 
Illness Perception Questionnaire (BIPQ) to both the DS and 
CC groups, patients 18 years of age or older, describing their 
behavioral profile at baseline and at the end of the study.
The secondary objective 
(#5) is to evaluate the safety 
of Albuterol eMDPI.
This secondary endpoint is the reporting of adverse events 
related to Albuterol eMDPI at participating investigational 
centers.
The safety endpoints for this study include the following for all 
patients in both groups:
!
adverse event data
!
adverse device effect data
Notes: The Digital System (DS) group will include eligible study population patients who will use the DS (eMDPI, 
App, DHP [Cloud solution], and dashboard) during the treatment period. The concurrent control (CC) group will 
include eligible patients who will be treated with their standard of care albuterol-administering rescue inhalers and 
will not use the DS during the treatment period. 
Exploratory Objectives and Endpoints: 
Exploratory objectives and endpoints are as follows:
 
 
 
 
 
 
 
 
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
9
General Study Design: This is a 12-week treatment, multicenter, open-label, randomized, 
parallel group comparison feasibility study to evaluate the effectiveness of the Albuterol eMDPI 
DS, including inhaler, App, DHP (Cloud solution), and dashboard, to optimize outcomes in 
patients at least 13 years of age or older with asthma.
The study will consist of a screening/baseline visit (Visit 1), a 12-week open-label treatment 
period with Visit 2, and a follow-up telephone call (2 weeks following treatment completion).
Patients with suboptimal asthma control will be enrolled in the study and randomized in a 1:1 
ratio to 1 of 2 parallel groups stratified by investigational center: DS group patients utilizing the 
Albuterol eMDPI DS, including inhaler, App, DHP (Cloud solution), and dashboard, and CC 
group patients who will include eligible patients who will be treated with their standard of care 
albuterol-administering rescue inhalers and will not use the DS during the treatment period. 
Similar data will be collected regarding outcomes for the CC group: ACT after 12 to 14 weeks, 
BMQ and BIPQ responses, and the frequency of CAEs. 
All patients will have a screening/baseline visit (Visit 1), at which they will be asked if they use 
a smart device and use different applications on their smartphones. A baseline ACT score for all 
patients, and BMQ and BIPQ responses for patients 18 years of age or older, will be collected. 
Once randomized, patients in the DS group will be trained on the use of the Albuterol eMDPI DS 
(including instructions on how to use both the eMDPI and the App) and, upon demonstrating 
competency, will receive 2 Albuterol eMDPI devices for use as rescue bronchodilators to replace 
their rescue treatment during the study. Additional Albuterol eMDPI devices may be supplied 
during the treatment period, based on patients’ needs. Patients in the CC group will be 
reimbursed or given a voucher to use to purchase their existing rescue medications. 
Investigational centers will receive similar instruction regarding features of the App, as well as 
features of the associated dashboard, which mirrors the digital information obtained from the 
eMDPI and App, including frequency and times of SABA rescue use and associated inspiratory 
flow parameters measured by the eMDPI with each inhalation.
The CC group will be followed according to the clinical judgment of the investigator; the asthma 
of patients in the CC group will be managed in a manner consistent with the clinical judgement 
of the investigator and based on asthma management guidelines (eg, GINA). Similar to the 
management of the CC group, the DS group patients will be followed by the investigational 
centers with the addition of objective information on Albuterol eMDPI usage being available to 
both patients and investigational centers through the App and the dashboard, respectively. The 
iHCPs will check the dashboard at least once a week and use this information, as per their 
clinical judgment, to modify patients’ asthma management. Clinically Driven Assessments for 
both groups, if necessary, should be arranged per the clinical judgement of the iHCP managing 
the patient and can be via a telephone call or an on-site visit.
For all patients, at Visit 2 and at each Clinically Driven Assessment, the iHCP will record 
answers to Asthma Management questions, including discussions regarding adherence, or inhaler 
technique, treatment adjustments, or additions of new treatments, including biologic medication 
usage. Additionally, in the case of a Clinically Driven Assessment, (for patients in the DS 
group), the iHCP will be asked whether or not the contact with the patient was originated from 
the iHCP interaction with the dashboard. 
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
10
At the end of the treatment period (12 weeks), final assessments of the DS and CC group patients 
will be made, as specified in Table 3. A follow-up telephone call will be made by the 
investigational center to all patients, 2 weeks later, and will confirm the DS group patients have 
returned to previous asthma treatments.
It should also be noted that no specific clinical decisions are being mandated. One secondary 
objective of this study is to describe how clinicians actually use the information provided by the 
DS to manage their patients.
Study procedures and assessments with their time points are shown in Table 3. The study 
schematic diagram is shown in Figure 2.
Method of Randomization and Blinding:
Patients will be randomly assigned to the DS group or CC group in a 1:1 ratio stratified by 
investigational center, respectively, using a Randomization and Trial Supply Management 
(RTSM) system. 
This is an open-label study, and therefore, blinding is not applicable.
Investigational Medicinal Products: Dose, Pharmaceutical Form, Route of Administration, 
and Administration Rate:
Test IMP:
Albuterol eMDPI DS with 4 components:
!
Device 1: Albuterol eMDPI
!
Device 2: Albuterol eMDPI Patient-facing smart device App
!
Device 3: DHP (Cloud solution)
!
Device 4: Provider-facing dashboard (dashboard)
Investigational medicinal products are defined as test IMP, reference IMP, and placebo IMP 
(Table 2).
Table 2:
Investigational Medicinal Products Used in the Study
IMP name
Test IMP
Placebo IMP
Reference IMP
Trade name and INN, if 
applicable, or 
company-assigned number
Albuterol eMDPI
None
None
Formulation
Oral inhalation powder
NA
NA
Unit dose strength(s)/Dosage 
level(s)
117 mcg of albuterol sulfate 
(equivalent to 97 mcg of albuterol 
base) from the device reservoir to 
provide a delivered dose of 108 mcg 
of albuterol sulfate (equivalent to 
90 mcg of albuterol base)
NA
NA
Route of administration
Oral inhalation
NA
NA
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
11
Table 2:
Investigational Medicinal Products Used in the Study (Continued)
IMP name
Test IMP
Placebo IMP
Reference IMP
Dosing instructions/Dosing 
schedule/Titration 
periods/Treatment periods
1 to 2 oral inhalations every 4 to 6 
hours, as needed
NA
NA
Packaging
NA
NA
NA
Manufacturer
Teva Pharmaceutical Industries, Ltd. 
Jerusalem, Israel, or Teva 
Pharmaceuticals Ireland, Waterford, 
Ireland
NA
NA
Albuterol eMDPI=albuterol sulfate electronic dry powder inhaler; IMP=investigational medicinal product; 
INN=International Nonproprietary Name; NA=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. However, as the dosing of the test 
IMP is on an as-needed basis, there is no set maximum exposure. 
Study Duration: Approximately 12 months (from Q4 2020 to Q4 2021) 
End of Study: End of study is defined as the follow-up telephone call for the last patient.
Plans for Treatment or Care after the Patient Has Ended Participation in the Study: No 
treatment is planned after the end of the study; DS patients will be placed back on their usual 
SABA rescue therapy at treatment end and follow up through their iHCPs.
Selection of Patients/Study Population
Inclusion Criteria: Patients may be included in the study only if they meet all of the following 
criteria:
a.
The patient is 13 years or older at the time of screening.
b. The patient has a documented diagnosis of asthma established at the investigational 
center at the time of informed consent or the investigator confirms a diagnosis of 
asthma.
c.
The patient is currently on treatment with an ICS with a LABA.
d. The patient has an ACT score of less than 19 at the screening or baseline visit.
e.
The patient is currently using inhaled albuterol sulfate as rescue medication and is 
willing to discontinue all other rescue medications and replace them with the study-
provided Albuterol eMDPI.
f.
[Revision 1] The patient can read and communicate in English and is familiar with 
and is willing to use his/her own smart device that meets the minimum App 
requirements and download and use the App.
g. The patient is able to provide written informed consent.
h. The patient must be willing and able to comply with study requirements and 
restrictions and to remain at the investigational center for the required duration during 
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
12
the study period, and willing to return to the investigational center for the follow-up 
procedures and assessments as specified in this protocol.
Exclusion Criteria: Patients will be excluded from participating in this study if they meet any of 
the following criteria:
a.
The patient has any clinically significant uncontrolled medical condition (treated or 
untreated) other than asthma, which in the view of the investigator would preclude 
participation.
b. The patient was hospitalized for severe asthma in the last 30 days.
c.
The patient has any medical or psychiatric condition that, in the opinion of the 
investigator, could jeopardize or would compromise the patient’s ability to participate 
in this study.
d. The patient has a diagnosis of Chronic Obstructive Pulmonary Disease (COPD) or 
Asthma-COPD Overlap (ACO).
e.
The patient is a current smoker or has a greater than 10 pack-year history of smoking.
f.
The patient is currently being treated with systemic corticosteroids (oral, 
intramuscular, or intravenous) or has been treated within the last 30 days. 
g. [Revision 1] The patient has any treatment with biologics for asthma (eg, 
omalizumab, anti-interleukin (IL) 5, anti-IL5R, anti-IL4R), or has had such treatment 
within the last 90 days. However, during the study, patients can be escalated to 
therapy with such agents if clinically indicated in the judgment of the investigator as 
part of their asthma management and remain in the study.)
h. The patient has a known hypersensitivity to any components of the IMPs stated in this 
protocol.
i.
[New criterion] The patient has previously participated in a Digihaler study or is 
currently being treated prior to enrollment with a digital inhaler system, including the 
Digihaler system or an external “bolt on” digital system designed to monitor inhaler 
usage, such as the Propeller Health or Adherium systems.
Statistical Considerations
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 in the clinical study report 
(CSR).
Sample Size Rationale:
Sample size estimates are based upon the assumption that the absolute differences between the 
DS and CC groups and the associated operational characteristics will be similar to the absolute 
differences and operational characteristics of the DS and CC groups noted in the sample size 
rationale for the study design.
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
13
The recommended sample size for the study is 150 evaluable patients per group 
(30 investigational centers, with each investigational center enrolling at least 10 patients), 
300 patients in total. Accounting for a dropout rate of 10%, this leads to a recommended total 
number of 330 enrolled patients. 
With this sample size and assuming a true absolute difference in proportions (treatment effect as 
the estimated response rate for the CC group is 60% and for the DS group is 73%) between the 
groups of at least 13%, the probability that the posterior probability will be at least 95% is 0.77 
(power) (analogous to 1-sided p-value < 0.05). Assuming no treatment effect (difference in 
proportions between the groups is 0%, ie, Type 1 error), then the probability that posterior 
probability will be at least 95% is 0.05.
It should be noted that both power and Type 1 error are dependent on the absolute difference 
between the DS and the CC groups as illustrated in Figure 1 below by the operational 
characteristics calculated for the study design:
Figure 1:
Operational Characteristics Calculated for the Study Design
Analysis Sets
Intent-to-Treat Analysis Set (ITT)
The intent-to-treat (ITT) analysis set will include all randomized patients. In the ITT analysis set, 
treatment will be assigned based on the treatment to which patients were randomized, regardless 
of which treatment they actually received. This analysis population will be used for 
summarization of patient disposition and demographic and baseline characteristics, as 
appropriate.
Modified Intent-to-Treat Analysis Set (mITT)
The modified intent-to-treat (mITT) analysis set is a subset of the ITT analysis set including only 
patients who receive at least 1 dose of IMP (IMP is albuterol eMDPI for the DS group and 
standard-of-care albuterol-administering rescue medication for the CC group) and at least 
1 postbaseline assessment on any of the study endpoints (primary, secondary, or exploratory). 
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Parallel-group, Controlled Study - Asthma
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In the mITT analysis set, treatment will be assigned based on the treatment to which patients 
were randomized, regardless of which treatment they actually received. This analysis will be 
used for all primary, secondary, and exploratory endpoint analyses.
Safety Analysis Set
This analysis set will include all patients in the DS group who receive at least 1 dose of IMP and 
all patients in the CC group. In the safety analysis set, treatment will be assigned based on the 
treatment patients actually received, regardless of the treatment to which they were randomized, 
unless otherwise specified. This analysis set will be used for all safety analyses.
Additional analysis sets may be defined in the Statistical Analysis Plan, if appropriate.
Analysis
Primary Analysis:
The primary endpoint is the proportion of patients reaching well-controlled asthma as defined by 
an ACT score of greater than or equal to 20 or a clinically important improvement in asthma 
control as defined by an increase of at least 3 units on the ACT score from baseline at the end of 
the 12-week treatment period (responder analysis of DS versus CC group with responders 
defined by an ACT score of greater than or equal to 20 or an increase by greater than or equal to 
3 units on the ACT score).
Estimand framework:
1. Analysis will be performed on the mITT set. 
2. A binary distribution is assumed for the primary endpoint. Patients who discontinue early 
due to technology failure, disliking the digital platform, disease worsening, adverse 
experience or disliking the IMP will be counted as treatment failures. For those who 
discontinue early not due to these reasons, the ACT value assessed at the Early 
Termination (ET) visit will be used. 
3. Summary measure: A successful differentiation between the 2 groups will be determined 
by a Bayesian posterior probability for  >0 greater than 0.95 (1-sided). The following 
statistical methods will be utilized:
Logistic regression model allowing for different response rates at enrolling investigational 
centers will be used for testing the hypothesis :  = 0, :  > 0 in the following model:


1 −
=  +    + 
where i = treatment group, j = investigational center, xij = treatment group i for investigational 
center j, pij = response proportion of treatment group i in investigational center j. 
Non-informative priors will be assumed for all coefficients.
Estimates of odds ratio and individual proportions with corresponding credible intervals will be 
presented.
Sensitivity Analysis: If appropriate, sensitivity analyses will be specified in the Statistical 
Analysis Plan.
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Secondary Analysis:
All secondary endpoints will be based on the mITT analysis set and analyzed descriptively. 
For continuous variables, descriptive statistics (number [n], mean, standard deviation, median, 
minimum, and maximum) will be provided for observed values and changes from baseline to 
each time point. For categorical variables, patient counts and percentages will be provided.
Other Analysis: NA
Analysis of Exploratory/Other Endpoints:
 
Multiple Comparisons and Multiplicity: 
Since there is only 1 primary endpoint-based statistical analysis and the multiple secondary 
endpoints will be analyzed using descriptive statistical analysis techniques, no adjustments for 
multiple comparisons/multiplicity will be made for the preplanned multiple 
comparisons/endpoints.
Safety Analyses: Safety analyses will be performed on the safety analysis set.
Safety assessments and time points are provided in Table 3.
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Each patient will be counted only once in each preferred term (PT) or system organ 
class (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) (defined as related or with missing relationship) (overall and 
by severity), serious adverse events, adverse events causing withdrawal from the study, and 
adverse device effects. Summaries will be presented by treatment group and for all patients. 
Patient listings of serious adverse events and adverse events leading to withdrawal will be 
presented.
Changes in vital signs measurements data will be summarized descriptively. All values will be 
compared with predefined criteria to identify potentially clinically significant values or changes, 
and such values will be listed.
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics.
For continuous variables, descriptive statistics (n, mean, standard deviation, median, minimum, 
and maximum) will be provided for observed 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, adverse device 
effects, and potentially clinically significant abnormal values (vital signs) 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.
Planned Interim Analysis: There will be no formal interim analysis.
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TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
AMENDMENT HISTORY .............................................................................................................2
INVESTIGATOR AGREEMENT...................................................................................................3
COORDINATING INVESTIGATOR AGREEMENT...................................................................5
CLINICAL STUDY PROTOCOL SYNOPSIS WITH AMENDMENT 04 ...................................6
LIST OF ABBREVIATIONS........................................................................................................22
1.
INTRODUCTION AND BACKGROUND INFORMATION ..................................24
1.1.
Introduction.................................................................................................................24
1.2.
Findings from Nonclinical and Clinical Studies.........................................................25
1.3.
Known and Potential Benefits and Risks to Patients..................................................26
1.3.1.
Known and Potential Benefits and Risks of the Test Investigational 
Medicinal Product(s) ..................................................................................................26
2.
STUDY OBJECTIVES AND ENDPOINTS..............................................................27
2.1.
Primary and Secondary Study Objectives and Endpoints ..........................................27
2.1.1.
Justification of Primary Endpoint...............................................................................28
2.2.
Exploratory Objectives and Endpoints.......................................................................28
3.
STUDY DESIGN .......................................................................................................30
3.1.
General Study Design and Study Schematic Diagram ...............................................30
3.2.
Planned Number of Patients and Countries................................................................31
3.3.
Justification for Study Design and Selection of Population.......................................32
3.4.
Stopping Rules for the Study......................................................................................32
3.5.
Schedule of Study Procedures and Assessments........................................................32
4.
SELECTION AND WITHDRAWAL OF PATIENTS..............................................35
4.1.
Patient Inclusion Criteria ............................................................................................35
4.2.
Patient Exclusion Criteria...........................................................................................35
4.3.
Withdrawal Criteria and Procedures for the Patient...................................................36
4.4.
Replacement of Patients .............................................................................................37
4.5.
Rescreening.................................................................................................................37
4.6.
Screening Failure........................................................................................................37
5.
TREATMENTS..........................................................................................................38
5.1.
Investigational Medicinal Products Used in the Study...............................................38
5.1.1.
Test Investigational Medicinal Product......................................................................38
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5.1.1.1.
Starting Dose and Dose Levels...................................................................................39
5.1.1.2.
Dose Modification and Dose Stratification ................................................................39
5.1.2.
Medical Devices .........................................................................................................40
5.1.2.1.
Application .................................................................................................................40
5.1.2.2.
Teva Digital Health Platform (Cloud Solution)..........................................................40
5.1.2.3.
Dashboard...................................................................................................................40
5.1.3.
Reference Investigational Medicinal Product or Device............................................40
5.1.4.
Placebo Investigational Medicinal Product or Device................................................40
5.2.
Preparation, Handling, Labeling, Storage, and Accountability for IMPs...................41
5.2.1.
Storage and Security...................................................................................................41
5.2.2.
Labeling......................................................................................................................41
5.2.3.
Accountability.............................................................................................................41
5.3.
Justification for Investigational Medicinal Product....................................................42
5.3.1.
Justification for Dose of Test Investigational Medicinal Product ..............................42
5.4.
Treatment After the End of the Study.........................................................................42
5.5.
Restrictions .................................................................................................................42
5.6.
Prior and Concomitant Medication or Therapy..........................................................43
5.7.
Procedures for Monitoring Patient Compliance .........................................................43
5.8.
Randomization and Blinding......................................................................................43
5.9.
Data Monitoring Committee.......................................................................................43
6.
ASSESSMENT OF EFFICACY ................................................................................44
6.1.
Assessments of Patient-Reported Outcomes ..............................................................44
6.1.1.
Asthma Control Test...................................................................................................44
6.1.2.
Beliefs about Medicines Questionnaire......................................................................44
6.1.3.
Brief Illness Perception Questionnaire .......................................................................44
6.1.4.
System Usability Questionnaire .................................................................................45
7.
ASSESSMENT OF SAFETY.....................................................................................46
7.1.
Adverse Events ...........................................................................................................46
7.1.1.
Definition of an Adverse Event ..................................................................................46
7.1.2.
Recording and Reporting of Adverse Events .............................................................47
7.1.3.
Severity of an Adverse Event .....................................................................................48
7.1.4.
Relationship of an Adverse Event to the Investigational Medicinal Product.............48
7.1.5.
Serious Adverse Events..............................................................................................48
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7.1.5.1.
Definition of a Serious Adverse Event .......................................................................49
7.1.5.2.
Expectedness...............................................................................................................49
7.1.5.3.
Reporting a Serious Adverse Event............................................................................50
7.1.6.
Protocol-Defined Adverse Events of Special Interest ................................................51
7.1.7.
Protocol Deviations Because of an Adverse Event ....................................................51
7.2.
Adverse Device Effects ..............................................................................................52
7.2.1.
Adverse Device Effect Reporting...............................................................................52
7.2.2.
Serious Adverse Device Effects .................................................................................52
7.2.2.1.
Serious Adverse Device Effect Reporting..................................................................52
7.3.
Pregnancy ...................................................................................................................53
7.4.
Medication Error and Special Situations Related to the Investigational 
Medicinal Product.......................................................................................................54
7.5.
Clinical Laboratory Tests ...........................................................................................54
7.6.
Physical Examinations................................................................................................54
7.7.
Vital Signs ..................................................................................................................54
7.8.
Electrocardiography....................................................................................................55
8.
ASSESSMENT OF PHARMACOKINETICS / PHARMACODYNAMICS / 
BIOMARKERS / PHARMACOGENOMICS/ 
IMMUNOGENICITY/ANCILLARY STUDIES.......................................................56
9.
STATISTICS ..............................................................................................................57
9.1.
Sample Size and Power Considerations .....................................................................57
9.2.
Analysis Sets...............................................................................................................58
9.2.1.
Intent-to-Treat Analysis Set........................................................................................58
9.2.2.
Modified Intent-to-Treat Analysis Set........................................................................58
9.2.3.
Safety Analysis Set.....................................................................................................58
9.3.
Data Handling Conventions........................................................................................58
9.3.1.
Handling Withdrawals and Missing Data...................................................................58
9.4.
Study Population.........................................................................................................58
9.4.1.
Patient Disposition......................................................................................................58
9.4.2.
Demographic and Baseline Characteristics ................................................................59
9.5.
Analyses......................................................................................................................59
9.5.1.
Primary Endpoint........................................................................................................59
9.5.2.
Secondary Endpoints ..................................................................................................59
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Parallel-group, Controlled Study - Asthma
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9.5.3.
Exploratory/Other Endpoints......................................................................................60
9.5.4.
Planned Method of Analysis.......................................................................................60
9.5.4.1.
Primary Analysis ........................................................................................................60
9.5.4.2.
Sensitivity Analysis ....................................................................................................60
9.5.4.3.
Secondary Analysis ....................................................................................................61
9.5.4.4.
Other Analyses............................................................................................................61
9.5.4.5.
Exploratory Analysis ..................................................................................................61
9.6.
Multiple Comparisons and Multiplicity......................................................................61
9.7.
Safety Analysis ...........................................................................................................61
9.8.
Tolerability Analysis ..................................................................................................62
9.9.
Planned Interim Analysis............................................................................................62
9.10.
Reporting Deviations from the Statistical Plan ..........................................................62
10.
QUALITY CONTROL AND QUALITY ASSURANCE .........................................63
11.
COMPLIANCE STATEMENT..................................................................................63
12.
DATA MANAGEMENT AND RECORD KEEPING ..............................................63
13.
FINANCING AND INSURANCE.............................................................................64
14.
PUBLICATION POLICY ..........................................................................................64
15.
REFERENCES ...........................................................................................................65
16.
SUMMARY OF CHANGES TO PROTOCOL .........................................................67
16.1.
Amendment 04 Dated 12 March 2021........................................................................67
16.2.
Amendment 03 Dated 30 July 2020 ...........................................................................69
16.3.
Amendment 02 Dated 26 February 2019....................................................................86
16.4.
Amendment 01 Dated 13 December 2018..................................................................93
APPENDIX A.
CLINICAL LABORATORIES AND OTHER DEPARTMENTS AND 
INSTITUTIONS.......................................................................................................108
APPENDIX B.
STUDY PROCEDURES AND ASSESSMENTS BY VISIT.........................109
APPENDIX C.
QUALITY CONTROL AND QUALITY ASSURANCE ..............................112
APPENDIX D.
ETHICS ...........................................................................................................114
APPENDIX E.
LOST TO FOLLOW-UP .................................................................................116
APPENDIX F.
PRODUCT COMPLAINTS.............................................................................117
APPENDIX G.
DATA MANAGEMENT AND RECORD KEEPING ...................................121
APPENDIX H.
PUBLICATION POLICY...............................................................................124
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LIST OF TABLES
Table 1:
Primary and Secondary Study Objectives and Endpoints ............................................7
Table 2:
Investigational Medicinal Products Used in the Study...............................................10
Table 3:
Study Procedures and Assessments............................................................................32
Table 4:
Investigational Medicinal Products Used in the Study...............................................41
Table 5:
The Relationship of an Adverse Event to the Investigational Medicinal 
Product........................................................................................................................48
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Parallel-group, Controlled Study - Asthma
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LIST OF FIGURES
Figure 1:
Operational Characteristics Calculated for the Study Design ....................................13
Figure 2:
Overall Study Schematic Diagram .............................................................................31
Figure 3:
Current Inhaler (Left) Versus Inhaler with Additional Electronics Module 
(Right).........................................................................................................................39
Figure 4:
Decision Tree for Adverse Events and Adverse Device Effects Classification .........53
Figure 5:
Operational Characteristics Calculated for the Study Design ....................................57
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LIST OF ABBREVIATIONS
Abbreviation
Term
ACO
Asthma- chronic obstructive pulmonary disease (COPD) Overlap
ACT
Asthma Control Test
App
smart device application
BIPQ
Brief Illness Perception Questionnaire
BLA
Biological License Application
BMQ
Beliefs about Medicines Questionnaire
CAE
clinical asthma exacerbation
CC
concurrent control
CFR
Code of Federal Regulations (USA)
COPD
chronic obstructive pulmonary disease
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
DHP
Digital Health Platform
DS
Digital System
ED
emergency department
EIB
exercise-induced bronchospasm
EMA
European Medicines Agency
eModule
electronic module
eMDPI
multidose dry powder inhaler with integrated electronic module
ET
Early Termination
EU
European Union
EudraCT
European Clinical Trials
FDA
Food and Drug Administration
FEV1
forced expiratory volume in 1 second
GCP
Good Clinical Practice
GERD
gastroesophageal reflux disease
GINA
Global Initiative for Asthma 
GPSP
Global Patient Safety and Pharmacovigilance
IB
Investigator’s Brochure
ICF
informed consent form
ICH
The International Council on Harmonisation
ICS
inhaled corticosteroid
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Parallel-group, Controlled Study - Asthma
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Abbreviation
Term
IEC
Independent Ethics Committee
iHCP
investigational center healthcare provider
IL
interleukin
IMP
investigational medicinal product
IND
Investigational New Drug
iOS
iPhone operating system
IRB
Institutional Review Board
ISO
International Organization for Standardization
ITT
intent-to-treat
LABA
long-acting beta2 agonist
LAMA
long-acting muscarinic antagonist
LSO
local safety officer
MDI
metered dose inhaler
MDPI
multidose dry powder inhaler 
MID
minimally important difference
mITT
modified intent-to-treat
NDA
New Drug Application
NIH
National Institute of Health
PRO
patient-reported outcome
PT
preferred term
RSI
reference safety information
RTSM
Randomization and Trial Supply Management
SABA
short-acting beta2 agonists
SOP
Standard Operating Procedure
SUS
System Usability Scale
SUSAR
suspected unexpected serious adverse reaction
SOC
system organ class
US/USA
United States (of America)
WHO
The World Health Organization
WHO Drug
World Health Organization Drug Dictionary
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1.
INTRODUCTION AND BACKGROUND INFORMATION
1.1.
Introduction
Asthma is one of the most common chronic diseases. This is a heterogeneous condition that often 
affects the airway passages of the lungs and is characterized by airway inflammation and 
bronchial hyper-responsiveness that vary over time in their occurrence, frequency, and intensity. 
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. It is believed that these asthma symptoms, in association with suboptimal treatment 
or aging, may lead to chronic changes in airway structure and function, increasing the morbidity 
and mortality of those affected (Global Initiative for Asthma [GINA] 2018). 
As the recommended drug for relief of acute asthmatic symptoms and as the prophylaxis for 
exercise-induced bronchoconstriction, short-acting beta2 agonists (SABAs), such as albuterol, are 
a mainstay of asthma management. Albuterol sulfate is a beta2-adrenergic agonist with the 
chemical name α1 [(tert butylamino) methyl]-4-hydroxy-m-xylene-α,αʹ-diol sulfate (2:1) [salt]. 
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. 
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 developed the breath-
actuated inhaler PROAIR® RESPICLICK® (albuterol sulfate inhalation powder), which utilizes a 
formulation blend of albuterol sulfate 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). 
PROAIR RESPICLICK has been available in the United States (US) since March 2015. It is 
indicated for treatment or prevention of bronchospasm in patients 4 years of age and older with 
reversible obstructive airway disease and prevention of exercise-induced bronchospasm in 
patients 4 years of age and older. 
On 21 December 2018, the US Food and Drug Administration (FDA) approved Albuterol 
multidose dry powder inhaler (MDPI) with an integrated electronic module (eMDPI) as 
PROAIR® DIGIHALER™ (albuterol sulfate inhalation powder), 90 mcg of albuterol base per 
actuation, for the same indication as PROAIR RESPICLICK. PROAIR DIGIHALER contains a 
built-in electronic module (eModule; ie, the Digihaler) that detects, records, and stores data on 
inhaler events for transmission to a mobile application (App). More detailed prescribing 
information for this product may be found in the Investigator’s Brochure (IB).
In this study, 90 mcg of albuterol sulfate is delivered via PROAIR DIGIHALER. Teva has 
developed the eModule (ie, the Digihaler) as part of a Digital System (DS) to assist a patient with 
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asthma to appropriately use the eMDPI inhaler. The system is described in more practical terms 
as an inhaler with integrated data logger capable of storing and transmitting timestamped data.
The information from the eModule will be transmitted wirelessly (Bluetooth Low Energy) to the 
smart device App. From the App, data may be transmitted to the Digital Health Platform (DHP), 
which consists of a Cloud solution, and then to a provider-facing dashboard. The DHP is used to 
provide patient-specific data to the iHCP via the dashboard, a secure web interface. The 
following devices will be evaluated in this study:
Device 1: The Albuterol eMDPI, which is the test investigational medicinal product 
(IMP)
Device 2: Patient-facing App
Device 3: DHP (Cloud solution) 
Device 4: Provider-facing dashboard
The purpose of the study is to evaluate whether outcomes for patients using the Albuterol eMDPI 
DS can be optimized better than a concurrent control (CC) group who will be treated with their 
standard of care albuterol-administering rescue inhalers and will not use the DS during the 
treatment period. The study will also assess mean weekly SABA usage and the number of 
SABA-free days, the asthma management actions of investigational heath care providers (iHCPs) 
using the dashboard as part of the DS, and will collect information using patient questionnaires 
that focus on patients’ beliefs and perceptions about their disease and inhaler satisfaction, as well 
as patient and investigational center personnel questionnaires on system usability.
1.2.
Findings from Nonclinical and Clinical Studies
Brief summaries of the clinical studies are provided in this section. 
Bronchospasm Associated with Asthma: In two 12-week, randomized, double-blind, 
placebo-controlled studies of identical design (Study 1 and Study 2), albuterol sulfate MDPI 
(153 patients) was compared to a matched placebo dry powder inhaler (163 patients) in asthmatic 
patients 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 albuterol sulfate MDPI 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. 
Consistent results were observed in Study 2. In a double-blind, randomized, placebo-controlled, 
single-dose, crossover study evaluating albuterol sulfate MDPI and PROAIR® HFA1 in 71 adult 
and adolescent patients 12 years of age and older with persistent asthma, albuterol sulfate MDPI 
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 albuterol sulfate 
MDPI 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 
                                                
1 PROAIR® HFA is a registered trademark of Teva Respiratory, LLC.
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Parallel-group, Controlled Study - Asthma
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38) of patients as compared to 42% (16 of 38) of patients when they received placebo. Patients 
who participated in these clinical studies were allowed to use concomitant steroid therapy.
More detailed information is provided in the IB.
Clinical Safety: A total of 1289 subjects were treated with albuterol sulfate MDPI 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 albuterol sulfate MDPI 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.
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(s)
This open-label study is being undertaken to evaluate whether outcomes for patients using the 
Albuterol eMDPI DS can be optimized better than a CC group who will be treated with their 
standard of care albuterol-administering rescue inhalers and will not use the DS during the 
treatment period. In addition to assessing the technical reliability experienced by patients using 
the Albuterol eMDPI DS, the study also uses 2 patient questionnaires, the Beliefs about 
Medicines Questionnaire (BMQ) and the Brief Illness Perception Questionnaire (BIPQ) for all 
patients, 18 years of age or older, in both groups, as well as the System Usability Scale (SUS) for 
patients, 18 years of age or older, in the DS group and investigational center personnel to 
complete. 
Albuterol eMDPI is a rescue/reliever agent that includes an eModule on top of the approved 
PROAIR RESPICLICK inhaler. The Albuterol eMDPI DS consists of the Albuterol eMDPI, the 
App, the Cloud solution, and the dashboard. The Albuterol eMDPI can be used with or without 
the additional devices (App, Cloud solution, and dashboard) that are being evaluated in this 
study. The on-board electronics and power source in the eMDPI are fully integrated into the 
inhaler and are designed to operate for the life of the inhaler without intervention. The eModule 
records timestamped pre-defined events. The inclusion of the eModule has been shown to have 
no impact on the dose delivery compared with the approved product without the eModule 
(performance and functional testing on file at Teva). Additional information regarding benefits 
and risks of Albuterol eMDPI to patients may be found in the IB.
In summary, the benefit and risk assessment for Albuterol eMDPI is favorable following review 
of the outlined data.
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2.
STUDY OBJECTIVES AND ENDPOINTS
2.1.
Primary and Secondary Study Objectives and Endpoints
The primary and secondary study objectives and endpoints are:
Objectives
Endpoints
The primary objective of 
this study is to demonstrate 
the effectiveness of the DS 
compared to a CC group. 
The primary endpoint is the proportion of patients for the DS 
and CC groups achieving meaningful improvement, which is 
defined as an Asthma Control Test (ACT) score greater than or 
equal to 20 at the end of the 12-week treatment period or an 
increase of at least 3 units on the ACT score from baseline at 
the end of the 12-week treatment period. 
The secondary objective 
(#1) is to describe the 
asthma management actions 
by iHCPs for all patients in 
both groups.
This secondary endpoint is the frequency and types of 
interventions done to improve asthma control including:
!
number of discussions between patient and iHCP 
regarding inhaler technique or adherence
!
number of adjustments of therapy including:
o
increased or decreased doses of inhaled 
medication
o
change to different inhaled medication
o
additional inhaled medication
o
addition of a systemic corticosteroid medication 
for asthma or another controller, including a 
long-acting muscarinic antagonist (LAMA) or 
biologics
!
frequency of intervention to manage comorbid 
conditions associated with poor asthma control 
(gastroesophageal reflux disease [GERD], sinusitis, 
etc.)
The secondary objective 
(#2) is to evaluate SABA 
usage and the number of 
SABA-free days in the DS 
group.
This secondary endpoint is the change from baseline in the 
mean weekly SABA usage and the change from baseline in the 
number of SABA-free days over the 12-week treatment period 
for the DS group.
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Objectives
Endpoints
The secondary objective 
(#3) is to assess the usability 
and acceptability of the DS 
by patients in the DS group 
and the investigational 
center personnel.
This secondary endpoint is the assessment of the DS (eMDPI, 
App and dashboard) acceptability and usability, utilizing the 
SUS, completed by the patients in the DS group, 18 years of 
age or older, and the investigational center personnel at the end 
of the study.
The secondary objective 
(#4) is to assess behavioral 
correlates of responsiveness 
to digital health technology 
among patients for all 
patients in both groups.
This secondary endpoint is the assessment of patients’ beliefs 
and perceptions about their disease and treatment, utilizing the 
BMQ and the BIPQ to both the DS and CC groups, patients 18 
years of age or older, describing their behavioral profile at 
baseline and at the end of the study.
The secondary objective 
(#5) is to evaluate the safety 
of Albuterol eMDPI.
This secondary endpoint is the reporting of adverse events 
related to Albuterol eMDPI at participating investigational 
centers.
The safety endpoints for this study include the following for all 
patients in both groups:
!
adverse event data
!
adverse device effect data
Notes: The Digital System (DS) group will include eligible study population patients who will use the DS (eMDPI, 
App, DHP [Cloud solution], and dashboard) during the treatment period. The concurrent control (CC) group will 
include eligible patients who will be treated with their standard of care albuterol-administering rescue inhalers and 
will not use the DS during the treatment period. 
2.1.1.
Justification of Primary Endpoint
Current asthma guidelines emphasize that asthma symptom control is a key therapeutic goal and 
recommend assessments of asthma control as a guide to step therapy. The ACT has been 
recommended by the National Institute of Health (NIH) as useful objective scoring system to 
measure asthma symptom control as a measure of core outcomes for both clinical trials and 
observational studies (Cloutier et al 2012). ACT scores indicating poorer symptom control have 
been associated with higher risk of asthma exacerbations as well as asthma related health care 
resource utilization (Ko et al 2012). In general, an ACT score of greater than 20 indicates well-
controlled asthma (Nathan et al 2004) and the minimally important difference (MID) that 
represents a clinically significant change in ACT has been demonstrated to be 3 units (Schatz et 
al 2009).
2.2.
Exploratory Objectives and Endpoints
Exploratory objectives and endpoints are as follows:
 
 
 
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3.
STUDY DESIGN
3.1.
General Study Design and Study Schematic Diagram
This is a 12-week treatment, multicenter, open-label, randomized, parallel group comparison 
feasibility study to evaluate the effectiveness of the Albuterol eMDPI DS, including inhaler, 
App, DHP (Cloud solution), and dashboard, to optimize outcomes in patients at least 13 years of 
age or older with asthma.
The study will consist of a screening/baseline visit (Visit 1), a 12-week open-label treatment 
period with Visit 2, and a follow-up telephone call (2 weeks following treatment completion).
Patients with suboptimal asthma control will be enrolled in the study and randomized in a 1:1 
ratio to 1 of 2 parallel groups stratified by investigational center: DS group patients utilizing the 
Albuterol eMDPI DS, including inhaler, App, DHP (Cloud solution), and dashboard, and CC 
group patients who will be treated with their standard of care albuterol-administering rescue 
inhalers and will not use the DS during the treatment period. Similar data will be collected 
regarding outcomes for the CC group: ACT after 12 to 14 weeks, BMQ and BIPQ responses, and 
the frequency of CAEs. 
All patients will have a screening/baseline visit (Visit 1), at which they will be asked if they use 
a smart device and use different applications on their smart devices. A baseline ACT score for all 
patients, and BMQ and BIPQ responses for patients 18 years of age or older, will be collected. 
Once randomized, patients in the DS group will be trained on the use of the Albuterol eMDPI DS 
(including instructions on how to use both the eMDPI and the App) and, upon demonstrating 
competency, will receive 2 Albuterol eMDPI devices for use as rescue bronchodilators to replace 
their rescue treatment during the study. Additional Albuterol eMDPI devices may be supplied 
during the treatment period, based on patients’ needs. Patients in the CC group will be 
reimbursed or given a voucher to use to purchase their existing rescue medications. 
Investigational centers will also receive similar instruction regarding features of the App, as well 
as features of the associated dashboard, which mirrors the digital information obtained from the 
eMDPI and App, including frequency and times of SABA rescue use and associated inspiratory 
flow parameters measured by the eMDPI with each inhalation.
The CC group will be followed according to the clinical judgment of the investigator; the asthma 
of patients in the CC group will be managed in a manner consistent with the clinical judgement 
of the investigator and based on asthma management guidelines (eg, GINA). Similar to the 
management of the CC group, the DS group patients will be followed by the investigational 
centers with the addition of objective information on Albuterol eMDPI usage being available to 
both patients and investigational centers through the App and the dashboard, respectively. The 
iHCPs will check the dashboard at least once a week and use this information, as per their 
clinical judgment, to modify patients’ asthma management. Clinically Driven Assessments for 
both groups, if necessary, should be arranged per the clinical judgement of the iHCP managing 
the patient and can be via a telephone call or an on-site visit.
For all patients, at Visit 2 and at each Clinically Driven Assessment, if necessary, the iHCP will 
record answers to Asthma Management questions, including discussions regarding adherence, or 
inhaler technique, treatment adjustments, or additions of new treatments, including biologic 
medication usage. Additionally, in the case of a Clinically Driven Assessment (for patients in the 
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DS group), the iHCP will be asked whether or not the contact with the patient was originated 
from the iHCP interaction with the dashboard. 
At the end of the treatment period (12 weeks), final assessments of the DS and CC group patients 
will be made, as specified in Table 3. A follow-up telephone call will be made by the 
investigational center to all patients, 2 weeks later, and will confirm the DS group patients have 
returned to previous asthma treatments.
It should also be noted that no specific clinical decisions are being mandated. One secondary 
objective of this study is to describe how clinicians actually use the information provided by the 
DS to manage their patients.
Figure 2:
Overall Study Schematic Diagram
ACT=Asthma Control Test; ADEs=adverse device effects; AEs=adverse events; Albuterol eMDPI=albuterol sulfate 
electronic multidose dry powder inhaler; BIPQ=Brief Illness Perception Questionnaire; BMQ= Beliefs about 
Medicines Questionnaire; CC=concurrent control; DS=Digital System; iHCPs=investigational center health care 
providers; SUS=System Usability Scale.
Note: The BIPQ, BMQ, and SUS questionnaire will be completed by patients 18 years of age or older.
3.2.
Planned Number of Patients and Countries
A total of 330 patients will be enrolled in the study (accounting for 10% early dropouts) and the 
total number of evaluable patients is planned to be 300 (150 in each group). Details on definition 
of evaluable patients and sample size are given in Section 9.1.
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The study is planned to be conducted in the US in approximately 30 investigational centers. The 
study is expected to start in Q4 2020 and last until approximately Q4 2021.
3.3.
Justification for Study Design and Selection of Population
Sample size estimates are based upon the assumption that the absolute differences between the 
DS and CC groups and the associated operational characteristics will be similar to the absolute 
differences and operational characteristics of the DS and CC groups noted in the sample size 
rationale for the study design.
The population for the study was chosen based on level of asthma control, as the objective of the 
study is to assess potential improvement in asthma control with the Albuterol eMDPI DS.
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 (Section 7.1.5) as they are reported from the 
investigational centers to identify safety concerns.
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 the following:
!
new toxicological or pharmacological findings or safety issues invalidate the earlier 
positive benefit-risk assessment
!
discontinuation of the development of the IMP or device
If the whole study is stopped, patients who 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 3. Detailed 
descriptions of each method of procedures and assessments are provided in Section 6 (efficacy 
assessments) and Section 7 (safety assessments). Study procedures and assessments by visit are 
listed in Appendix B.
Table 3:
Study Procedures and Assessments
Study period
Screening/
Baseline 
visit
Treatment period 
(12 weeks)
Follow-up 
telephone 
calla
Clinically 
Driven 
Assessment(s)
(if necessary)
Unscheduled 
IMP dispensing 
visit
End of 
Treatment/Early 
Termination visit
Visit number
Visit 1
Visit 2
Day and allowed time 
windows
Day 1b
Day 84 + 7 days
Day 98 + 7 
days
Procedures and assessments
Informed consent/assent
X
Inclusion and exclusion criteria
X
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Study period
Screening/
Baseline 
visit
Treatment period 
(12 weeks)
Follow-up 
telephone 
calla
Clinically 
Driven 
Assessment(s)
(if necessary)
Unscheduled 
IMP dispensing 
visit
End of 
Treatment/Early 
Termination visit
Visit number
Visit 1
Visit 2
Day and allowed time 
windows
Day 1b
Day 84 + 7 days
Day 98 + 7 
days
Procedures and assessments
Medical history
X
Current medication and 
treatment history related to 
asthma
X
Inform patients of study 
restrictions and compliance 
requirements
X
ACT scorec
X
X
BMQ and BIPQc
X
X
Assign patient number and 
provide unique email account 
for DS group patients
X
Train and Dispense Test IMP to 
DS groupd
X
Xe
X
Registration and Onboarding 
(App)
X
Adverse events and adverse 
device effects inquiry
X
X
X
X
X
Vital signs measurement
X
X
iHCP will ask Asthma 
Management questions 
regarding adherence, inhaler 
technique, treatment 
adjustments, and biologic 
medication usage
X
X
Administer post-intervention 
PRO questionnaire (SUS) to DS 
group patients and 
investigational center personnelf
X
Concomitant medication inquiry
X
X
X
X
X
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Table 3:
Study Procedures and Assessments (Continued)
Study period
Screening/
Baseline 
visit
Treatment period 
(12 weeks)
Follow-up 
telephone 
calla
Clinically 
Driven 
Assessment(s)
(if necessary)
Unscheduled 
IMP 
dispensing 
visit
End of 
Treatment/Early 
Termination visit
Visit number
Visit 1b
Visit 2
Day and allowed time 
windows
Day 1
Day 84 + 7 days
Day 98 + 7 
days
Procedures and assessments
Test IMP collection and 
accountability
X
X
Remove App from the patient’s
smart device
X
Confirmation that patient has 
returned to previous asthma 
treatment
Xg
a End of study is defined as the follow-up telephone call for the last patient.
b Screening and enrollment are expected to occur on the same day. The maximum allowable duration between screening and 
enrollment is 7 days.
c ACT is to be completed first by all patients, followed by the BMQ, and then the BIPQ (both by patients 18 years of age or 
older).
d Patients will be provided the Test IMP, along with training on use and proper technique, by the investigational centers.
e If on-site and necessary.
f The SUS should be the last questionnaire provided to patients, 18 years of age or older, at the end of treatment visit or at the 
Early Termination (ET) visit. Each investigational center will receive 1 SUS questionnaire to complete following the last 
patient visit at the investigational center.
g The follow-up telephone call will be made to all patients, including those who end the study prematurely (except patients who 
withdraw consent). If a patient in the DS group ends the study prematurely, in addition to following up on ongoing AEs and 
concomitant medications, the investigational center will also confirm that the patient has returned to their previous asthma 
treatment. 
ACT=Asthma Control Test; App=smart device application; BIPQ=Brief Illness Perception Questionnaire; BMQ=Beliefs about 
Medicines Questionnaire; DS=digital system; ET=early termination; iHCP=investigational center health care provider; 
IMP=investigational medicinal product; PRO=patient-reported outcome; SUS=System Usability Scale. 
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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).
Changes to inclusion or exclusion criteria are detailed in Section 16.
4.1.
Patient Inclusion Criteria
Patients may be randomized/enrolled in this study only if they meet all of the following criteria:
a.
The patient is 13 years or older at the time of screening.
b. The patient has a documented diagnosis of asthma established at the investigational 
center at the time of informed consent or the investigator confirms a diagnosis of 
asthma.
c.
The patient is currently on treatment with an ICS with a long-acting beta2 agonist 
(LABA).
d. The patient has an ACT score of less than 19 at the screening or baseline visit.
e.
The patient is currently using inhaled albuterol sulfate as rescue medication and is 
willing to discontinue all other rescue medications and replace them with the study-
provided Albuterol eMDPI.
f.
[Revision 1] The patient can read and communicate in English and is familiar with 
and is willing to use his/her own smart device that meets the minimum App 
requirements and download and use the App.
g. The patient is able to provide written informed consent.
h. The patient must be willing and able to comply with study requirements and 
restrictions and to remain at the investigational center for the required duration during 
the study period, and willing to return to the investigational center for the follow-up 
procedures and assessments as specified in this protocol.
4.2.
Patient Exclusion Criteria
Patients will not be randomized/enrolled in this study if they meet any of the following criteria:
a.
The patient has any clinically significant uncontrolled medical condition (treated or 
untreated) other than asthma, which in the view of the investigator would preclude 
participation.
b. The patient was hospitalized for severe asthma in the last 30 days.
c.
The patient has any medical or psychiatric condition that, in the opinion of the 
investigator, could jeopardize or would compromise the patient’s ability to participate 
in this study.
d. The patient has a diagnosis of Chronic Obstructive Pulmonary Disease (COPD) or 
Asthma-COPD Overlap (ACO).
e.
The patient is a current smoker or has a greater than 10 pack-year history of smoking.
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f.
The patient is currently being treated with systemic corticosteroids (oral, 
intramuscular, or intravenous) or has been treated within the last 30 days. 
g. [Revision 1] The patient has any treatment with biologics for asthma (eg, 
omalizumab, anti-interleukin (IL) 5, anti-IL5R, anti-IL4R), or has had such treatment 
within the last 90 days. (However, during the study, patients can be escalated to 
therapy with such agents if clinically indicated in the judgment of the investigator as 
part of their asthma management and remain in the study.)
h. The patient has a known hypersensitivity to any components of the IMPs stated in this 
protocol. 
i.
[New criterion] The patient has previously participated in a Digihaler study or is 
currently being treated prior to enrollment with a digital inhaler system, including the 
Digihaler system or an external “bolt on” digital system designed to monitor inhaler 
usage, such as the Propeller Health or Adherium systems.
4.3.
Withdrawal Criteria and Procedures for the Patient
Each patient is free to withdraw from the study or discontinue from IMP or using the devices at 
any time, without prejudice to their continued care. Patient must be withdrawn from the study if 
any of the following events occur:
1. Patient withdraws consent or requests discontinuation from the IMP or withdrawal from 
the study for any reason.
2. Patient develops an illness that would interfere with his/her continued participation.
3. Patient is noncompliant with the study procedures and assessments or administration of 
Albuterol eMDPI, in the opinion of the investigator.
4. Patient takes prohibited concomitant medications as defined in this protocol (ie, other 
SABA products). 
5. The sponsor requests withdrawal of the patient.
6. Patient experiences an adverse event or other medical condition which 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 from the 
study or discontinuation from IMP. Results of any evaluations and observations, together with a 
narrative describing the reason(s) for withdrawal from the study or discontinuation from IMP, 
must be recorded in the source documents. The case report form (CRF) must document the 
primary reason for withdrawal from the study or discontinuation from IMP.
See Appendix E 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 from the study or discontinuation from IMP is an adverse event 
and/or adverse device effect, 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 
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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; the adverse events page and/or adverse device effect page and 
the termination page of the CRF will be completed at that time. The investigator must inform the 
contract research organization (CRO) as soon as possible of each patient who is being considered 
for withdrawal due to adverse events. Additional reports must be provided when requested.
If a patient is withdrawn from the study or discontinues IMP for multiple reasons that include 
adverse events, the relevant page of the CRF should indicate that the withdrawal was related to 
an adverse event. An exception to this requirement will be the occurrence of an adverse event 
that in the opinion of the investigator is not severe enough to warrant discontinuation but that 
requires the use of a prohibited medication, thereby requiring discontinuation of the patient. In 
such a case, the reason for discontinuation would be “need to take a prohibited medication,” not 
the adverse event.
In the case of patients lost to follow-up, attempts to contact the patient must be made and 
documented in the patient’s medical records and transcribed to the CRF.
All assessments should be performed according to the protocol for the end of treatment visit or 
upon early termination if possible. Patients are required to return the Albuterol eMDPI (used and 
unused) upon withdrawal from the study.
4.4.
Replacement of Patients
A patient who is enrolled but does not complete the treatment period will not be replaced.
4.5.
Rescreening
A patient who is screened but not enrolled within 7 days of screening, because he/she did not 
satisfy inclusion/exclusion criteria or enrollment did not occur within the specified time, may be 
considered for rescreening once if, for example, there is a change in the patient’s medical 
background or a modification of study inclusion and exclusion criteria.
Patients may have individual parameters retested at the discretion of both the investigator and the 
sponsor.
If the patient is rescreened, the informed consent form (ICF) will need to be re-signed.
4.6.
Screening Failure
Screening failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study. 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
The Teva eMDPI Digital System consists of 4 devices. Device 1 is the Albuterol eMDPI, which 
is the test IMP. The 3 investigational medical devices are the following:
Device 2: Patient-facing App
Device 3: DHP (Cloud solution) 
Device 4: Provider-facing dashboard
At Visit 1, patients in the DS group will be trained on the use of the Albuterol eMDPI DS 
(including instructions on how to use both the eMDPI and the App) and, upon demonstrating 
competency, will receive 2 Albuterol eMDPI devices for use as rescue bronchodilators to replace 
their rescue treatment during the study. Additional Albuterol eMDPI devices may be supplied 
during the treatment period, based on patients’ needs. Patients will be instructed to return all 
inhalers to the investigational center at the end of treatment visit or at early termination. 
5.1.1.
Test Investigational Medicinal Product
Albuterol eMDPI (marketed in the US as PROAIR DIGIHALER) is an inhalation-driven eMDPI 
containing a blend of albuterol sulfate 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. 
Teva has developed the eModule as part of a system to assist a patient with asthma to 
appropriately use the eMDPI inhaler. The system is described in more practical terms as an 
inhaler with an integrated data logger capable of storing and transmitting timestamped data to 
support the data logging functionality.
The on-board electronics and power source are fully integrated into the eMDPI and are designed 
to operate for the life of the inhaler without intervention, ie, the battery does not require 
replacement or recharging. 
The addition of the required electronics has no impact on the pharmaceutical performance of the 
inhaler or on the required user steps to take a dose. A schematic of the inhaler with the additional 
eModule is shown in Figure 3.
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Figure 3:
Current Inhaler (Left) Versus Inhaler with Additional Electronics Module 
(Right)
Additional details may be found in Table 4 and in the IB.
The information from the eModule may be transmitted wirelessly (Bluetooth Low Energy) to an 
App. From the App, data may be transmitted to the DHP, which consists of a Cloud solution, and 
then to a dashboard. This allows the patient and/or the caregiver to track when and how well the 
inhaler was used.
By consenting to enroll in the study, the patient must also download the smart device App (with 
the assistance of investigational center personnel), accept the smart device App’s Privacy Notice 
and Terms of Use, and also agree to share his/her data to a provider-facing dashboard utilized by 
the iHCP and investigational center study team. An ICF will be provided to the patients which 
will elaborate, among other ways, Teva’s ways of use and storing of patient data collected 
through the smart device App. The patient will be entering into a direct contractual relationship 
with Teva which will govern, among other things, Teva’s rights to use and store patient data 
collected through the smart device App. If the patient does not accept the smart device App’s 
Privacy Notice and Terms of Use and does not also agree to share their data to the provider-
facing dashboard utilized by the iHCP and investigational center study team, then the patient 
cannot enroll in the study. At the end of treatment/ET visit (Visit 2), investigational center 
personnel will remove the App from the patient’s smart device.
5.1.1.1.
Starting Dose and Dose Levels
The prescribed dose will be 90 mcg, 1 to 2 inhalations every 4 to 6 hours, as needed. No dose 
escalations are planned.
5.1.1.2.
Dose Modification and Dose Stratification
Not applicable.
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5.1.2.
Medical Devices
Instructions for medical device use are provided in the Study Pharmacy Manual.
5.1.2.1.
Application
The software App is a customer facing software/focused smart device application for patients 
using the Albuterol eMDPI Inhalation Powder combination product. The intention of the smart 
device App is to engage patients with asthma and/or COPD (and their caregivers) by tracking 
medication usage, raising awareness of medication use patterns, allowing users to self-assess 
their respiratory symptoms on a daily basis, sharing information on local environmental 
conditions, and producing user reports to review their data over time.
The software consists of a smart device application compatible for iPhone operating systems 
(iOS) and Android operating systems that will store data locally on the patient’s smart device. 
The App will receive a patient’s inhaler use/event data automatically from the inhaler devices via 
Bluetooth on a smart device. The smart device camera will be used for scanning and pairing. 
This data will allow the patient to track their usage of medication, inhalation results, and self-
assessments related to their asthma and/or COPD. The App gets environment information for the 
specific location of the patient.
5.1.2.2.
Teva Digital Health Platform (Cloud Solution)
The Teva DHP is a system that stores and transfers inhaler use/event data collected from the 
App. The Cloud solution automatically synchronizes with the App after events and/or at 
predetermined time periods/intervals. An internet connection to the smart device (eg, wireless or 
cellular phone network) is required in order for communication to be established between the 
App and the Cloud solution. The Cloud solution will not send any notifications to the App. The 
Cloud solution does not create, modify, or delete patient information.
Patient privacy will be maintained according to the laws and regulations, and patient identifiers 
will be substituted to maintain a patient’s privacy to reviewers of the data.
5.1.2.3.
Dashboard
The DHP may be used to provide patient-specific data to the iHCP via the dashboard, a secure 
web interface. The data available on the dashboard are the inhaler use data and patient 
self-assessments from the App. The patient has no interaction with the dashboard. Teva 
personnel will have no access to the dashboard.
5.1.3.
Reference Investigational Medicinal Product or Device
Not applicable.
5.1.4.
Placebo Investigational Medicinal Product or Device
Not applicable.
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Table 4:
Investigational Medicinal Products Used in the Study
IMP name
Test IMP
Placebo IMP
Reference IMP
Trade name 
Albuterol eMDPI
None
None
Formulation
Oral inhalation powder
NA
NA
Unit dose strength
117 mcg of albuterol sulfate (equivalent to 97 mcg of 
albuterol base) from the device reservoir to provide a 
delivered dose of 108 mcg of albuterol sulfate 
(equivalent to 90 mcg of albuterol base)
NA
NA
Route of 
administration
Oral inhalation
NA
NA
Dosing instructions
1 to 2 oral inhalations every 4 to 6 hours, as needed
NA
NA
Packaging
NA
NA
NA
Manufacturer
Teva Pharmaceutical Industries, Ltd. Jerusalem, Israel, 
or Teva Pharmaceuticals Ireland, Waterford, Ireland
NA
NA
eMDPI=multidose dry powder inhaler with integrated electronic module; IMP=investigational medicinal product; 
NA=not applicable.
5.2.
Preparation, Handling, Labeling, Storage, and Accountability for 
IMPs
5.2.1.
Storage and Security
The investigator or designee must confirm that appropriate temperature conditions have been 
maintained for all IMP received, and any discrepancies are reported and resolved before use of 
the IMP.
The IMP must be stored at room temperature (15°C to 25°C [59°F to 77°F]) and not exposed to 
extreme heat, cold, or humidity. The investigational center personnel are responsible for 
acknowledging receipt of the IMP using a Randomization and Trial Supply Management
(RTSM) system.
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 and any 
applicable forms.
The investigator is responsible for ensuring that deliveries of IMP 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 national and local regulations, and used in 
accordance with this protocol.
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Only patients enrolled in the study may receive IMP, and only authorized personnel at the 
investigational center may supply or administer IMP. All IMP must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions or appropriate instructions with access limited to the investigator and 
authorized personnel at the investigational center. 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 end of treatment (Visit 2) or at the ET 
visit.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IMP accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). Patients will return all inhalers at the end of the 
study to the investigational center for reconciliation.
A record of IMP accountability (ie, IMP and other study materials received, used, retained, and 
returned) must be prepared and signed by the principal investigator or designee, with an account 
given for any discrepancies. All empty, partially used, and unused inhalers will be collected at 
the end of the study and will be returned to the sponsor or designee per sponsor instructions.
Further guidance and information are provided in the Study Pharmacy Manual.
5.3.
Justification for Investigational Medicinal Product
5.3.1.
Justification for Dose of Test Investigational Medicinal Product
The prescribed dose of Albuterol eMDPI (now US FDA approved as PROAIR DIGIHALER) 
used in this study (ie, 90 mcg, 1 to 2 inhalations every 4 to 6 hours, as needed) was selected 
based on the prescribing information for PROAIR DIGIHALER.
PROAIR DIGIHALER 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 EIB. For the relief 
of acute asthma symptoms, PROAIR DIGIHALER is recommended at a dosage of 2 inhalations 
(ie, 180 mcg of albuterol base ex-mouthpiece) repeated every 4 to 6 hours, as needed. 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 
DIGIHALER 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 DIGIHALER 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 are advised to consult 
with their primary physician for treatment.
5.5.
Restrictions
There are no additional restrictions beyond the inclusion and exclusion criteria in this study and 
the prohibited medication noted in Section 5.6.
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5.6.
Prior and Concomitant Medication or Therapy
Any concomitant medication a patient is taking at screening and up to the final visit will be 
recorded on the CRF. Trade name and international nonproprietary 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 (WHO) drug 
dictionary (WHO Drug).
The use of other SABA products, by the DS group, is prohibited during this study except for the 
use of nebulized albuterol, as needed, in the ED for an acute exacerbation of asthma. 
At the end of treatment visit (Visit 2), 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 the final visit.
5.7.
Procedures for Monitoring Patient Compliance
Since the IMP is a rescue medication, it will be used on an “as needed” basis. The investigator 
will be responsible for dispensing IMP, training patients on the correct use of IMP, return of 
IMP, 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 patients will be randomly assigned to the DS group or CC group 
in a 1:1 ratio stratified by investigational center, using a RTSM system. Since this an open-label 
study, blinding is not applicable.
5.9.
Data Monitoring Committee
There will be no Data Monitoring Committee for this study.
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6.
ASSESSMENT OF EFFICACY
The efficacy of the drug product will not be evaluated in this study. The focus of this study is the 
engagement of the patient with the Albuterol eMDPI DS.
6.1.
Assessments of Patient-Reported Outcomes
6.1.1.
Asthma Control Test
The ACT is a simple, patient-completed tool used for the assessment of overall asthma control. 
The 5 items included in the ACT assess daytime and nighttime asthma symptoms, use of rescue 
medication, and impact of asthma on daily functioning. Each item in the ACT is scored on a 
5-point scale, with summation of all items providing scores ranging from 5 to 25. The scores 
span the continuum of poor control of asthma (score of 5) to complete control of asthma (score 
of 25), with a cutoff score of 19 and below indicating patients with poorly controlled asthma 
(Schatz et al 2006). 
The ACT should be the first questionnaire completed by all patients during a study visit (the 
second should be the BMQ, and the third the BIPQ (both by patients 18 years of age or older), 
and should precede any discussion between the patient and investigational center personnel. The 
self-administered version of the ACT will be answered by the patients at the investigational 
center at Visit 1, Visit 2, or at the Early Termination (ET) visit. The investigators and personnel 
will be provided with detailed instructions for administering the ACT in order to achieve 
maximum compliance in a clinical study environment and maximum data quality. Caregivers or 
investigational center personnel will not be allowed to interfere or communicate with the patient 
completing the questionnaire beyond restating the question(s) on the questionnaire exactly as 
they have been written. After completion of the ACT, investigational center personnel will check 
the questionnaires for completeness and legibility. Detailed instructions for administering, 
scoring, and analyzing the ACT are provided in the Statistical Analysis Plan.
6.1.2.
Beliefs about Medicines Questionnaire
The BMQ is used to assess cognitive representations of medicine (Horne, Weinman, and 
Hankins 1999). The BMQ-Specific (BMQ-S11) is an 11-item questionnaire that assesses 
representation of medication prescribed for personal use and the BMQ-General assesses beliefs 
about medicines in general. For the purposes of this study, the BMQ-S11 will be completed by 
patients, 18 years of age or older, at the investigational center at Visit 1, Visit 2, or at the ET 
visit. The BMQ should be the second questionnaire completed during a study visit following the 
ACT.
6.1.3.
Brief Illness Perception Questionnaire
The BIPQ is a 9-item questionnaire designed to rapidly assess cognitive and emotional 
representations of illness (Broadbent et al 2006). The BIPQ uses a single-item scale approach to 
assess perception on a 0-10 response scale. It is developed by forming one question that best 
summarizes the items contained in each subscale of the Illness Perception Questionnaire-Revised 
which has over 80 items. The BIPQ comprises 5 items on cognitive representation of illness 
perception: consequences, timeline, personal control, treatment control, and identity. There are 2 
items on emotional representation: concern and emotions; one item is on illness 
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comprehensibility. The last item is on perceived cause of illness, in which respondents list the 3 
most important causal factors in their illness. For this questionnaire, the general word 'illness' can 
be replaced by the name of a particular illness such as asthma. The word 'treatment' in the 
treatment control item can be replaced by a particular treatment such as 'surgery' or 
'physiotherapy' (Broadbent et al 2006). The discriminant validity of the questionnaire is 
supported by its ability to distinguish between different illnesses, namely asthma, diabetes, colds, 
myocardial infarct prior to discharge, and pre-diagnosis chest pain patients waiting stress 
exercise testing. The BIPQ will be answered by the patients, 18 years of age or older, at the 
investigational center at Visit 1, Visit 2, or at the ET visit. The BIPQ should be the third 
questionnaire completed during a study visit following the BMQ.
6.1.4.
System Usability Questionnaire
The SUS will be used to explore device acceptability and usability for patients in the DS group. 
It is a 10-question tool that provides a composite measure of the overall usability of the system 
being studied. It has been used extensively across many industries, patient types, and 
technologies, and has been used in studies of patients with asthma and COPD (Brooke 1996). 
The SUS will be answered by patients in the DS group, 18 years of age or older, at Visit 2, or at 
the ET visit. The SUS will be completed after all other questionnaires. 
An SUS regarding the use of the dashboard will be completed by investigational center personnel 
at the end of the study.
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7.
ASSESSMENT OF SAFETY
In this study, safety will be assessed by qualified study personnel by evaluating reported adverse 
events, adverse device effects, vital signs measurements, and use of concomitant medications.
Adverse events are categorized by ICH guidelines, and adverse device effects are categorized 
and classified according to International Organization for Standardization (ISO) standard 
14155:2011(E).
Device deficiencies that are not associated with an adverse event as well as those that have the 
potential to cause a serious adverse event are covered in Appendix F.
7.1.
Adverse Events
7.1.1.
Definition of an Adverse Event
An adverse event is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory findings) in patients or clinical investigation 
subjects, users or other persons, whether or not related (causal relationship) to 
the pharmaceutical product (treatment), investigational medical device, or comparator. This 
definition includes events related to the procedures involved. For users or other persons, this 
definition is restricted to events related to investigational medical devices. 
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. A new condition 
or the worsening of a pre-existing condition will be considered an adverse event. Stable chronic 
conditions (such as arthritis) that are present before study entry and do not worsen during this
study will not be considered adverse events.
Accordingly, an adverse event can include any of the following:
!
intercurrent illnesses
!
physical injuries
!
events possibly related to concomitant medication
!
significant worsening (change in nature, severity, or frequency) of the disease under 
study or other pre-existing conditions
!
drug/drug, drug/device, or device/device interactions
!
events occurring during diagnostic procedures of this study
Worsening of asthma that occurs during the study that is not typical of the patient’s daily 
symptoms or leads to the patient’s discontinuation will be considered an adverse event. 
A CAE will be defined by 1 of the following: 1) in-patient hospitalization because of asthma, 
2) emergency treatment because of asthma, 3) a worsening of asthma symptoms leading to the 
use of prednisone or systemic corticosteroids for 3 days or more, or 4) a reduction in FEV1 of 
20% or greater. Patients will be instructed to contact the study investigational center in the event 
of a CAE.
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All CAE events require documentation by the investigator in the CAE Page in the CRF, as well 
as in the adverse event CRF. All evaluations entered into the CAE Page require the 
investigational center to obtain source documentation of all CAEs that occur during the treatment 
period to confirm the accuracy of the information obtained from the patient. Any CAE that meets 
serious adverse event criteria will be reported as a serious adverse event (Section 7.1.5.1).
7.1.2.
Recording and Reporting of Adverse Events
For recording of an adverse event, the study period is defined for each patient as the time period 
from signature of the ICF to the end of the follow-up period (end of study [follow-up telephone 
call]). The period for reporting treatment-emergent adverse events is defined as the period after 
the first dose of IMP is administered and until the end of the follow-up period. 
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 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.
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 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 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.
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7.1.3.
Severity of an Adverse Event
The severity of each adverse event must be recorded as 1 of the following:
Mild:
No limitation of usual activities
Moderate: Some limitation of usual activities
Severe:
Inability to carry out usual activities
7.1.4.
Relationship of an Adverse Event to the Investigational Medicinal Product
The relationship of an adverse event to the IMP is characterized as follows (Table 5):
Table 5:
The Relationship of an Adverse Event to the Investigational Medicinal 
Product
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.
IMP=investigational medicinal product.
7.1.5.
Serious Adverse Events
For recording of a serious adverse event, the study period is defined for each patient as that time 
period from signature of the ICF to the end of the follow-up period. Serious adverse events 
occurring in a patient after the end of the follow-up period should be reported to the sponsor if 
the investigator becomes aware of them, following the procedures described in Section 7.1.5.3.1.
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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 a life-threatening adverse event (ie, the patient was at risk of death at the time of 
the event); it does not refer to an event which hypothetically might have caused death 
if it were more severe
!
requires inpatient hospitalization or prolongation of existing hospitalization, which 
means that hospital inpatient admission or prolongation of hospital stay were required 
for treatment of an adverse event, or that they occurred as a consequence of the event
Hospitalizations scheduled before the patient signed the ICF will not be considered 
serious adverse events, unless there was worsening of the pre-existing condition 
during the patient’s participation in this study.
!
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 1 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 for this study is the IB.
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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 IMP, must be reported to the 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 
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 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
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!
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)
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 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/MedWatch form/Extensible Markup Language file to the LSO/CRO 
for submission to the competent authorities, Independent Ethics Committee/Institutional Review 
Board (IEC/IRB), 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 IMP or study procedures, 
the sponsor will take appropriate steps to notify all investigators participating in sponsored 
clinical studies of Albuterol 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 Albuterol eMDPI
7.1.6.
Protocol-Defined Adverse Events of Special Interest
No protocol-defined adverse events of special interest were identified for this study. 
7.1.7.
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 
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this protocol as soon as possible to discuss the situation. The investigator, in consultation with 
the sponsor, will decide whether the patient should continue to participate in the study.
7.2.
Adverse Device Effects
An adverse device effect is an adverse event related to the use of an investigational medical 
device or a combination product. This includes adverse events resulting from insufficient or 
inadequate instructions for use, deployment, implantation, installation, operation, or any 
malfunction of the investigational medical device, including any event resulting from user error 
or from intentional misuse of the investigational medical device.
7.2.1.
Adverse Device Effect Reporting
Adverse device effects (Figure 4) must be recorded on both the source documentation and the 
CRF. 
All adverse device effects shall be reviewed by the investigator, the medical monitor, and the 
sponsor. The investigator and sponsor will record all relevant information regarding every 
adverse device effect/serious adverse device effect and device deficiency and will categorize 
each as guided in Section 7.2.
The investigator should make an initial determination whether the adverse event may be related 
to a device deficiency. 
Adverse device effects and device deficiencies will be listed in the clinical study report (CSR).
7.2.2.
Serious Adverse Device Effects
A serious adverse device effect is an adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event (Section 7.1.5.1).
An unanticipated serious adverse device effect is a serious adverse device effect that, by its 
nature, incidence, severity, or outcome, has not been listed in Appendix F (Appendix Table 1 and 
Appendix Table 2).
7.2.2.1.
Serious Adverse Device Effect Reporting
The investigator will report to the sponsor, without unjustified delay, all serious adverse device 
effects (within 24 hours); this information shall be promptly followed by detailed written reports 
as described below.
The process and contact details for serious adverse device effect reporting are the same as for 
serious adverse event reporting provided in Section 7.1.5.3.
Events shall be reported to the IEC/IRB by the investigator and to the regulatory authorities by 
the sponsor using the appropriate form according to national and local regulations.
The investigator should use Appendix F (Appendix Table 1 and Appendix Table 2) to make an 
initial determination whether the serious adverse event may be related to a device deficiency.
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Figure 4:
Decision Tree for Adverse Events and Adverse Device Effects Classification
AE=adverse event; ADE=adverse device effect; CRF=case report form; IEC=Independent Ethics Committee; 
IRB=Institutional Review Board; SADE=serious adverse device effect; SAE=serious adverse event.
7.3.
Pregnancy
All pregnancies of women participating in the study, that occur during the study, or within at 
least 5 half-lives or 30 days for unknown 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 participating in the study 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.
Since there is no evidence of teratogenicity, genotoxicity, fetotoxicity, or spermatotoxicity for 
this IMP, female partners will not be required to sign an ICF to monitor the outcome of the 
pregnancy.
If the pregnancy in the woman participating in the study does not continue to term, 1 of the 
following actions will be taken:
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!
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.
7.4.
Medication Error and Special Situations Related to the 
Investigational Medicinal Product
Any administration of IMP that is not in accordance with the study protocol should be reported 
in the patient’s source documents (Appendix C), regardless of whether or not an adverse event 
occurs as a result.
The following are types of medication errors and special situations:
1. Medication error: Any unintentional error in the prescribing, dispensing, or 
administration of a medicinal product while in the control of the healthcare professional, 
patient, or consumer.
2. Overdose: Administration of a quantity of a medicinal product given per administration 
or cumulatively which is above the maximum recommended dose according to the 
authorized product information. Clinical judgment should always be applied. Any dose of 
IMP (whether the test IMP or reference 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. Occupational exposure: Exposure to an IMP as a result of one’s professional or 
nonprofessional occupation.
7.5.
Clinical Laboratory Tests
No clinical laboratory tests are scheduled to be performed during this study.
7.6.
Physical Examinations
No physical examinations are scheduled to be performed during this study.
7.7.
Vital Signs
Vital signs (blood pressure [systolic/diastolic], pulse rate, and respiratory rate) will be measured 
at the time points detailed in Table 3. All vital signs results outside of the reference ranges will 
be judged by the investigator as belonging to 1 of the following categories:
!
abnormal and not clinically significant
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!
abnormal and clinically significant
Before blood pressure and pulse are measured, the patient must rest in a seated position for at 
least 5 minutes. The same position and arm should be used each time vital signs are measured for 
a given patient. For any abnormal vital sign value, the measurement should be repeated as soon 
as possible. Any vital sign value that is judged by the investigator as clinically significant will be 
recorded both on the source documentation and the CRF as an adverse event, and monitored as 
described in Section 7.1.2.
In addition, potentially clinically significant values will be predefined by the sponsor for selected 
vital sign parameters and will be detailed in the Statistical Analysis Plan.
7.8.
Electrocardiography
No electrocardiogram measurements are scheduled to be performed during 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 in the CSR.
9.1.
Sample Size and Power Considerations
Sample size estimates are based upon the assumption that the absolute differences between the 
DS and CC groups and the associated operational characteristics will be similar to the absolute 
differences and operational characteristics of the DS and CC groups noted in the sample size 
rationale for the study design.
The recommended sample size for the study is 150 evaluable patients per group 
(30 investigational centers with each investigational center enrolling at least 10 patients), 
300 patients in total. Accounting for a dropout rate of 10%, this leads to a recommended total 
number of 330 enrolled patients.
With this sample size and assuming a true absolute difference in proportions (treatment effect as 
the estimated response rate for the CC group is 60% and for the DS group is 73%) between the 
groups of at least 13%, the probability that the posterior probability will be at least 95% is 0.77 
(power) (analogous to 1-sided p-value < 0.05) (Merchant et al 2016). Assuming no treatment 
effect (difference in proportions between the groups is 0%, ie, Type 1 error) then the probability 
is 0.05 that posterior probability will be at least 95% is 0.05.
It should be noted that both power and Type 1 error are dependent on the absolute difference
between the DS and the CC groups as illustrated in Figure 5 below by the operational 
characteristics calculated for the study design:
Figure 5:
Operational Characteristics Calculated for the Study Design
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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 randomized patients. In the intent-to-treat 
(ITT) analysis set, treatment will be assigned based on the treatment to which patients were 
randomized, regardless of which treatment they actually received. This analysis population will 
be used for summarization of patient disposition and demographic and baseline characteristics, 
as appropriate.
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 including only 
patients who receive at least 1 dose of IMP (IMP is albuterol eMDPI for the DS group and 
standard-of-care albuterol-administering rescue medication for the CC group) and at least 
1 postbaseline assessment on any of the study endpoints (primary, secondary, or exploratory). 
In the mITT analysis set, treatment will be assigned based on the treatment to which patients 
were randomized, regardless of which treatment they actually received. This analysis will be 
used for all primary, secondary, and exploratory endpoint analyses. 
9.2.3.
Safety Analysis Set
This analysis set will include all patients in the DS group who receive at least 1 dose of IMP and 
all patients in the CC group. In the safety analysis set, treatment will be assigned based on the 
treatment patients actually received, regardless of the treatment to which they were randomized, 
unless otherwise specified. This analysis set will be used for all safety analyses.
Additional analyses sets may be defined in the Statistical Analysis Plan, if appropriate.
9.3.
Data Handling Conventions
For all variables, only the observed data from the patients will be used in the statistical analyses, 
ie, there is no plan to estimate (impute) missing data, unless otherwise specified in the Statistical 
Analysis Plan. 
9.3.1.
Handling Withdrawals and Missing Data
For the primary endpoint, missing data will not be imputed, unless otherwise specified in the 
Statistical Analysis Plan.
9.4.
Study Population
The ITT Analysis Set (Section 9.2.1) will be used for all study population summaries noted 
below, unless otherwise specified. Summaries will be presented for all patients.
9.4.1.
Patient Disposition
Data from patients screened; patients screened but not randomized and reason for not being 
randomized; patients in the ITT analysis set; patients in the ITT analysis set who did not attempt 
to download the App; patients in the ITT analysis set who did not use the inhaler; patients in the 
mITT and safety analysis sets; patients who completed the study; and patients who withdrew 
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from the study and the reason for withdrawal will be summarized using descriptive summary 
statistics (number, %).
9.4.2.
Demographic and Baseline Characteristics
Patient demographic and baseline characteristics, including medical history, current medication 
at screening/baseline, and treatment history related to asthma, will be summarized using 
descriptive statistics. For continuous variables, descriptive statistics (number, mean, standard 
deviation, median, minimum, and maximum) will be provided. For categorical variables, patient 
counts and percentages will be provided. Categories for missing data will be presented if 
necessary. This will be based on the ITT analysis population.
9.5.
Analyses
9.5.1.
Primary Endpoint
The primary endpoint is the proportion of patients reaching well-controlled asthma as defined by 
an ACT score of greater than or equal to 20 or a clinically important improvement in asthma 
control as defined by an increase of at least 3 units on the ACT score from baseline at the end of 
the 12-week treatment period (responder analysis of DS versus CC group with responders 
defined by an ACT score of greater than or equal to 20 or an increase by greater than or equal to 
3 units on the ACT score).
9.5.2.
Secondary Endpoints
Secondary endpoint #1 is the frequency and types of interventions done to improve asthma 
control including:
!
number of discussions between patient and iHCP regarding inhaler technique or 
adherence
!
number of adjustments of therapy including:
o
increased or decreased doses of inhaled medication
o
change to different inhaled medication
o
additional inhaled medication
o
addition of a systemic corticosteroid medication for asthma or another controller, 
including a LAMA or biologics
!
frequency of intervention to manage comorbid conditions associated with poor asthma 
control GERD, sinusitis, etc.)
Secondary endpoint #2 is the change from baseline in the mean weekly SABA usage and the 
change from baseline in the number of SABA-free days over the 12-week treatment period for 
the DS group.
Secondary endpoint #3 is the assessment of the DS (eMDPI, App and dashboard) acceptability 
and usability, utilizing the SUS, completed by the patients in the DS group, 18 years of age or 
older, and investigational center personnel at the end of the study.
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Secondary endpoint #4 is the assessment of patients’ beliefs and perceptions about their disease 
and treatment, utilizing the BMQ and the BIPQ for both the DS and CC groups, patients 18 years 
of age or older, describing their behavioral profile at baseline and at the end of the study.
9.5.3.
Exploratory/Other Endpoints
The exploratory endpoints are:
 
 
 
 
 
9.5.4.
Planned Method of Analysis
9.5.4.1.
Primary Analysis
To analyze the primary variable, the following estimand framework will be used:
1. 1. Analysis will be performed on the mITT set. 
2. A binary distribution is assumed for the primary endpoint. Patients who discontinue early 
due to technology failure, disliking the digital platform, disease worsening, adverse 
experience or disliking the IMP will be counted as treatment failures For those who 
discontinue early not due to these reasons, the ACT value assessed at the ET visit will be 
used.
3. Summary measure: A successful differentiation between the 2 groups will be determined 
by a Bayesian posterior probability for  >0 greater than 0.95 (1-sided). The following 
statistical methods will be utilized:
Logistic regression model allowing for different response rates at enrolling investigational 
centers will be used for testing the hypothesis :  = 0, :  > 0 in the following model:


1 −
=  +    + 
where i = treatment group, j = investigational center, xij = treatment group i for investigational 
center j, pij = response proportion of treatment group i in investigational center j. 
Non-informative priors will be assumed for all coefficients.
Estimates of odds ratio and individual proportions with corresponding credible intervals will be 
presented.
9.5.4.2.
Sensitivity Analysis
If appropriate, sensitivity analyses will be specified in the Statistical Analysis Plan.
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9.5.4.3.
Secondary Analysis
All summaries of all secondary endpoints will be based on the mITT analysis set and analyzed 
descriptively. 
For continuous variables, descriptive statistics (number [n], mean, standard deviation, median, 
minimum, and maximum) will be provided for observed values and changes from baseline to 
each time point. For categorical variables, patient counts and percentages will be provided.
9.5.4.4.
Other Analyses
No other analyses are planned.
9.5.4.5.
Exploratory Analysis
 
9.6.
Multiple Comparisons and Multiplicity
Since there is only 1 primary endpoint and the multiple secondary endpoints will be analyzed 
using descriptive statistical analysis techniques, no adjustments for multiple 
comparisons/multiplicity will be made for the preplanned multiple comparisons/endpoints.
9.7.
Safety Analysis
Safety analyses will be performed using the safety analysis set. For categorical variables, patient 
counts and percentages will be provided. 
Safety assessments and time points are provided in Table 3.
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Each patient will be counted only once in each preferred term or System Organ 
Class (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; defined as related or with missing relationship 
[Section 7.1.4]; overall; and by severity), serious adverse events, adverse events causing 
withdrawal from the study, and adverse device effects. Summaries will be presented by treatment 
group and for all patients. Patient listings of serious adverse events and adverse events leading to 
withdrawal will be presented.
Changes in vital signs measurements data will be summarized descriptively. All values will be 
compared with predefined criteria to identify potentially clinically significant values or changes, 
and such values will be listed. 
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics.
For continuous variables, descriptive statistics (n, mean, standard deviation, median, minimum, 
and maximum) will be provided for observed values and changes from baseline to each time 
point. For categorical variables, patient counts and percentages will be provided. Descriptive 
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summaries of serious adverse events, patient withdrawals due to adverse events, adverse device 
effects, and potentially clinically significant abnormal values (vital signs) 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 is not applicable to this study.
9.9.
Planned Interim Analysis
No interim analyses are planned.
9.10.
Reporting Deviations from the Statistical Plan
Deviations from the statistical plan, along with the reasons for the deviations, will be described 
in any 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.
Refer to Appendix F for the definition of a clinical product complaint or device deficiency and 
investigator responsibilities in the management of a clinical product complaint or device 
deficiency. 
11.
COMPLIANCE STATEMENT
This study will be conducted in full accordance with the ICH Harmonised Tripartite Guideline, 
Guideline for GCP E6 and any applicable national and local laws and regulations (eg, Title 21 
Code of Federal Regulations [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 IMP 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 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB), and with competent authorities.
See Appendix D for the ethics expectations of informed consent or assent, competent authorities 
and IEC and IRB, confidentiality regarding study patients, and requirements for registration of 
the clinical study.
12.
DATA MANAGEMENT AND RECORD KEEPING
See Appendix G for information regarding data management and record keeping. This includes 
information on direct access to source data and documents, data collection, data quality control, 
and archiving of CRFs and source documents.
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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.
The 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, eg, 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 H for information regarding the publication policy.
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15.
REFERENCES
Allen SC, Jain M, Ragab S, Malik N. Acquisition and short-term retention of inhaler techniques 
require intact executive function in elderly subjects. Age Ageing 2003;32:299-302.
Broadbent E, Petrie KJ, Main J, Weinman J. The Brief Illness Perception Questionnaire. J 
Psychosomatic Res 2006;60:631-7.
Brooke J. SUS: a 'quick and dirty' usability scale. In: Jordan PW, Thomas B, Weerdmeester BA, 
McClelland IL, editors. Usability evaluation in industry. London: Taylor & Francis, 
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Cloutier MM, Schatz M, Castro M, Clark N, Kelly HW, Mangione-Smith R, et al. Asthma 
outcomes: composite scores of asthma control. J Allergy Clin Immunol 2012;129(3 Suppl):S24-
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Dolovich MB, Ahrens RC, Hess DR, Anderson P, Dhand R, Rau JL, et al. Device selection and 
outcomes of aerosol therapy: evidence-based guidelines. American College of Chest 
Physicians/American College of Asthma, Allergy, and Immunology. Chest 2005;127:335-71.
Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2018. 
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Horne R, Weinman J, Hankins M. The Beliefs About Medicine Questionnaire: The development 
and evaluation of a new method for assessing the cognitive representation of medication. 
Psychology and Health 1999;14(1):1-24.
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/.
Kamps AWA, van Ewijk B, Roorda RJ, Brand PLP. Poor inhalation technique, even after 
inhalation instructions, in children with asthma. Pediatr Pulmonol 2000;29:39-42.
Ko FWS, Hui DSC, Leung T-F, Chu H-Y, Wong GWK, Tung AHM, et al. Evaluation of the 
asthma control test: a reliable determinant of disease stability and a predictor of future 
exacerbations. Respirology 2012;17(2):370-8.
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(3):193-9.
Lenney J, Innes JA, Crompton GK. Inappropriate inhaler use: assessment of use and patient 
preference of seven inhalation devices. Respir Med 2000;94:496-500.
Merchant, RK, Inamdar R, Quade, RC. Effectiveness of population health management using the 
Propeller Health Asthma Platform: a randomized clinical trial. J Allergy Clin Immunol Pract. 
2016 May-Jun;4(3):455-63.
Molimard M, Raherison C, Lignot S, Depont F, Abouelfath A, Moore N. Assessment of handling 
of inhaler devices in real life: an observational study in 3811 patients in primary care. J Aerosol 
Med 2003;16(3):249-54.
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
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Nathan RA, Sorkness CA, Kosinski M, Schatz M, Li JT, Marcus P, et al. Development of the 
Asthma Control Test: a survey for assessing asthma control. J Allergy Clin Immunol 
2004;113(1):59-65. 
Price DB, Pearce L, Powell SR, Shirley J, Sayers MK. Handling and acceptability of the 
Easi-Breathe device compared with a conventional metered dose inhaler by patients and practice 
nurses. Int J Clin Pract 1999;53(1):31-6.
Schatz M, Kosinski M, Yarlas AS, Hanlon J, Watson ME, Jhingran P. The minimally important 
difference of the Asthma Control Test. J Allergy Clin Immunol 2009;124(4):719-23. 
Schatz M, Sorkness CA, Li JT, Marcus P, Murray JJ, Nathan RA, et al. Asthma Control Test: 
reliability, validity, and responsiveness in patients not previously followed by asthma specialists. 
J Allergy Clin Immunol 2006;117(3):549-56.
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
67
16.
SUMMARY OF CHANGES TO PROTOCOL
16.1.
Amendment 04 Dated 12 March 2021
The primary reason for this amendment is to add an exclusion criterion to preclude patients with 
previous exposure to the Digihaler device from participating in the study. This amendment is 
considered to be substantial (ie, requires approval by CA, IEC, and/or IRB) by the sponsor’s 
Authorized Representative. 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.
Minor editorial changes (typos, punctuation, replacing text with abbreviations, etc) have been 
made to the protocol and protocol synopsis, as appropriate.
Changes to the Protocol
Original text with changes shown
New wording
Reason/Justification for 
change
Section 2.1 Primary and Secondary Study Objectives and Endpoints
This secondary endpoint will describe is the 
frequency and types of interventions done to 
improve asthma control including:
This secondary endpoint is the 
frequency and types of 
interventions done to improve 
asthma control including:
Clarified phrasing.
Section 3.1 Introduction
The study will consist of a 
screening/baseline visit (Visit 1), a 12-week 
open-label treatment period with Visit 2, 
and a follow-up telephone call (2 weeks 
following treatment completion.
The study will consist of a 
screening/baseline visit (Visit 1), 
a 12-week open-label treatment 
period with Visit 2, and a 
follow-up telephone call (2 weeks 
following treatment completion.
Revised for clarity and 
specificity.
All patients will have a screening/baseline 
visit (Visit 1), at which they will be asked if 
they use a smart device and use different 
applications on their smart devices.
All patients will have a 
screening/baseline visit (Visit 1), 
at which they will be asked if they 
use a smart device and use 
different applications on their 
smart devices.
Revised for clarity and 
specificity.
For all patients, at Visit 2 and at each 
Clinically Driven Assessment, if necessary, 
the iHCP will record answers to Asthma 
Management questions regarding what 
interventions occurred as a consequence of 
the Clinically Driven Assessment, including 
discussions regarding adherence, or inhaler 
technique, treatment adjustments, or 
additions of new treatments, including 
biologic medication usage. Additionally, in 
the case of a Clinically Driven Assessment 
(for patients in the DS group), the iHCP will 
be asked whether or not the contact with the 
For all patients, at Visit 2 and at 
each Clinically Driven 
Assessment, if necessary, the 
iHCP will record answers to 
Asthma Management questions, 
including discussions regarding 
adherence, or inhaler technique, 
treatment adjustments, or 
additions of new treatments, 
including biologic medication 
usage. Additionally, in the case of 
a Clinically Driven Assessment 
(for patients in the DS group), the 
iHCP will be asked whether or not 
Clarified phrasing.
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
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Original text with changes shown
New wording
Reason/Justification for 
change
patient was originated from the iHCP 
interaction with the dashboard.
the contact with the patient was 
originated from the iHCP 
interaction with the dashboard.
Section 4.1 Patient Inclusion Criteria
f. [Revision 1] The patient can read and 
communicate in English and is familiar with 
and is willing to use his/her own smart 
device that meets the minimum App 
requirements and download and use the 
App.
f. [Revision 1] The patient can 
read and communicate in English 
and is familiar with and is willing 
to use his/her own smart device 
that meets the minimum App 
requirements and download and 
use the App.
Revised for clarity and 
specificity.
Section 4.2 Patient Exclusion Criteria
g. [Revision 1] The patient has any 
treatment with biologics for asthma (eg, 
omalizumab, anti-interleukin (IL) 5, anti-
IL5R, anti-IL4R), or has had such treatment 
within the last 90 days. (However, during 
the study, patients can be escalated to 
therapy with such agents if clinically 
indicated in the judgment of the investigator 
as part of their asthma management and 
remain in the study.)
[Revision 1] The patient has any 
treatment with biologics for 
asthma (eg, omalizumab, anti-
interleukin (IL) 5, anti-IL5R, anti-
IL4R), or has had such treatment 
within the last 90 days. (However, 
during the study, patients can be 
escalated to therapy with such 
agents if clinically indicated in the 
judgment of the investigator as 
part of their asthma management 
and remain in the study.)
Clarified escalation of 
biological therapy for 
asthma is permitted during 
the study if clinically 
required for disease 
management.
i. [New criterion] The patient is currently 
being treated prior to enrollment with a 
digital inhaler system, including the 
Digihaler system or an external “bolt on” 
digital system designed to monitor inhaler 
usage, such as the Propeller Health or 
Adherium systems.
i. [New criterion] The patient has 
previously participated in a 
Digihaler study or is currently 
being treated prior to enrollment 
with a digital inhaler system, 
including the Digihaler system or 
an external “bolt on” digital 
system designed to monitor 
inhaler usage, such as the 
Propeller Health or Adherium 
systems.
Added an additional 
exclusion criterion.
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 
visitend of treatment (Visit 2) or at the ET 
visitearly termination.
Patients will be instructed to 
return all IMP (empty, partially 
used, and unused inhalers) to the 
investigational center at end of 
treatment (Visit 2) or at the ET 
visit.
Revised for clarity and 
specificity.
Section 6.1.4 System Usability Questionnaire
An SUS regarding the use of the dashboard
will be completed by investigational center 
personnel, regarding the use of the 
dashboard, at the end of the study.
An SUS regarding the use of the 
dashboard will be completed by 
investigational center personnel at 
the end of the study.
Revised for clarity.
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
69
Original text with changes shown
New wording
Reason/Justification for 
change
Section 7.4 Medication Error and Special Situations Related to the Investigational Medicinal Product.
6.Breastfeeding: Suspected adverse 
reactions which occur in infants following 
exposure to a medicinal product from breast 
milk.
Text was deleted.
Removed breastfeeding as a 
special situation related to 
IMP since there are no
exclusions/special provisions 
listed in the protocol or 
package insert in regards to 
pregnancy, women of 
childbearing potential, or 
breastfeeding.
Section 9.5.2 Secondary Endpoints
Secondary endpoint #1 will describeis the 
frequency and types of interventions done to 
improve asthma control including:
Secondary endpoint #1 is the 
frequency and types of 
interventions done to improve 
asthma control including:
Clarified phrasing.
Appendix C QUALITY CONTROL AND QUALITY ASSURANCE
Study Monitoring
In case of an emergency situation (eg, the 
COVID-19 pandemic), where study 
monitors may not be able to access the 
investigational centers for on-site visits, 
investigational centers will be monitored 
remotely, where allowed, and in accordance 
with local regulations.
Study Monitoring
In case of an emergency situation 
(eg, the COVID-19 pandemic), 
where study monitors may not be 
able to access the investigational 
centers for on-site visits, 
investigational centers will be 
monitored remotely, where 
allowed, and in accordance with 
local regulations.
Clarified that remote 
monitoring is permitted in 
case of an emergency 
situation.
Audit and Inspection
In case of an emergency situation (eg, the 
COVID-19 pandemic), where auditors may 
not be able to access the investigational 
centers for on-site visits, investigational 
centers will be monitored remotely, where 
allowed, and in accordance with local 
regulations.
Audit and Inspection
In case of an emergency situation 
(eg, the COVID-19 pandemic), 
where auditors may not be able to 
access the investigational centers 
for on-site visits, investigational 
centers will be monitored 
remotely, where allowed, and in 
accordance with local regulations.
Clarified that remote audits 
and inspections are 
permitted in case of an 
emergency situation.
16.2.
Amendment 03 Dated 30 July 2020
The primary reason for this amendment is to clarify the definitions of the analysis sets. 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. All major changes to the protocol 
body are listed below in the table, and are reflected in the synopsis, as applicable. Minor editorial 
changes (typos, punctuation, etc) have been made to the protocol (and protocol synopsis, as 
appropriate).
Table 3 (Study Procedures and Assessments) and the synopsis have been revised to reflect the 
changes below.
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
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Changes to the Protocol
Original text with changes shown
New wording
Reason/Justification for 
change
Title page
Sponsor
Teva Branded Pharmaceutical
Products R&D, Inc.
41 Moores Road 145 Brandywine Parkway
Frazer, Pennsylvania 19355 West Chester, 
PA 19380
United States of America
Sponsor
Teva Branded Pharmaceutical
Products R&D, Inc.
145 Brandywine Parkway 
West Chester, PA 19380 
United States of America
Revised to reflect new 
sponsor address.
© 2020 2019 Teva Branded Pharmaceutical 
Products R&D, Inc.
© 2020 Teva Branded 
Pharmaceutical Products R&D, 
Inc.
Revised with correct year.
Section 1.1 Introduction
As the recommended drug for relief of acute 
asthmatic symptoms and as the prophylaxis 
for exercise-induced bronchoconstriction, 
short-acting beta2 agonists (SABAs), such 
as albuterol, are a mainstay of asthma 
management. Albuterol sulfate 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 (albuterol sulfate) RESPICLICK® 
Inhalation Powder is available in the United 
States (US) 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).
… To eliminate the necessity for 
coordinating actuation with inspiration, 
Teva has developed the breath-actuated 
inhaler PROAIR® RESPICLICK®, which 
utilizes a formulation blend of albuterol 
sulfate with lactose as an excipient…. 
Albuterol sulfate 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 US 
since March of 2015.
On 21 December 2018, the US FDA 
approved Albuterol eMDPI as PROAIR 
RESPICLICK® DIGIHALER™ (albuterol 
sulfate inhalation powder) has been 
available in the United States (US) since 
As the recommended drug for 
relief of acute asthmatic 
symptoms and as the prophylaxis 
for exercise-induced 
bronchoconstriction, short-acting 
beta2 agonists (SABAs), such as 
albuterol, are a mainstay of 
asthma management. Albuterol 
sulfate is a beta2-adrenergic 
agonist with the chemical name 
α1 [(tert butylamino) methyl]-4-
hydroxy-m-xylene-α,αʹ-diol 
sulfate (2:1) [salt]…. 
....To eliminate the necessity for 
coordinating actuation with 
inspiration, Teva developed the 
breath-actuated inhaler 
PROAIR® RESPICLICK®, 
which utilizes a formulation blend 
of albuterol sulfate with lactose as 
an excipient….
PROAIR RESPICLICK (albuterol 
sulfate inhalation powder) has 
been available in the United 
States (US) since March 2015. It 
is indicated for treatment or 
prevention of bronchospasm in 
patients 4 years of age and older 
with reversible obstructive airway 
disease and prevention of 
exercise-induced bronchospasm 
in patients 4 years of age and 
older. On 21 December 2018, the 
US FDA approved Albuterol 
multidose dry powder inhaler 
Reorganized the section to 
better explain the 
relationship between 
PROAIR DIGIHALER and 
PROAIR RESPICLICK, as 
FDA-approved labeling is 
now available for 
DIGIHALER that was not 
available at the time of 
Amendment 02.
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
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Original text with changes shown
New wording
Reason/Justification for 
change
March 2015. It is indicated), 90 mcg of 
albuterol base per actuation, for treatment or 
prevention of bronchospasm in patients 4 
years of age and older with reversible 
obstructive airway disease and prevention of 
exercise-induced bronchospasm in patients 
4 years of age and older. On 21 December 
2018, the US FDA approved Albuterol 
multidose dry powder inhaler (MDPI) with 
an integrated electronic module (eMDPI) as 
PROAIR® DIGIHALER™ (albuterol 
sulfate inhalation powder), 90 mcg of 
albuterol base per actuation, for the same 
indication as PROAIR RESPICLICK. 
PROAIR DIGIHALER contains a built-in 
electronic module (eModule; ie, the 
Digihaler) that detects, records, and stores 
data on inhaler events for transmission to a 
mobile application (App). More detailed 
prescribing information for this product may 
be found in the Investigator’s Brochure 
(IB).
In this study, 90 mcg of albuterol sulfate is 
delivered via PROAIR DIGIHALER.
(MDPI) with an integrated 
electronic module (eMDPI) as 
PROAIR® DIGIHALER™ 
(albuterol sulfate inhalation 
powder), 90 mcg of albuterol base 
per actuation, for the same 
indication as PROAIR 
RESPICLICK. PROAIR 
DIGIHALER contains a built-in 
electronic module (eModule; ie, 
the Digihaler) that detects, 
records, and stores data on inhaler 
events for transmission to a 
mobile application (App). More 
detailed prescribing information 
for this product may be found in 
the Investigator’s Brochure (IB).
In this study, 90 mcg of albuterol 
sulfate is delivered via PROAIR 
DIGIHALER….
The purpose of the study is to evaluate 
whether outcomes for patients using the 
Albuterol eMDPI DS can be optimized
outcomes better than a concurrent control 
(CC) group who will be treated with their 
standard of care albuterol-administering 
rescue inhalers and will not use the DS 
during the treatment period.
The purpose of the study is to 
evaluate whether outcomes for 
patients using the Albuterol 
eMDPI DS can be optimized 
better than a concurrent control 
(CC) group who will be treated 
with their standard of care 
albuterol-administering rescue 
inhalers and will not use the DS 
during the treatment period.
Clarified phrasing.
Section 1.2 Findings from Nonclinical and Clinical Studies
In the clinical development program for 
PROAIR RESPICLICK, the IMP was 
reported using nomenclature other than that 
of the then unbranded product. In the 
descriptions of the PROAIR RESPICLICK 
studies in 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 the clinical studies are 
provided in this section. 
Bronchospasm Associated with Asthma: In 
two 12-week, randomized, double-blind, 
placebo-controlled studies of identical 
design (Study 1 and Study 2), albuterol 
sulfate MDPI (153 patients)PROAIR 
Brief summaries of the clinical 
studies are provided in this 
section. 
Bronchospasm Associated with 
Asthma: In two 12-week, 
randomized, double-blind, 
placebo-controlled studies of 
identical design (Study 1 and 
Study 2), albuterol sulfate MDPI 
(153 patients) was compared to a 
matched placebo dry powder 
inhaler (163 patients) in asthmatic 
patients 12 to 76 years of age at a 
dose of 180 mcg albuterol 4 times
daily…. Serial measurements of 
forced expiratory volume in 1 
Updated text to more closely 
match the DIGIHALER 
labeling, which was not 
available at the time of 
Amendment 02.
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Parallel-group, Controlled Study - Asthma
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Original text with changes shown
New wording
Reason/Justification for 
change
RESPICLICK was compared to a matched 
placebo dry powder inhaler (in 153 and 163 
patients) in asthmatic patients with asthma, 
respectively, 12 to 76 years of age at a dose 
of 180 mcg albuterol 4 times daily…. Serial 
measurements of forced expiratory volume 
in 1 second (FEV1) demonstrated that 2 
inhalations of albuterol sulfate 
MDPIPROAIR 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. Consistent results 
were observed inResults of Study 2. were 
consistent with those of Study 1. In a 
double-blind, randomized, placebo-
controlled, single-dose, crossover study 
evaluating albuterol sulfate MDPIPROAIR 
RESPICLICK and PROAIR® HFA in 71 
adult and adolescent patients 12 years of age 
and older with persistent asthma, albuterol 
sulfate MDPIPROAIR 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 albuterol sulfate 
MDPIPROAIR 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 when theywho
received placebo….
…
Clinical Safety: A total of 1289 subjects 
were treated with albuterol sulfate 
MDPIPROAIR RESPICLICK during the 
clinical development program…. In a long-
term study of 168 patients treated with 
albuterol sulfate MDPIPROAIR 
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. 
second (FEV1) demonstrated that 
2 inhalations of albuterol sulfate 
MDPI 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. Consistent results 
were observed in Study 2. In a 
double-blind, randomized, 
placebo-controlled, single-dose, 
crossover study evaluating 
albuterol sulfate MDPI and 
PROAIR® HFA in 71 adult and 
adolescent patients 12 years of 
age and older with persistent 
asthma, albuterol sulfate MDPI 
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 albuterol sulfate 
MDPI 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 
when they received placebo....
…
Clinical Safety: A total of 1289 
subjects were treated with 
albuterol sulfate MDPI during the 
clinical development program…. 
In a long-term study of 168 
patients treated with albuterol 
sulfate MDPI 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 
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
73
Original text with changes shown
New wording
Reason/Justification for 
change
In a small cumulative dose study, tremor, 
palpitations, and headache were the most 
frequently occurring (≥5%) adverse events.
small cumulative dose study, 
tremor, palpitations, and headache 
were the most frequently 
occurring (≥5%) adverse events.
Section 1.3.1 Known and Potential Benefits and Risks of the Test Investigational Medicinal Product(s)
This open-label study is being undertaken to 
evaluate whether outcomes for patients 
using the Albuterol eMDPI DS can be 
optimized outcomes better than a CC group 
who will be treated with their standard of 
care albuterol-administering rescue inhalers 
and will not use the DS during the treatment 
period.
This open-label study is being 
undertaken to evaluate whether 
outcomes for patients using the 
Albuterol eMDPI DS can be 
optimized better than a CC group 
who will be treated with their 
standard of care albuterol-
administering rescue inhalers and 
will not use the DS during the 
treatment period.
Clarified phrasing.
… Furthermore, the steps to take a dose of 
the Albuterol 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….
Text was deleted
Removed context of 
RESPICLICK, since 
approved USPI for 
DIGIHALER is now 
available.
Section 2.1 Primary and Secondary Study Objectives and Endpoints
o
addition of an oral or parenteral a 
systemic corticosteroid medication for 
asthma or another controller, including a 
long-acting muscarinic antagonist (LAMA) 
or biologics
o
addition of a systemic 
corticosteroid medication for 
asthma or another controller, 
including a long-acting 
muscarinic antagonist (LAMA) or 
biologics
Revised for clarity and 
specificity.
Section 2.2 Exploratory Objectives and Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 3.1 General Study Design and Study Schematic Diagram
Once randomized, patients in the DS group 
will have their rescue treatment switched to 
thebe trained on the use of the Albuterol 
eMDPI DS, (including instructions on how 
to use both the eMDPI and the App) and, 
Once randomized, patients in the 
DS group will be trained on the 
use of the Albuterol eMDPI DS 
(including instructions on how to 
use both the eMDPI and the App) 
Clarified the training that 
patients in the DS group 
receive on the Albuterol 
eMDPI and that additional 
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
74
Original text with changes shown
New wording
Reason/Justification for 
change
upon demonstrating competency, will 
receive 2 Albuterol eMDPI devices for use 
as rescue bronchodilators to replace their 
rescue treatment during the study. 
Additional Albuterol eMDPI devices may 
be supplied during the treatment period, 
based on patients’ needs.
and, upon demonstrating 
competency, will receive 2 
Albuterol eMDPI devices for use 
as rescue bronchodilators to 
replace their rescue treatment 
during the study. Additional 
Albuterol eMDPI devices may be 
supplied during the treatment 
period, based on patients’ needs.
devices may be supplied as 
necessary.
The CC group will be followed according to 
the clinical judgment of the investigator; the 
asthma of patients in the CC group will be 
managed in a manner consistent with the 
clinical judgement of the investigator and 
based on asthma management guidelines 
(eg, GINA). Similar to the management of 
the CC group, the DS group patients 
willThe DS group patients will then be 
followed by the investigational centers with 
the addition of objective information on 
Albuterol eMDPI usage being available to 
both patients and investigational centers 
through the App and the dashboard, 
respectively. The iHCPs will check the 
dashboard at least once a week and use this 
information, as per their clinical judgment, 
to make specific adjustments modify 
patients’, in a manner consistent with their 
clinical judgement, based on asthma 
management. guidelines (eg, GINA). 
Clinically Driven Assessments for both 
groups, if necessary, should be arranged per 
the clinical judgement of the iHCP 
managing the patient and can be via a 
telephone call or an on-site visit.
The CC group will be followed 
according to the clinical judgment 
of the investigator; the asthma of 
patients in the CC group will be 
managed in a manner consistent 
with the clinical judgement of the 
investigator and based on asthma 
management guidelines (eg, 
GINA). Similar to the 
management of the CC group, the 
DS group patients will be 
followed by the investigational 
centers with the addition of 
objective information on 
Albuterol eMDPI usage being 
available to both patients and 
investigational centers through the 
App and the dashboard, 
respectively. The iHCPs will 
check the dashboard at least once 
a week and use this information, 
as per their clinical judgment, to 
modify patients’ asthma 
management. Clinically Driven 
Assessments for both groups, if 
necessary, should be arranged per 
the clinical judgement of the 
iHCP managing the patient and 
can be via a telephone call or an 
on-site visit.
Clarified the management of 
the CC group.
At the end of the treatment period (12 
weeks), final assessments of the DS and CC 
group patients will be made, as specified in 
Table 3. and ACT score registered for all 
patients. Patients, 18 years of age or older, 
will also complete the BMQ and BIPQ. 
Both DS patients, 18 years of age or older, 
and the investigational center personnel will 
complete the SUS questionnaire. DS 
patients will then return to their usual rescue 
inhalers, which they were on prior to study 
participation. A follow-up telephone call 
will be made by the investigational center to 
At the end of the treatment period 
(12 weeks), final assessments of 
the DS and CC group patients will 
be made, as specified in Table 3. 
A follow-up telephone call will be 
made by the investigational center
to all patients, 2 weeks later, and 
will confirm the DS group 
patients have returned to previous 
asthma treatments.
Revised to streamline 
presentation.
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Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
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Original text with changes shown
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Reason/Justification for 
change
all patients, 2 weeks later, and will confirm 
the DS group patients have returned to 
previous asthma treatments.
Figure 2:
Overall Study Schematic Diagram
See New wording column.
The figure has been modified to 
reflect additional procedures for 
Clinically Driven Assessments.
Updated for consistency with 
new procedures in Table 3.
Section 3.2 Planned Number of Patients and Countries
The study is expected to start in Q2 2019
Q4 2020 and last until approximately Q2 
2020 Q4 2021.
The study is expected to start in 
Q4 2020 and last until 
approximately Q4 2021.
Updated the anticipated start 
and end dates of the study.
Section 3.5 Schedule of Study Procedures and Assessments
Table 3 Study Procedures and Assessments
See New wording column.
Table 3 Study Procedures and 
Assessments has been modified as 
described below:
!
The row for “Dispense 
test IMP to DS group” 
has been modified to 
include “Train.”
!
A row has been added 
for the procedure 
“Remove App from the 
patient’s smart device,” 
to be done at the End of 
Treatment/Early 
Termination visit.
!
Xs have been added to 
indicate that assessment 
of adverse 
events/adverse device 
effects and concomitant 
medications will be 
performed during 
Clinically Driven 
Assessments and 
Unscheduled IMP 
Dispensing visits, if any.
!
An X has been added to 
indicate that test IMP 
collection and 
accountability will be 
performed during 
Unscheduled IMP 
Dispensing visits, if any.
Added to clarify and reflect 
additional procedures at the 
End of Treatment/Early 
Termination visit, Clinically 
Driven Assessments, and nd 
Unscheduled IMP 
Dispensing visits.
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
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Original text with changes shown
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Reason/Justification for 
change
d Patients will be provided the Test IMP, 
along with training on use and proper 
technique, by the investigational centers.
d Patients will be provided the 
Test IMP, along with training 
on use and proper technique, by 
the investigational centers.
Clarified the training that 
patients in the DS group 
receive on the Albuterol 
eMDPI.
g  …. If a patient in the DS group ends the 
study prematurely, in addition to following 
up on ongoing AEs and concomitant 
medications, the investigational centersite
will also confirm that the patient has 
returned to their previous asthma treatment.
g  …. If a patient in the DS group 
ends the study prematurely, in 
addition to following up on 
ongoing AEs and concomitant 
medications, the investigational 
center will also confirm that the 
patient has returned to their 
previous asthma treatment.
Updated terminology for 
consistency across the 
protocol.
Section 5.1 Investigational Medicinal Products Used in the Study
Patients At Visit 1, patients in the DS group 
will be trained on the use of the Albuterol 
eMDPI DS (including instructions on how 
to use both the eMDPI and the App) and, 
upon demonstrating competency, will 
receive 2 Albuterol eMDPI devices at visit
1. Patients will receive instructions for using 
the Albuterol eMDPI from the 
investigational center personnel use as 
rescue bronchodilators to replace their 
rescue treatment during the study. 
Additional Albuterol eMDPI devices may 
be supplied during the treatment period, 
based on patients’ needs.
At Visit 1, patients in the DS 
group will be trained on the use of 
the Albuterol eMDPI DS 
(including instructions on how to 
use both the eMDPI and the App) 
and, upon demonstrating 
competency, will receive 2 
Albuterol eMDPI devices for use 
as rescue bronchodilators to 
replace their rescue treatment 
during the study. Additional 
Albuterol eMDPI devices may be 
supplied during the treatment 
period, based on patients’ needs.
Clarified the training that 
patients in the DS group 
receive on the Albuterol 
eMDPI and added that 
additional devices may be 
supplied as necessary.
Section 5.1.1 Test Investigational Medicinal Product
Albuterol eMDPI (marketed in the US as 
PROAIR DIGIHALERRESPICLICK) is an 
inhalation-driven eMDPI containing a blend 
of albuterol sulfate and alpha-lactose 
monohydrate. Albuterol eMDPI is the result 
of adding an eModule electronic sensor to 
the Albuterol MDPI.
Albuterol eMDPI (marketed in 
the US as PROAIR DIGIHALER) 
is an inhalation-driven eMDPI 
containing a blend of albuterol 
sulfate and alpha-lactose 
monohydrate….
Updated to focus on 
DIGIHALER rather than 
RESPICLICK, as FDA-
approved labeling for 
DIGIHALER is now 
available.
By consenting to enroll in the study, the 
patient must also download the smart device 
App (with the assistance of investigational 
center personnel), accept the smart device 
App’s Privacy Notice and Terms of Use, 
and also agree to share his/her data to a 
provider-facing dashboard utilized by the 
iHCP and investigational center study team.
By consenting to enroll in the 
study, the patient must also 
download the smart device App 
(with the assistance of 
investigational center personnel), 
accept the smart device App’s 
Privacy Notice and Terms of Use, 
and also agree to share his/her 
data to a provider-facing 
dashboard utilized by the iHCP 
and investigational center study 
team.  
Clarified that investigational 
center personnel will provide 
assistance to download the 
App.
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
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Reason/Justification for 
change
At the end of treatment/ET visit (Visit 2), 
investigational center personnel will remove 
the App from the patient’s smart device.
At the end of treatment/ET visit 
(Visit 2), investigational center 
personnel will remove the App 
from the patient’s smart device.
Added sentence to reflect 
additional procedure at the 
End of Treatment/Early 
Termination visit.
Section 5.1 Investigational Medicinal Products Used in the Study
Table 4: Investigational Medicinal Products Used in the Study
See New wording column.
Table 4 Investigational Medicinal 
Products Used in the Study has 
been revised as described below:
Ɣ
Unit dose strength has been
revised to: “117 mcg of albuterol
sulfate (equivalent to 97 mcg of
albuterol base) from the device
reservoir to provide a delivered
dose of 108 mcg of albuterol
sulfate (equivalent to 90 mcg of
albuterol base).”
Ɣ
Teva Pharmaceuticals Ireland
was added to the Manufacturer
row.
Clarified dose (nominal 
versus metered) and updated 
manufacturer.
Section 5.1.2 Medical Devices
Instructions for medical device use are 
provided in the Study ReferencePharmacy
Manual.
Instructions for medical device 
use are provided in the Study 
Pharmacy Manual.
Updated reference to the 
source of information.
Section 5.1.2.1 Application
The App gets environment information from 
1 or more web services for the specific 
location of the patient.
The App gets environment 
information for the specific 
location of the patient.
Clarified meaning of 
environment information.
Section 5.2.3 Accountability
Each IMP shipment will include a packing 
slip listing the contents of the shipment, 
return instructions, and any applicable 
forms.
….
Further guidance and information are 
provided in the Study ReferencePharmacy
Manual.
Each IMP shipment will include a 
packing slip listing the contents of 
the shipment and any applicable 
forms.
….
Further guidance and information 
are provided in the Study 
Pharmacy Manual.
Updated reference to the 
source of information.
Section 5.3.1 Justification for Dose of Test Investigational Medicinal Product
The prescribed dose of Albuterol eMDPI 
(now US FDA approved as PROAIR 
DIGIHALER) used in this study (ie, 90 
mcg, 1 to 2 inhalations every 4 to 6 hours, 
as needed) was selected based on the 
prescribing information for PROAIR 
DIGIHALER.RESPICLICK, which has the 
The prescribed dose of Albuterol 
eMDPI (now US FDA approved 
as PROAIR DIGIHALER) used 
in this study (ie, 90 mcg, 1 to 2 
inhalations every 4 to 6 hours, as 
needed) was selected based on the 
Updated to focus on 
DIGIHALER rather than 
RESPICLICK, as FDA-
approved labeling for 
DIGIHALER is now 
available.
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
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Original text with changes shown
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Reason/Justification for 
change
same drug delivery design as Albuterol 
eMDPI.
PROAIR DIGIHALERRESPICLICK 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 EIB. For the relief of acute 
asthma symptoms, PROAIR 
DIGIHALERRESPICLICK is 
recommended at a dosage of 2 inhalations 
(ie, 180 mcg of albuterol base ex-
mouthpiece) repeated every 4 to 6 hours, as 
needed…. The recommended dosage for 
PROAIR DIGIHALERRESPICLICK 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 DIGIHALERRESPICLICK is 
effective for the treatment or prevention of 
bronchospasm in adult and adolescent 
patients with obstructive airway disease.
prescribing information for 
PROAIR DIGIHALER.
PROAIR DIGIHALER 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 EIB. For the 
relief of acute asthma symptoms, 
PROAIR DIGIHALER is 
recommended at a dosage of 2 
inhalations (ie, 180 mcg of 
albuterol base ex-mouthpiece) 
repeated every 4 to 6 hours, as 
needed…. The recommended 
dosage for PROAIR DIGIHALER 
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 
DIGIHALER is effective for the 
treatment or prevention of 
bronchospasm in adult and 
adolescent patients with 
obstructive airway disease.
Section 6.1.1 Asthma Control Test
Detailed instructions for administering, 
scoring, and analyzing the ACT are 
provided in the Study Reference 
Manualstatistical analysis plan.
Detailed instructions for 
administering, scoring, and 
analyzing the ACT are provided 
in the statistical analysis plan.
Changed cross-reference, as 
there will not be a Study 
Reference Manual.
Section 7 Assessment of Safety
In this study, safety will be assessed by 
qualified study personnel by evaluating 
reported adverse events, device safety (as 
assessed by adverse device effects, vital 
signs measurements, and serious adverse 
device effects), and use of concomitant 
medications. 
Adverse events are categorized by ICH 
guidelines, and adverse device effects are 
categorized and classified according to 
International Organization for 
Standardization (ISO) standard 
14155:2011(E), as shown in Table 5. Device 
deficiencies that are not associated with an 
adverse event are covered in Section 9
and Appendix F.(.
In this study, safety will be 
assessed by qualified study 
personnel by evaluating reported 
adverse events, adverse device 
effects, vital signs measurements, 
and use of concomitant 
medications.
Adverse events are categorized by 
ICH guidelines, and adverse 
device effects are categorized and 
classified according to 
International Organization for 
Standardization (ISO) standard 
14155:2011(E).
Device deficiencies that are not 
associated with an adverse event 
Text was updated to be 
consistent with the latest 
Teva protocol template.
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
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Original text with changes shown
New wording
Reason/Justification for 
change
[Table 5 deleted]
Device deficiencies that are not associated 
with an adverse event as well as those that 
have the potential to cause a serious adverse 
event are covered in Appendix F.
as well as those that have the 
potential to cause a serious 
adverse event are covered in 
Appendix F.
Section 7.1.1 Definition of an Adverse Event
•
drug/drug, drug/device, or 
device/device interactions
•
drug/drug, drug/device, or 
device/device interactions
Text was updated to be 
consistent with the latest 
Teva protocol template.
Section 7.1.5.2 Expectedness
The sponsor will be responsible for 
determining whether an adverse event is 
expected or unexpected. An adverse event 
will be considered unexpected if the nature, 
severity, or frequency of the event is not 
consistent with the reference safety 
information (RSI) in the IB described in 
Section 7.1. 6for the medical device used in 
this study.
[Text was deleted.]
Text was updated to be 
consistent with the latest 
Teva protocol template.
Section 7.1.5.3.1. Investigator Responsibility
For all countries, the sponsor’s GPSP will 
distribute the Council for International 
Organizations of Medical Sciences 
form/MedWatch form/Extensible Markup 
Language file to the LSO/CRO for 
submission to the competent authorities, 
Independent Ethics Committee/Institutional 
Review Board (IEC/IRB), and investigators, 
according to regulations.
For all countries, the sponsor’s 
GPSP will distribute the Council 
for International Organizations of 
Medical Sciences 
form/MedWatch form/Extensible 
Markup Language file to the 
LSO/CRO for submission to the 
competent authorities, 
Independent Ethics 
Committee/Institutional Review 
Board (IEC/IRB), and 
investigators, according to 
regulations.
Text was updated to be 
consistent with the latest 
Teva protocol template.
Section 7.1.6 Protocol-Defined Adverse Events of Special Interest
Section 7.1.6 Protocol-Defined Adverse 
Events Not for Expedited Reporting of 
Special Interest
All adverse events will be reported 
according to regulatory requirements.
Section 7.1.6 Protocol-Defined 
Adverse Events of Special 
Interest
[Sentence was deleted.]
Heading and text were 
updated to be consistent with 
the latest Teva protocol 
template.
Section 7.2 Adverse Device Effects
An adverse device effect is an adverse event 
related to the use of an investigational 
medical device or a combination product.
An adverse device effect is an 
adverse event related to the use of 
an investigational medical device 
or a combination product.
Text was updated to be 
consistent with the latest 
Teva protocol template.
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
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Original text with changes shown
New wording
Reason/Justification for 
change
Section 7.2.1 Adverse Device Effect Reporting
Adverse device effects (Figure 4) and 
device deficiencies shall be reported in a 
study specific adverse device effect form.
must be recorded on both on the source 
documentation and the CRF.
….The investigator and sponsor will record 
all relevant information regarding every 
adverse device effect/serious adverse device 
effect and device deficiency and will 
categorize each as guided in Section 7.2. . 
Adverse device effects and device 
deficiencies will be listed in the clinical 
study report (CSR). Examples of adverse 
device effects and recommended actions to 
be taken are presented in Appendix F.
[Figure 4 moved to Section 7.2.2.1]
The investigator should make an initial 
determination whether the adverse event 
may be related to a device deficiency. 
Adverse device effects and device 
deficiencies will be listed in the clinical 
study report (CSR).
Adverse device effects (Figure 4) 
must be recorded on both the 
source documentation and the 
CRF. 
….The investigator and sponsor 
will record all relevant 
information regarding every 
adverse device effect/serious 
adverse device effect and device 
deficiency and will categorize 
each as guided in Section 7.2.
The investigator should make an 
initial determination whether the 
adverse event may be related to a 
device deficiency. 
Adverse device effects and device 
deficiencies will be listed in the 
clinical study report (CSR).
Text was updated to be 
consistent with the latest 
Teva protocol template.
Section 7.2.2. Serious Adverse Device Effects
A serious adverse device effect is an 
adverse device effect that has resulted in 
any of the consequences characteristic of a 
serious adverse event (Section 7.1.5.1( or 
that might have led to any of these 
consequences if suitable action had not been 
taken, intervention had not been made, or if 
circumstances had been less opportune).
An unanticipated serious adverse device 
effect is a serious adverse device effect that, 
by its nature, incidence, severity, or 
outcome, has not been listed in 
Section 7.1. 6of this protocol.Appendix F 
(Appendix Table 71 and Appendix Table 
82).
A serious adverse device effect is 
an adverse device effect that has 
resulted in any of the 
consequences characteristic of a 
serious adverse event (Section 
7.1.5.1).
An unanticipated serious adverse 
device effect is a serious adverse 
device effect that, by its nature, 
incidence, severity, or outcome, 
has not been listed in Appendix F 
(Appendix Table 1 and Appendix 
Table 2).
Text was updated to be 
consistent with the latest 
Teva protocol template.
Section 7.2.2.1. Serious Adverse Device Effect Reporting
The investigator will report to the sponsor, 
without unjustified delay, all serious adverse 
device effects (within 24 hours) and device 
deficiencies that could have led to a serious 
adverse device effect;); this information 
shall be promptly followed by detailed 
written reports as described below.
The investigator will report to the 
sponsor, without unjustified 
delay, all serious adverse device 
effects (within 24 hours); this 
information shall be promptly 
followed by detailed written 
reports as described below.
Text was updated to be 
consistent with the latest 
Teva protocol template.
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
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Original text with changes shown
New wording
Reason/Justification for 
change
The process and contact details for serious 
adverse device effect reporting are the same 
as for serious adverse event reporting 
provided in Section 7.1.5.3.
Events shall be reported to the Ethics 
CommitteeIEC/IRB by the investigator and 
to the regulatory authorities by the sponsor 
using the appropriate form according to the
timelines detailed belownational and local 
regulations.
The following events are considered 
reportable events (Figure 4investigator 
should use Appendix F (Appendix Table 71 
and Appendix Table 82):
•
any Table 8)  to make an initial 
determination whether the serious adverse 
event or serious adverse device effect
•
any may be related to a device 
deficiency that might have led to a serious 
adverse device effect if.
[Figure 4 Decision Tree for Adverse Events 
and Adverse Device Effects Classification; 
moved from Section 7.2.1]
•
suitable action had not been taken (or)
•
intervention had not been made (or)
•
if circumstances had been less fortunate
•
new findings/updates in relation to 
already reported events.
The timelines for reporting are as follows:
•
for a serious adverse event or serious 
adverse device effect that indicates an 
imminent risk of death, serious injury, or 
serious illness and requires prompt remedial 
action for patients, users, or other persons 
•
immediately, but not later than 2 
calendar days after awareness by the 
sponsor of a new reportable event or of new 
information in relation with an already 
reported event.
•
for any other reportable events as 
described above or a new finding/update
•
immediately, but not later than 7 
calendar days following the date of 
awareness by the sponsor of the new 
reportable event or of new information in 
relation with an already reported event.
All serious adverse device effects will be 
listed in the CSR.
The process and contact details 
for serious adverse device effect 
reporting are the same as for 
serious adverse event reporting 
provided in Section 7.1.5.3.
Events shall be reported to the 
IEC/IRB by the investigator and 
to the regulatory authorities by the 
sponsor using the appropriate 
form according to national and 
local regulations.
The investigator should use 
Appendix F (Appendix Table 1 
and Appendix Table 2) to make 
an initial determination whether 
the serious adverse event may be 
related to a device deficiency.
[Figure 4 Decision Tree for 
Adverse Events and Adverse 
Device Effects Classification; 
moved from Section 7.2.1]
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
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Original text with changes shown
New wording
Reason/Justification for 
change
Section 7.4. Medication Error and Special Situations Related to the Investigational Medicinal Product
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 patient’s, or as a deviation, in 
the patients’ source documents 
(Appendix C), regardless of whether or not 
an adverse event occurs as a result.
…
5. Off label use: Situations where an IMP is 
intentionally used for a medical purpose not 
in accordance with the authorized product 
information.
Any administration of IMP that is 
not in accordance with the study 
protocol should be reported in the 
patient’s source documents 
(Appendix C), regardless of 
whether or not an adverse event 
occurs as a result.
…
[Deleted item 5]
Text was updated to be 
consistent with the latest 
Teva protocol template.
Section 9 Assessment of Device Performance
[Deleted section]
[Deleted section]
Text was updated to be 
consistent with the latest 
Teva protocol template by 
moving the content of this 
section to Appendix F 
Product Complaints.
Section 9.2.1 Intent-to-Treat Analysis Set
The intent-to-treat (ITT) This analysis set 
will include all randomized patients. who 
were enrolled in the study (signed ICF) and 
meet inclusion/exclusion criteria. A patient 
is considered enrolled according to the 
status reported in the database.
The intent-to-treat (ITT) analysis 
set will include all randomized 
patients.
Clarified this analysis set.
Section 9.2.2 Modified Intent-to-Treat Analysis Set
The modified intent-to-treat (mITT)This
analysis set is a subset of the ITT analysis 
set includingand will only include all 
enrolled patients who receivecompleted at 
least 1 dose of IMP (IMP is albuterol 
eMDPI for the DS group and standard-of-
care albuterol-administering rescue 
medication for the CC group) and at least 1 
postbaseline assessment on any ofas 
recorded per the CRF and confirmed by the 
status reported in the study endpoints 
(primary, secondary, or exploratory).
database. Data collected from patients after 
treatment discontinuation will not be 
included in the modified intent to treat 
(mITT) analysis set.
The modified intent-to-treat 
(mITT) analysis set is a subset of 
the ITT analysis set including
only patients who receive at least 
1 dose of IMP (IMP is albuterol 
eMDPI for the DS group and 
standard-of-care albuterol-
administering rescue medication
for the CC group) and at least 
1 postbaseline assessment on any 
of the study endpoints (primary, 
secondary, or exploratory).
Clarified this analysis set.
Section 9.2.3 Safety Analysis Set
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
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Original text with changes shown
New wording
Reason/Justification for 
change
This analysis set will include all randomized
patients in the DS group who receive at least 
1 dose of IMP and all patients in the CC 
group.
This analysis set will include all 
patients in the DS group who 
receive at least 1 dose of IMP and 
all patients in the CC group.
Clarified this analysis set.
Section 9.4.1 Patient Disposition
Data from patients screened; patients 
screened but not randomizedenrolled and 
reason for not being randomizednon
enrollment; patients in the ITT analysis 
setwho are enrolled; patients in the ITT 
analysis setenrolled but who did not attempt 
to download the App; patients in the ITT 
analysis setenrolled but who did not use the 
inhaler; patients in the ITT, mITT and safety 
analysis sets; patients who completed the 
study; and patients who withdrew from the 
study and the reason for withdrawal will be
summarized using descriptive summary 
statistics (number, %).
Data from patients screened; 
patients screened but not 
randomized and reason for not 
being randomized; patients in the 
ITT analysis set; patients in the 
ITT analysis set who did not 
attempt to download the App; 
patients in the ITT analysis set 
who did not use the inhaler; 
patients in the mITT and safety 
analysis sets; patients who 
completed the study; and patients 
who withdrew from the study and 
the reason for withdrawal will be 
summarized using descriptive 
summary statistics (number, %).
Clarified how patient 
disposition will be 
summarized.
Section 9.5.4.1 Primary Analysis
3.
Summary measure: A successful 
differentiation between the 2 groups will be 
determined by a Bayesian posterior 
probability for β1 >0 greater than 0.95 
(1-sided). The following statistical methods 
will be utilized:
3.
Summary measure: A 
successful differentiation between 
the 2 groups will be determined 
by a Bayesian posterior 
probability for  >0 greater than 
0.95 (1-sided). The following 
statistical methods will be 
utilized:
Clarified β1.
Section 9.5.2 Secondary Endpoints
o
addition of an oral or parenteral a 
systemic corticosteroid medication for 
asthma or another controller, including a 
LAMA or biologics
o
addition of a systemic 
corticosteroid medication for 
asthma or another controller, 
including a LAMA or biologics
Revised for clarity and 
specificity.
Section 9.5.3 Exploratory/Other Endpoints
 
 
 
 
 
 
 
.
Section 10 Quality Control and Quality Assurance
Refer to Appendix F for the definition of a 
clinical product complaint or device 
deficiency and investigator responsibilities 
Refer to Appendix F for the 
definition of a clinical product 
complaint or device deficiency 
and investigator responsibilities in 
Text was updated to be 
consistent with the latest 
Teva protocol template.
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
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Original text with changes shown
New wording
Reason/Justification for 
change
in the management of a clinical product 
complaint or device deficiency.
the management of a clinical 
product complaint or device 
deficiency.
Appendix A Clinical Laboratories and Other Departments and Institutions
Appendix B Study Procedures and Assessments by Visit
1.
Procedures for Screening/Baseline Visit 
(Visit 1, Day 1)
See New wording column.
1.
Procedures for 
Screening/Baseline Visit (Visit 1, 
Day 1)
•
train patients in the DS group 
on use and proper technique of 
the albuterol multidose dry 
powder inhaler with integrated 
electronic module (Albuterol 
eMDPI)
Clarified the training that 
patients in the DS group 
receive on the Albuterol 
eMDPI.
3.
Procedures for End of Treatment/Early 
Termination Visit (Visit 2, Day 84 + up to 7 
days)
•
remove the App from the patient’s 
smart device
3.
Procedures for End of 
Treatment/Early Termination 
Visit (Visit 2, Day 84 + up to 7 
days)
•
remove the App from the 
patient’s smart device
Added an additional 
procedure to the End of 
Treatment/Early Termination 
visit.
4.
Procedures for Clinically Driven 
Assessment(s) (If Necessary)
See New wording column.
4.
Procedures for Clinically 
Driven Assessment(s) (If 
Necessary)
•
conduct adverse events and 
adverse device effects inquiry
•
conduct concomitant 
medication inquiry
Added additional procedures 
to these optional visits.
5.
Procedures for an Unscheduled 
Investigational Medicinal Product 
Dispensing Visit
See New wording column.
5.
Procedures for an 
Unscheduled Investigational 
Medicinal Product Dispensing 
Visit
•
conduct adverse events and 
adverse device effects inquiry
•
conduct concomitant 
medication inquiry
•
perform Albuterol eMDPI 
collection and accountability
Added additional procedures 
to these optional visits.
APPENDIX F. PRODUCT COMPLAINTS
I.
Clinical Product Complaints / Device 
Deficiency
….
Each investigational center will be 
responsible for reporting a possible clinical 
I.
Clinical Product Complaints / 
Device Deficiency
….
Each investigational center will 
be responsible for reporting a 
Text was updated to be 
consistent with the latest 
Teva protocol template.
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Original text with changes shown
New wording
Reason/Justification for 
change
product complaint by completing the 
product complaint form (adverse device 
effect form) provided by Teva and emailing 
it to 
clinical.productcomplaints@tevapharm.com 
within 48 hours of becoming aware of the 
issue.
For complaints involving a 
device/combination product or other 
retrievable item, it is required that the 
device/combination product (or item) be 
sent back to the sponsor for investigative 
testing whenever possible.
….
The investigator will record in the source 
documentation a description of the product 
complaint, the initial determination whether 
the deficiency could have led to a serious 
adverse event (Section II), and any actions 
taken to resolve the complaint and to 
preserve the safety of the patient.
….
See New wording column.
possible clinical product 
complaint by completing the 
product complaint form provided 
by Teva and emailing it to 
clinical.productcomplaints@tevap
harm.com within 48 hours of 
becoming aware of the issue.
For complaints involving a 
device/combination product or 
other retrievable item, it is 
required that the 
device/combination product (or 
item) be sent back to the sponsor 
for investigative testing whenever 
possible.
….
The investigator will record in the 
source documentation a 
description of the product 
complaint, the initial 
determination whether the 
deficiency could have led to a 
serious adverse event (Section II), 
and any actions taken to resolve 
the complaint and to preserve the 
safety of the patient.
….
II.
Assessment of Device 
Performance 
Device performance will be 
assessed by device deficiencies 
and product complaints.
A device deficiency is defined as 
any inadequacy of an 
investigational medical device 
with respect to its identity, 
quality, durability, reliability, 
safety, or performance (Appendix 
Figure 1). This definition includes 
malfunctions, use errors, 
inadequate labeling (eg, 
unintelligible label, incorrect 
expiry date), and product 
complaints that are related to the 
eMDPI. 
The investigator should use 
Appendix Table 1 and Appendix 
Table 2 to help make an initial 
determination whether the device 
deficiency could have led to a 
serious adverse event and notify 
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
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Original text with changes shown
New wording
Reason/Justification for 
change
the sponsor by completing the 
product complaint form provided 
by Teva and emailing it to 
clinical.productcomplaints@tevap
harm.com. 
Device deficiencies with potential 
serious adverse device effect are 
defined as deficiencies that might 
have led to a serious adverse 
device effect if (Appendix Figure 
1):
•
suitable action had not been 
taken (or)
•
intervention had not been 
made (or)
•
circumstances had been less 
fortunate
[Inserted Appendix Figure 1: 
Decision Tree for Device 
Deficiencies, Appendix Table 1: 
Potential Use-Related 
Deficiencies that Could Lead to 
Serious Adverse Events, and 
Appendix Table 2: Potential 
Design-Related Deficiencies that 
Could Lead to Serious Adverse 
Events]
16.3.
Amendment 02 Dated 26 February 2019
The primary reason for this amendment is to change unscheduled visits or telephone calls to 
Clinically Driven Assessments, if necessary, to clarify that these visits were generated by the 
interaction between HCP and the data provided by the dashboard. Other nonsignificant 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.
Table 3 (Study Procedures and Assessments), Table 4 (Investigational Medicinal Products Used 
in the Study), and Figure 2 (Overall Study Schematic Diagram) have been revised to reflect 
changes described below.
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Changes to the Protocol
Original text with changes shown
New wording
Reason/Justification for 
change
Title page
Lay person title: A Study to Test if Using 
the Albuterol eMDPI System is Effective in 
Getting Better Control of Asthma in 
Patients at Least 13 Years of Age with 
Asthma Compared to Usual Care
Lay person title: A Study to Test 
if Using the Albuterol eMDPI 
System is Effective in Getting 
Better Control of Asthma in 
Patients at Least 13 Years of Age 
Compared to Usual Care 
Deleted text to minimize 
redundancy. 
© 2019 2018 Teva Branded Pharmaceutical 
Products R&D, Inc.
© 2019 Teva Branded 
Pharmaceutical Products R&D, 
Inc.
Revised with correct year.
List of Abbreviations (Other sections affected by this change: Sections 1.3.1, 3.1, and 3.5 and Appendix B)
Brief Medication Beliefs about Medicines
Questionnaire
Beliefs about Medicines 
Questionnaire
Revised to correct the title of 
the questionnaire.
Section 1.1 Introduction (Other sections affected by this change: Sections 5.1.1 and 5.3.1)
On 21 December 2018, the US FDA 
approved Albuterol eMDPI as PROAIR® 
DIGIHALER™ (albuterol sulfate inhalation 
powder), 90 mcg of albuterol base per 
actuation, for treatment or prevention of 
bronchospasm in patients 4 years of age and 
older with reversible obstructive airway 
disease and prevention of exercise-induced 
bronchospasm in patients 4 years of age and 
older.
On 21 December 2018, the US 
FDA approved Albuterol eMDPI 
as PROAIR® DIGIHALER™ 
(albuterol sulfate inhalation 
powder), 90 mcg of albuterol base 
per actuation, for treatment or 
prevention of bronchospasm in 
patients 4 years of age and older 
with reversible obstructive airway 
disease and prevention of 
exercise-induced bronchospasm 
in patients 4 years of age and 
older.
Added text due to FDA 
approval.
Teva has developed is developing the 
eModule as part of a Digital System (DS) to 
assist a patient with asthma to appropriately 
use the eMDPI inhaler.
Teva has developed the eModule 
as part of a Digital System (DS) 
to assist a patient with asthma to 
appropriately use the eMDPI 
inhaler.
Revised to make past tense. 
Section 2.1 Primary and Secondary Study Objectives and Endpoints (Other sections affected by this 
change: Sections 10.5.1.)
The primary endpoint is the proportion of 
patients for DS and CC group patients 
achieving meaningful improvement defined 
as:
!
the proportion of patients with an 
ACT score greater than or equal to 
20 at the end of the 12-week 
treatment period
OR
!
the proportion of patients with an 
increase of at least 3 ACT units on 
The primary endpoint is the 
proportion of patients for the DS 
and CC groups achieving 
meaningful improvement, which 
is defined as an Asthma Control 
Test (ACT) score greater than or 
equal to 20 at the end of the 12 
week treatment period or an 
increase of at least 3 units on the 
ACT score from baseline at the 
end of the 12-week treatment 
period.
Revised to change format 
from bulleted list to 
paragraph, and ACT text 
revised for clarity.
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Parallel-group, Controlled Study - Asthma
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Original text with changes shown
New wording
Reason/Justification for 
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the ACT score from baseline at the 
end of the 12-week treatment 
period
Section 2.1 Primary and Secondary Study Objectives and Endpoints (Other sections affected by this 
change: Section 10.5.2)
o
number of discussions between
patient and HCP regarding inhaler
technique or adherence
o
number of discussions
between patient and
HCP regarding inhaler
technique or adherence
Revised for clarity and 
specificity.
Section 2.1 Primary and Secondary Study Objectives and Endpoints (Other sections affected by this 
change: Section 10.5.2)
o
addition of an oral or biologic
parenteral medication for asthma,)
including biologics
o
addition of an oral or
parenteral medication for
asthma, including
biologics
Revised for clarity and 
specificity.
Section 2.2. Exploratory Objectives and Endpoints (Other sections affected by this change: Section 10.5.3)
 
 
 
 
 
 
Section 2.2. Exploratory Objectives and Endpoints (Other sections affected by this change: Section 10.5.3)
 
 
 
 
 
 
 
 
 
Section 3.1. General Study Design and Study Schematic Diagram (Other sections affected by this change: 
Section 3.5 and Appendix B) 
Unscheduled visits or telephone calls
Clinically Driven Assessments, if necessary,
should be arranged, per the clinical 
judgement of the iHCP, managing the 
patient and can be via a telephone call or an 
on-site visit.
Clinically Driven Assessments, if 
necessary, should be arranged per 
the clinical judgement of the 
iHCP managing the patient and 
can be via a telephone call or an 
on-site visit.
Revised for clarity.
Section 3.1 General Study Design and Study Schematic Diagram
A follow-up telephone call will be made by 
the investigational center to all patients, 2 
weeks later, to and will confirm the DS 
group patients have patient has returned to 
previous asthma treatments.
A follow-up telephone call will be 
made by the investigational center 
to all patients, 2 weeks later, and 
will confirm the DS group 
patients have returned to previous 
asthma treatments.
Revised for clarity.
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Original text with changes shown
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Reason/Justification for 
change
Section 3.2 Planned Number of Patients and Countries
The study is expected to start in Q2 Q1
2019 and last until approximately Q2 Q1
2020.
The study is expected to start in 
Q2 2020 and last until 
approximately Q2 2021.
Revised with correct quarter.
Section 3.5 Schedule of Study Procedures and Assessments (Other sections affected by this change: 
Section , 4.3, 5.1, 5.6, and Appendix B)
End of Study Treatment
End of Treatment
Revised for accuracy since 
End of Study is defined as 
the follow-up telephone call 
for the last patient.
Table 3 Study Procedures and Assessments
g
The follow-up telephone call will be 
made to all patients, including those who 
end the study prematurely (except patients 
who withdraw consent).  If a patient in the 
DS group ends the study prematurely, in 
addition to following up on ongoing AEs 
and concomitant medications, the site will 
also confirm that the patient has returned to 
their previous asthma treatment.
g
The follow-up telephone call 
will be made to all patients, 
including those who end the study 
prematurely (except patients who 
withdraw consent).  If a patient in 
the DS group ends the study 
prematurely, in addition to 
following up on ongoing AEs and 
concomitant medications, the site 
will also confirm that the patient 
has returned to their previous 
asthma treatment.
Added footnote g for clarity. 
Section 4.2. Patient Exclusion Criteria
d.
The patient has a diagnosis of 
Chronic Obstructive Pulmonary 
Disease (COPD) or Asthma-COPD 
Overlap (ACO).
d.
The patient has a 
diagnosis of Chronic 
Obstructive Pulmonary 
Disease (COPD) or Asthma-
COPD Overlap (ACO).
Added an additional 
exclusion criterion.
Section 4.5 Rescreening
If the patient is rescreened, the an informed 
consent form (ICF) will may need to be 
resigned re-signed.
If the patient is rescreened, the 
informed consent form (ICF) will 
need to be re-signed.
Revised for accuracy.
Section 5.1.2.3 
Dashboard
The data available on the dashboard are the 
inhaler use data from the App and patient 
self-assessments from the App.
The data available on the 
dashboard are the inhaler use data 
and patient self-assessments from 
the App.
Revised for accuracy.
Section 5.2.3. 
Accountability
All Eempty, partially used, and unused 
inhalers will be collected at the end of the 
study, and all data will be downloaded from 
the inhalers. and will be returned to the 
sponsor or designee per sponsor 
instructions.
All empty, partially used, and 
unused inhalers will be collected 
at the end of the study and will be 
returned to the sponsor or 
designee per sponsor instructions.
Edited text to provide 
clarity.
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
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Original text with changes shown
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Reason/Justification for 
change
Table 4 Investigational Medicinal Products Used in the Study
Oral inhalation
Oral inhalation
Revised for accuracy and 
specificity to distinguish 
from nasal inhalation.
Section 6.1.1.
Asthma Control Test
The scores span the continuum of poor 
control of asthma (score of 5) to complete 
control of asthma (score of 25), with a 
cutoff score of 19 and below indicating 
patients with poorly controlled asthma 
(Schatz et al 2006).
The scores span the continuum of 
poor control of asthma (score of 
5) to complete control of asthma 
(score of 25), with a cutoff score 
of 19 and below indicating 
patients with poorly controlled 
asthma (Schatz et al 2006).
Revised for accuracy.
Section 6.1.2.
Beliefs about Medicines Questionnaire
6.1.2.
Brief Medication Beliefs about 
Medicines Questionnaire
The BMQ is a self reporting tool to measure 
screening adherence and barriers to 
adherence. The tool includes a 5 item 
Regimen Screen that asks patients how they 
took each medication in the past week, a 2
item Belief Screen that asks about drug 
effects and bothersome features, and a 2
item Recall Screen about potential 
difficulties remembering. The BMQ will be 
answered by patients, The BMQ is used to 
assess cognitive representations of medicine 
(Horne, Weinman, and Hankins 1999). The 
BMQ-Specific (BMQ-S11) is an 11-item 
questionnaire that assesses representation of 
medication prescribed for personal use and 
the BMQ-General assesses beliefs about 
medicines in general. For the purposes of 
this study, the BMQ-S11 will be completed 
by patients, 18 years of age or older, at the 
investigational center at Visit 1, Visit 2, or 
at the ET visit. 
6.1.2.
Beliefs about Medicines 
Questionnaire
The BMQ is used to assess 
cognitive representations of 
medicine (Horne, Weinman, and 
Hankins 1999). The BMQ-
Specific (BMQ-S11) is an 11-
item questionnaire that assesses 
representation of medication 
prescribed for personal use and 
the BMQ-General assesses beliefs 
about medicines in general. For 
the purposes of this study, the 
BMQ-S11 will be completed by 
patients, 18 years of age or older, 
at the investigational center at 
Visit 1, Visit 2, or at the ET visit.
Revised to correct the name 
and description of the 
questionnaire and to add 
reference.
Section 7.1.1.
Definition of an Adverse Event
A CAE will be defined by 1 of the 
following: 1) in-patient hospitalization 
because of asthma, 2) emergency treatment 
because of asthma, 3) a worsening of 
asthma symptoms leading to the use of 
prednisone or systemic corticosteroids for 3 
days or more, or 4) a reduction in FEV1 of 
20% or greater.
A CAE will be defined by 1 of 
the following: 1) in-patient 
hospitalization because of asthma, 
2) emergency treatment because 
of asthma, 3) a worsening of 
asthma symptoms leading to the 
use of prednisone or systemic 
corticosteroids for 3 days or 
more, or 4) a reduction in FEV1 
of 20% or greater.
Added text for clarity and 
specificity.
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Parallel-group, Controlled Study - Asthma
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Original text with changes shown
New wording
Reason/Justification for 
change
Section 7.1.6.
Protocol-Defined Adverse Events Not for Expedited Reporting
All adverse events will be reported 
according to regulatory requirements. No 
protocol-defined adverse events of special 
interest were identified for this study.
All adverse events will be 
reported according to regulatory 
requirements. No protocol-
defined adverse events of special 
interest were identified for this 
study.
Added for clarity.
Section 7.3. Pregnancy
All pregnancies of women participating in 
the study and female partners of men 
participating in the study, that occur during 
the study, or within at least 5 half-lives or 
30 days for unknown 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.
All pregnancies of women 
participating in the study, that 
occur during the study, or within 
at least 5 half-lives or 30 days for 
unknown 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.
Deleted text to minimize 
redundancy.
Section 10.1.
Sample Size and Power Considerations (Other sections affected by this change: Section 
16)
With this sample size and assuming a true 
absolute difference in proportions 
(treatment effect as the estimated response 
rate for the CC group is 60% and for the DS 
group is 73%) between the groups of at least 
13%, the probability that the posterior 
probability will be at least 95% is 0.77 
(power) (analogous to 1-sided p-value < 
0.05) (Merchant et al 2016).
With this sample size and 
assuming a true absolute 
difference in proportions 
(treatment effect as the estimated 
response rate for the CC group is 
60% and for the DS group is 
73%) between the groups of at 
least 13%, the probability that the 
posterior probability will be at 
least 95% is 0.77 (power) 
(analogous to 1-sided p-value 
< 0.05) (Merchant et al 2016).
Added for clarity and 
specificity.
Section 10.5.
Analyses
Efficacy analysis
analysis
Deleted text since efficacy
of the drug product will not 
be evaluated in this study.
Appendix A Clinical Laboratories and Other Departments and Institutions
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Original text with changes shown
New wording
Reason/Justification for 
change
 
 
Added for completeness.
Appendix B Study Procedures and Assessments by Visit
The following procedures and assessments 
will be performed at unscheduled visits and 
unscheduled phone calls a Clinically Driven 
Assessment: 
!
conduct adverse events and 
adverse device effects inquiry
!
conduct concomitant medication 
inquiry 
!
record reason for unscheduled visit 
or call
!
measure vital signs (unscheduled 
visit only)
!
dispense Albuterol eMDPI as 
needed (unscheduled visit only if 
on-site and necessary)
!
perform Albuterol eMDPI 
collection and accountability 
(unscheduled visit only)
!
review patient compliance
!
iHCP asks Asthma Management 
questions
The following procedures and 
assessments will be performed at 
a Clinically Driven Assessment: 
!
iHCP asks Asthma 
Management questions
!
dispense Albuterol 
eMDPI as needed (if on-
site and necessary)
Revised to align with 
Table 3, and edited order of 
bullets to prioritize Asthma 
Management questions.
5.
Procedures for an Unscheduled 
Investigational Medicinal Product 
Dispensing Visit
The following procedures and assessments 
will be performed at an unscheduled IMP 
dispensing visit:
•
dispense test investigational medicinal 
product (IMP) to DS group patients
5.
Procedures for an 
Unscheduled Investigational 
Medicinal Product Dispensing 
Visit
The following procedures and 
assessments will be performed at 
an unscheduled IMP dispensing 
visit:
•
dispense test investigational 
medicinal product (IMP) to DS 
group patients
Added text to align with 
Table 3.
Appendix C Quality Control and Quality Assurance
Protocol deviations violations
Protocol deviations
Edited due to template 
change.
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Parallel-group, Controlled Study - Asthma
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16.4.
Amendment 01 Dated 13 December 2018
The primary reason for this amendment is the deletion of inclusion criterion “d”. This 
amendment is considered to be significant (ie, requires approval by CA, IEC, and/or IRB) by the 
sponsor’s Authorized Representative. Other nonsignificant 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.
Table 3 (Study Procedures and Assessments) and Figure 2 (Overall Study Schematic Diagram) 
have been revised to reflect changes described below.
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
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Changes to the Protocol
Original text with changes shown
New wording
Reason/Justification for 
change
Title page (Other sections affected by this change: Investigator Agreement, Coordinating Investigator 
Agreement, Sections 3.1 and 4.1 )
CONNected Electronic Inhalers Asthma 
Control Trial 1 (“CONNECT 1”), a 12-
Week Treatment, Multicenter, Open-Label, 
Randomized, Parallel Group Comparison, 
Feasibility Study to Evaluate the 
Effectiveness of the Albuterol eMDPI 
Digital System, to Optimize Outcomes in 
Patients at Least 1213 Years of Age or 
Older with Asthma
CONNected Electronic Inhalers 
Asthma Control Trial 1 
(“CONNECT 1”), a 12-Week 
Treatment, Multicenter, 
Open-Label, Randomized, 
Parallel Group Comparison, 
Feasibility Study to Evaluate the 
Effectiveness of the Albuterol 
eMDPI Digital System, to 
Optimize Outcomes in Patients at 
Least 13 Years of Age or Older 
with Asthma
Minimum age changed to 
match the minimum age 
requirement for use of the 
App.
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
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Original text with changes shown
New wording
Reason/Justification for 
change
Title page
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 
and/or its affiliates.
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 and/or its 
affiliates.
Added by Teva legal.
List of Abbreviations
OCS   oral corticosteroid
ET        Early Termination
MID     minimally important 
difference
RTSM  Randomization and Trial 
Supply Management
Abbreviation OCS deleted –
no longer in text
Abbreviations ET, MID, and 
RTSM added
Section 1.1 Introduction (Other section affected by this change: Section 5.1.1)
From the App, data may be transmitted to 
the Digital Health Platform (DHP), which 
consists of a cloud solution, and then to a
and provider-facing dashboard.
From the App, data may be 
transmitted to the Digital Health 
Platform (DHP), which consists 
of a cloud solution, and then to a 
provider-facing dashboard.
Reworded to clarify that the 
dashboard is not part of the 
DHP.
Section 1.1 Introduction (Other sections affected by this change: Section 1.3.1, 2.1, 6.1.4, and 10.5.2)
The study will also assess mean weekly 
SABA usage and the number of SABA-free 
days, the asthma management actions of 
investigational heath care providers (iHCPs) 
using the dashboard as part of the DS, and 
will collect information using patient 
questionnaires that focus on patients’ beliefs 
and perceptions about their disease and 
inhaler satisfaction, as well as patient and 
investigativeional center personnel 
questionnaires on system usability.
The study will also assess mean 
weekly SABA usage and the 
number of SABA-free days, the 
asthma management actions of 
investigational heath care 
providers (iHCPs) using the 
dashboard as part of the DS, and 
will collect information using 
patient questionnaires that focus 
on patients’ beliefs and 
perceptions about their disease 
and inhaler satisfaction, as well as 
patient and investigational center 
personnel system usability.
Corrected wording and 
added wording to clarify that 
the investigational center 
personnel will also complete 
a SUS regarding their 
interactions with the 
dashboard.
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Reason/Justification for 
change
Section 1.3.1 Known and Potential Benefits and Risks of the Test Investigational Medicinal Product(s) 
(Other sections affected by this change: Sections 2.1, 3.1, 6.1.1, 6.1.2, 6.1.3,  6.1.4, 10.5.2, and Appendix B)
In addition to assessing the technical 
reliability experienced by patients using the 
Albuterol eMDPI DS, the study also uses 2 
patient questionnaires, the Brief Medication 
Questionnaire (BMQ) and the Brief Illness 
Perception Questionnaire (BIPQ) for all 
patients, 18 years of age or older, in both 
groups, as well as the System Usability 
Scale (SUS) for patients, 18 years of age or 
older, in the DS group and investigational 
center personnel to complete. 
In addition to assessing the 
technical reliability experienced 
by patients using the Albuterol 
eMDPI DS, the study also uses 2 
patient questionnaires, the Brief 
Medication Questionnaire (BMQ) 
and the Brief Illness Perception 
Questionnaire (BIPQ) for all 
patients, 18 years of age or older, 
in both groups, as well as the 
System Usability Scale (SUS) for 
patients, 18 years of age or older, 
in the DS group and 
investigational center personnel to 
complete. 
Age of 18 years or older 
added to descriptions of the 
BMQ, BIPQ, and SUS 
questionnaires since these 
questionnaires are not 
validated in patients under 
18 years of age. 
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New wording
Reason/Justification for 
change
Section 2.2 Exploratory Objectives and Endpoints (Other section affected by this change: Section 3.1)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 3.1 General Study Design and Study Schematic Diagram (Other sections affected by this change: 
Section 5.8 and Appendix B) 
Patients with suboptimal asthma control 
will be enrolled in the study and 
randomized in a 1:1 ratio to 1 of 2 parallel 
groups stratified by investigational center: 
DS group patients utilizing the Albuterol 
eMDPI DS, including inhaler, App, DHP 
(Cloud solution), and dashboard, and CC 
group patients who will be treated with their 
standard of care albuterol-administering 
rescue inhalers and will not use the DS 
during the treatment period. Similar data 
will be collected regarding outcomes for the 
CC group: ACT after 12 to 14 weeks, BMQ 
and BIPQ responses, and the frequency of 
CAEs (moderate and/or severe).
…. A baseline ACT score for all patients, 
and BMQ, and BIPQ responses for patients 
18 years of age or older will be collected.
Patients with suboptimal asthma 
control will be enrolled in the 
study and randomized in a 1:1 
ratio to 1 of 2 parallel groups
stratified by investigational 
center: DS group patients 
utilizing the Albuterol eMDPI 
DS, including inhaler, App, DHP 
(Cloud solution), and dashboard, 
and CC group patients who will 
be treated with their standard of 
care albuterol-administering 
rescue inhalers and will not use 
the DS during the treatment 
period. Similar data will be 
collected regarding outcomes for 
the CC group: ACT after 12 to 14 
weeks, BMQ and BIPQ 
responses, and the frequency of 
CAEs. 
…. A baseline ACT score for all 
patients, and BMQ and BIPQ 
responses for patients 18 years of 
age or older will be collected.
Stratifying by investigational 
center in the analysis model 
to adjust for investigational 
center difference if there is 
any.
“for all patients” added to 
ACT score for clarity.
Section 3.1 General Study Design and Study Schematic Diagram (Other section affected by this change: 
Appendix B)
Patients in the CC group will be reimbursed 
or given a voucher to use to purchase their 
existing rescue medications.
Patients in the CC group will be 
reimbursed or given a voucher to 
use to purchase their existing 
rescue medications.
Added the option of 
reimbursement.
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Original text with changes shown
New wording
Reason/Justification for 
change
Section 3.1 General Study Design and Study Schematic Diagram 
For all patients, at Visit 2 and at each 
unscheduled visit or telephone call, the 
iHCP will record answers to various
Asthma Management questions regarding 
what interventions occurred as a 
consequence of the telephone call or visit, 
including discussions regarding adherence, 
or inhaler technique, treatment adjustments, 
or additions of new treatments, including 
biologic medication usage.
For all patients, at Visit 2 and at 
each unscheduled visit or 
telephone call, the iHCP will 
record answers to Asthma 
Management questions regarding 
what interventions occurred as a 
consequence of the telephone call 
or visit, including discussions 
regarding adherence, or inhaler 
technique, treatment adjustments, 
or additions of new treatments, 
including biologic medication 
usage.
Assigned a name to the 
iHCP questions.
Section 3.2 Planned Number of Patients and Countries
Planned Study Period: The study is 
expected to start in Q1/2019 and last until 
approximately Q1/2020.
Planned Study Period: The 
study is expected to start in Q1 
2019 and last until approximately 
Q1 2020.
Virgule removed and dates 
corrected under Study 
Duration.
Section 4 Selection and Withdrawal of Patients
Changes to inclusion or exclusion 
criteria are indicated below and 
detailed in Section 17.
Sentence added per 
amendment template.
Section 4.1 Patient Inclusion Criteria
c. The patient is currently on treatment with 
an moderate to high dose ICS with a long-
acting beta2 agonist (LABA).
d. The patient has been receiving the current 
asthma treatment in the investigational 
center for less than or equal to 12 weeks 
prior to informed consent.
f. The patient can read and communicate in 
English and is familiar with and is willing to 
use his/her own smart device and download 
and use the App.
c. The patient is currently on 
treatment with an ICS with a 
long-acting beta2 agonist (LABA).
f. The patient can read and 
communicate in English and is 
familiar with and is willing to use 
his/her own smart device and 
download and use the App.
Deleted “moderate to high 
dose”.  Any amount of ICS 
with LABA is acceptable.
Deleted “d” to not restrict 
the target population who 
will use the DS and changed 
the letters of the remaining 
inclusion criteria to update 
them accordingly.
Revised “f” since the App is 
only available in English.
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Original text with changes shown
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Reason/Justification for 
change
Section 4.2  Patient Exclusion Criteria
f. The patient is currently being treated with 
oral corticosteroids (OCS) systemic 
corticosteroids (oral, intramuscular, or 
intravenous) or has been treated within the 
last 30 days.
f. The patient is currently being 
treated with systemic 
corticosteroids (oral, 
intramuscular, or intravenous) or 
has been treated within the last 
30 days. 
Exclusion criterion 
expanded to include other 
types of corticosteroids.
Section 4.3 Withdrawal Criteria and Procedures for the Patient
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/or adverse device effect page and 
the termination page of the CRF will be 
completed at that time.
The specific event or test result 
(including repeated test results, as 
applicable) must be recorded both 
on the source documentation and 
in the CRF; the adverse events 
page and/or adverse device effect 
page and the termination page of 
the CRF will be completed at that 
time.
Sentence corrected to 
include the adverse device 
effect page as a CRF page to 
be completed at withdrawal.
Section 4.5 Rescreening
A patient who is screened but not enrolled 
within 7 days of screening, because
inclusion and exclusion criteria were not 
met  he/she did not satisfy 
inclusion/exclusion criteria or enrollment 
did not occur within the specified time, may 
be considered for rescreening once if, for 
example, there is a change in the patient’s 
medical background or a modification of 
study inclusion and exclusion criteria.
A patient who is screened but not 
enrolled within 7 days of 
screening, because he/she did not 
satisfy inclusion/exclusion criteria 
or enrollment did not occur within 
the specified time, may be 
considered for rescreening once 
if, for example, there is a change 
in the patient’s medical 
background or a modification of 
study inclusion and exclusion 
criteria.
Revised because the patient 
could not meet both 
inclusion and exclusion 
criteria. Reworded for 
clarity.
Section 5.1.1 Test Investigational Medicinal Product
The information from the eModule may be 
transmitted wirelessly (Bluetooth Low 
Energy) to an App. From the App, data may 
be transmitted to the DHP, which consists 
of a cloud solution, and then to a dashboard. 
This allows the patient and/or the caregiver 
to track when and how well the inhaler was 
used.
By consenting to enroll in the study, the 
patient must also download the smart device 
App (with the assistance of investigational 
site personnel), accept the smart device 
The information from the 
eModule may be transmitted 
wirelessly (Bluetooth Low 
Energy) to an App. From the 
App, data may be transmitted to 
the DHP, which consists of a 
cloud solution, and then to a 
dashboard. This allows the patient 
and/or the caregiver to track when 
and how well the inhaler was 
used.
By consenting to enroll in the 
study, the patient must also 
download the smart device App 
(with the assistance of 
Paragraph moved from 
earlier in this section to 
create better flow into new 
paragraph.
Teva Legal and Data Privacy 
provided more precise 
language surrounding 
privacy and terms of use.
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Original text with changes shown
New wording
Reason/Justification for 
change
App’s Privacy Notice and Terms of Use, 
and also agree to share his/her data to a 
provider-facing dashboard utilized by the 
iHCP and investigational center study 
team. An ICF will be provided to the 
patients which will elaborate, among other 
ways, Teva's ways of use and storing of 
patient data collected through the smart 
device App. The patient will be entering 
into a direct contractual relationship with 
Teva which will govern, among other 
things, Teva’s rights to use and store patient 
data collected through the smart device 
App. If the patient does not accept the 
smart device App’s Privacy Notice and 
Terms of Use and does not also agree to 
share their data to the provider-facing 
dashboard utilized by the iHCP and 
investigational center study team, then the 
patient cannot enroll in the study. 
investigational site personnel), 
accept the smart device App’s 
Privacy Notice and Terms of Use, 
and also agree to share his/her 
data to a provider-facing 
dashboard utilized by the iHCP 
and investigational center study 
team. An ICF will be provided to 
the patients which will elaborate, 
among other ways, Teva's ways 
of use and storing of patient data 
collected through the smart 
device App. The patient will be 
entering into a direct contractual 
relationship with Teva which will 
govern, among other things, 
Teva’s rights to use and store 
patient data collected through the 
smart device App. If the patient 
does not accept the smart device 
App’s Privacy Notice and Terms 
of Use and does not also agree to 
share their data to the provider-
facing dashboard utilized by the 
iHCP and investigational center 
study team, then the patient 
cannot enroll in the study. 
Section 5.1.2.1 Application
The intention of the smart device App is to 
engage patients with respiratory disease
asthma and/or COPD (and their caregivers) 
by tracking medication usage, raising 
awareness of medication use patterns, 
allowing users to self-assess their 
respiratory symptoms on a daily basis, 
sharing information on local environmental 
conditions, and producing user reports to 
review their data over time.
The software consists of a mobile smart 
device application compatible for iPhone 
operating systems (iOS) and Android 
operating systems that will store data locally 
on the patient's smart device. The App will 
receive a patient’s health data automatically 
from the inhaler devices via Bluetooth on a 
smart device. The smart device camera will 
be used for scanning and pairing. This data 
The intention of the smart device
App is to engage patients with 
asthma and/or COPD (and their 
caregivers) by tracking 
medication usage, raising 
awareness of medication use 
patterns, allowing users to self-
assess their respiratory symptoms 
on a daily basis, sharing 
information on local 
environmental conditions, and 
producing user reports to review 
their data over time.
The software consists of a smart 
device application compatible for 
iPhone operating systems (iOS) 
and Android operating systems 
that will store data locally on the 
patient's smart device. The App 
Changed “respiratory 
disease” to “asthma and/or 
COPD” to be more specific.
“Mobile” revised to” smart 
device” for consistency 
within the protocol. Type of 
data added.  The smart 
device camera sentence was 
moved to this section from 
Section 5.1.2.2 for 
correctness.
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Parallel-group, Controlled Study - Asthma
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Original text with changes shown
New wording
Reason/Justification for 
change
will allow the patient to track their usage of 
medication, inhalation results, and self-
assessments related to their asthma or 
COPD respiratory conditions. The App gets 
environment information from 1 or more 
web services.
will receive a patient’s health data 
automatically from the inhaler 
devices via Bluetooth on a smart 
device. The smart device camera 
will be used for scanning and 
pairing. This data will allow the 
patient to track their usage of 
medication, inhalation results, and 
self-assessments related to their 
asthma or COPD. The App gets 
environment information from 1 
or more web services.
Section 5.1.2.2 Teva Digital Health Platform (Cloud Solution)
The Teva DHP is a system that stores and 
transfers health data collected from the App
and the inhaler. The cloud solution 
automatically synchronizes with the App 
after every events captured and/or at 
predetermined time periods/intervals. An 
internet connection to the smart device (eg, 
via wireless or cellular phone network) is 
required in order for communication to be 
established between the App and the cloud 
solution.
The phone camera will be used for scanning 
and pairing. The cloud solution will not 
send any notifications to the App. The cloud 
solution does not create, modify, or delete 
patient information.
By consenting to enrollment in the study 
and approving the privacy policy and terms 
of use, the patient accepts data 
synchronization with the cloud solution. If a 
patient does not provide consent to 
synchronize his/her App, no data will be 
transmitted to the cloud solution. Patient 
privacy will be maintained according to the 
laws and regulations, and patient identifiers 
will be substituted to maintain a patient’s 
anonymity privacy to reviewers of the data.
The Teva DHP is a system that 
stores and transfers health data 
collected from the App. The 
cloud solution automatically 
synchronizes with the App after 
events and/or at predetermined 
time periods/intervals. An internet 
connection to the smart device 
(eg, wireless or cellular phone 
network) is required in order for 
communication to be established 
between the App and the cloud 
solution. The cloud solution will 
not send any notifications to the 
App. The cloud solution does not 
create, modify, or delete patient 
information
Patient privacy will be maintained 
according to the laws and 
regulations, and patient identifiers 
will be substituted to maintain a 
patient’s privacy to reviewers of 
the data.
Paragraphs reordered and 
language revised for clarity. 
Deleted language in this 
section and new language 
added to Section 5.1.1 for 
better placement within the 
document. 
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Original text with changes shown
New wording
Reason/Justification for 
change
Section 5.1.2.3 Dashboard
The data available on the dashboard are the 
inhaler data from the App and patient self-
assessments. , and environmental 
information received by the App. By 
default, data are not available on the 
dashboard (although stored on the cloud), 
unless the patient is required per the 
treatment group and gives consent to 
sharing of the data with the HCP in the 
informed consent. 
The data available on the 
dashboard are the inhaler data 
from the App and patient self-
assessments. The patient has no 
interaction with the dashboard. 
Teva personnel will have no 
access to the dashboard.
Environmental information 
included in error and now 
deleted. Deleted consent 
language and new language 
added to Section 5.1.1.
Section 5.2.1 Storage and Security (Other section affected by this change: Section 5.8)
The investigational center personnel are 
responsible for acknowledging receipt of 
the IMP using the interactive response 
technology a Randomization and Trial 
Supply Management (RTSM) system.
The investigational center 
personnel are responsible for 
acknowledging receipt of the IMP 
using a Randomization and Trial 
Supply Management (RTSM) 
system. 
Revised to make consistent 
with text used in the 
protocol.
Section 6.1.1 Asthma Control Test (Other sections affected by this change: Sections 6.1.2 and 6.1.3)
The self-administered version of the ACT 
will be answered by the patients at the 
investigational center at Visit 1, and Visit 2,
and at any unscheduled visit or at the Early 
Termination visit.
The self-administered version of 
the ACT will be answered by the 
patients at the investigational 
center at Visit 1, Visit 2, or at the 
Early Termination visit.
Corrected the visits when the 
questionnaires should be 
given to patients. 
Section 6.1.4 System Usability Questionnaire
The SUS will be answered by patients in the 
DS group, 18 years of age or older, at Visit 
2, or at the ET visit. The SUS will be 
completed after all other questionnaires.
A SUS will be completed by investigational 
center personnel, regarding the use of the 
dashboard, at the end of the study.
The SUS will be answered by 
patients in the DS group, 18 years 
of age or older, at Visit 2, or at 
the ET visit. The SUS will be 
completed after all other 
questionnaires.
A SUS will be completed by 
investigational center personnel, 
regarding the use of the 
dashboard, at the end of the study.
Clarified when the SUS will 
be completed by patients and 
investigational center 
personnel.
Section 7.1.1 Definition of an Adverse Event
An asthma exacerbation CAE will be 
defined by 1 of the following: 1) a reduction 
in FEV1 of 20% or greater, 2) 1) in-patient 
hospitalization because of asthma, 32) 
emergency treatment because of asthma, or 
43) use of prednisone or systemic 
A CAE will be defined by 1 of 
the following: 1) in-patient 
hospitalization because of asthma, 
2) emergency treatment because 
of asthma, 3) use of prednisone or 
systemic corticosteroids for 3 
Moved contents of Section 
7.1.7 to this section, deleted 
first paragraph, and 
reordered and corrected 
errors.
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Original text with changes shown
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Reason/Justification for 
change
corticosteroids for 3 days or more, or 4) a 
reduction in FEV1 of 20% or greater,.
Patients will be instructed to contact the 
study investigational center in the event of 
an asthma exacerbation CAE.
All CAE events require documentation by 
the investigator in the CAE Exacerbation
Page in the CRF, as well as in the adverse 
event CRF. All evaluations entered into the 
CAE Exacerbation Page require the 
investigational center to obtain source 
documentation of all asthma exacerbations 
CAEs that occur during the treatment period 
to confirm the accuracy of the information 
obtained from the patient. Any CAE that 
meets serious adverse event criteria will be 
reported as a serious adverse event 
(Section 7.1.5.1).
The process for reporting a protocol defined 
adverse event of special interest is the same 
as that for reporting a serious adverse event 
(Section 7.1.5.3). Protocol defined adverse 
events of special interest are to be reported 
to GPSP and can be either serious or 
nonserious, according to the criteria 
outlined in Section 7.1.5.1.
days or more, or 4) a reduction in 
FEV1 of 20% or greater. Patients 
will be instructed to contact the 
study investigational center in the 
event of a CAE.
All CAE events require 
documentation by the investigator 
in the CAE Page in the CRF, as 
well as in the adverse event CRF.  
All evaluations entered into the 
CAE Page require the 
investigational center to obtain 
source documentation of all 
CAEs that occur during the 
treatment period to confirm the 
accuracy of the information 
obtained from the patient. Any 
CAE that meets serious adverse 
event criteria will be reported as a 
serious adverse event 
(Section 7.1.5.1). 
Section 10.1 Sample Size and Power Considerations
The recommended sample size for the study 
is 150 evaluable patients per group (1030 
investigational centers, with each 
investigational center enrolling at least 15
10 patients), 300 patients in total.
The recommended sample size 
for the study is 150 evaluable 
patients per group (30 
investigational centers, with each 
investigational center enrolling at 
least 10 patients), 300 patients in 
total.
This change was made to 
correct the number of 
investigational centers and 
the number of patients to be 
enrolled at each 
investigational center.
Section 10.5.4.1 Primary Efficacy Analysis
2.  A binary distribution is assumed for the 
primary endpoint. Patients who discontinue 
early due to technology failure, disliking the 
digital platform, disease worsening, adverse 
experience or disliking the IMP will be 
counted as treatment failures. Patients who 
discontinue early due to reasons not 
2.
A binary distribution is 
assumed for the primary endpoint. 
Patients who discontinue early 
due to technology failure, 
disliking the digital platform, 
disease worsening, adverse 
experience or disliking the IMP 
The equation was changed 
because baseline ACT value 
is another factor we need to 
adjust assuming a correlation 
between change from 
baseline and baseline ACT 
scores.
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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
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Original text with changes shown
New wording
Reason/Justification for 
change
associated with these reasons will be 
assumed to have outcomes similar to others 
in their treatment group. For those who 
discontinue early not due to these reasons, 
the ACT value assessed at the ET visit will 
be used.
3.
Intercurrent events of withdrawal due 
to disliking technology, technology failure, 
disease worsening, adverse experiences, or 
disliking the IMP will be captured through 
definition of analysis set.
4.3. Summary measure: A successful 
differentiation between the 2 groups will be 
determined by a Bayesian posterior 
probability for  greater than 0.95 (1-
sided). The following statistical methods 
will be utilized:
Logistic regression model allowing for 
different response rates at enrolling 
investigational centers will be used for 
testing the hypothesis :  = 0, :  >
0 in the following model:


1 −
=  +   
+ 
Where pij denotes response proportion in
each group for each investigational center. 
Where i = treatment group, j = 
investigational center, xij = treatment group 
i for investigational center j,  pij  = response 
proportion of treatment group i in 
investigational center j.
will be counted as treatment 
failures For those who 
discontinue early not due to these 
reasons, the ACT value assessed 
at the ET visit will be used.
3.
Summary measure: A 
successful differentiation between 
the 2 groups will be determined 
by a Bayesian posterior 
probability for  greater than 
0.95 (1-sided). The following
statistical methods will be 
utilized:
Logistic regression model 
allowing for different response 
rates at enrolling investigational 
centers will be used for testing the 
hypothesis :  = 0, :  > 0
in the following model:


1 −
= 
+   
+ 
Where i = treatment group, j = 
investigational center, xij = 
treatment group i for 
investigational center j,  pij  = 
response proportion of treatment 
group i in investigational center j. 
Number 3 was deleted 
because it is no longer 
relevant since number 2 
already covers all the 
reasons for early 
termination.
Section 10.5.4.3 Secondary Efficacy Analysis (Other section affected by this change: Section 10.7)
For continuous variables, descriptive 
statistics (number [n], mean, standard 
deviation, median, minimum, and 
maximum) will be provided for actual
observed values and changes from baseline 
to each time point.
For continuous variables, 
descriptive statistics (number [n], 
mean, standard deviation, median, 
minimum, and maximum) will be 
provided for observed values and 
changes from baseline to each 
time point.
Word changed for accuracy.
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Original text with changes shown
New wording
Reason/Justification for 
change
Appendix A. Clinical Laboratories and Other Departments and Institutions
Teva Pharmaceuticals
Teva Pharmaceuticals
Teva Pharmaceuticals
Change of Safety Physician.
Appendix B. Study Procedures and Assessments by Visit, 1. Procedures for Screening/Baseline Visit (Visit 
1, Day 1) 
!
administer pre-intervention 
Asthma Control Test (ACT) to 
all patients 
!
administer Brief Medication 
Questionnaire (BMQ) and 
Brief Illness Perception 
Questionnaire (BIPQ) to 
patients 18 years of age or 
older
!
create and provide patient-
specific unique email account 
to patients in the Digital 
System (DS) group for 
registration and onboarding in 
the application (App)
!
reimburse or dispense voucher 
to patients in the concurrent 
control (CC) group
!
administer pre-
intervention Asthma 
Control Test (ACT) 
to all patients 
!
administer Brief 
Medication 
Questionnaire 
(BMQ) and Brief 
Illness Perception 
Questionnaire 
(BIPQ) to patients 
18 years of age or 
older
!
create and provide 
patient-specific 
unique email 
account to patients 
in the Digital 
System (DS) group 
for registration and 
onboarding in the 
application (App)
!
reimburse or 
dispense voucher to 
patients in the 
concurrent control 
(CC) group
Text revised to match Table 
3.
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Original text with changes shown
New wording
Reason/Justification for 
change
Appendix B, Study Procedures and Assessments by Visit, 3. Procedures for End of Study/Early 
Termination Visit (Visit 2, Day 84 + up to 7 days)
!
iHCP asks Asthma 
Management questions
!
administer ACT to all patients 
and BMQ and BIPQ, to all
patients, 18 years of age or 
older
!
administer System Usability 
Scale (SUS) to patients in the 
DS group, 18 years of age or 
older and investigational 
center personnel
!
iHCP asks Asthma 
Management 
questions
!
administer ACT to 
all patients and 
BMQ and BIPQ, to 
patients, 18 years of 
age or older
!
administer System 
Usability Scales 
(SUS) to patients in 
the DS group, 18 
years of age or 
older, and 
investigational 
center personnel
Text added to match text in 
Table 3.
Appendix B. Study Procedures and Assessments by Visit, 4. Unscheduled Visits or Phone Calls
The following procedures and 
assessments will be performed at
Procedures performed during
unscheduled visits and unscheduled 
phone calls include: 
!
conducting adverse events and 
adverse device effects inquiry
!
conducting concomitant 
medication inquiry 
!
recording reason for 
unscheduled visit or call
!
measureing vital signs 
(unscheduled visit only)
!
ACT, BMQ, and BIPQ 
(unscheduled visit only)
!
dispenseing Albuterol eMDPI 
as needed (unscheduled visit 
only)
The following procedures 
and assessments will be 
performed at unscheduled 
visits and unscheduled phone 
calls: 
!
conduct adverse 
events and adverse 
device effects 
inquiry
!
conduct concomitant 
medication inquiry 
!
record reason for 
unscheduled visit or 
call
!
measure vital signs 
(unscheduled visit 
only)
!
dispense Albuterol 
eMDPI as needed 
Text revised to match 
previous sections and to 
match Table 3
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Original text with changes shown
New wording
Reason/Justification for 
change
!
performing Albuterol eMDPI 
collection and accountability 
(unscheduled visit only)
!
reviewing patient compliance
!
iHCP asks Asthma 
management questions
(unscheduled visit 
only)
!
perform Albuterol 
eMDPI collection 
and accountability 
(unscheduled visit 
only)
!
review patient 
compliance
!
iHCP asks Asthma 
management 
questions
Appendix B, Study Procedures and Assessments by Visit, 5. Procedures for Follow-up Telephone Call 
(Day 98 + 7 days)
The following 
procedures and 
assessments will be 
performed at the follow-
up telephone call:
!
conduct adverse 
events and adverse 
device effects 
inquiry
!
conduct concomitant 
medication inquiry 
!
confirm that the 
patient has returned 
to previous asthma 
treatment
Text added to match text in 
Table 3.
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APPENDIX A. CLINICAL LABORATORIES AND OTHER 
DEPARTMENTS AND INSTITUTIONS
Sponsor’s Authorized Representative
Global Medical Affairs, Teva Pharmaceuticals
Sponsor’s Medical Expert/Contact Point 
Designated by the Sponsor for Further Information 
on the Study
 
Global Medical Affairs, 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
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APPENDIX B. STUDY PROCEDURES AND ASSESSMENTS BY VISIT
1. Procedures for Screening/Baseline Visit (Visit 1, Day 1)2
The following procedures and assessments will be performed at Visit 1:
!
obtain written informed consent/assent 
!
review inclusion and exclusion criteria
!
obtain medical history
!
obtain current medication and treatment history related to asthma
!
measure vital signs 
!
conduct adverse events and adverse device effects inquiry
!
inform patients of study restrictions and compliance requirements
!
administer pre-intervention Asthma Control Test (ACT) to all patients 
!
administer Beliefs about Medicines Questionnaire (BMQ) and Brief Illness 
Perception Questionnaire (BIPQ) to patients 18 years of age or older
!
randomize and assign patient number 
!
create and provide patient-specific unique email account to patients in the Digital 
System (DS) group for registration and onboarding in the application (App)
!
train patients in the DS group on use and proper technique of the albuterol multidose 
dry powder inhaler with integrated electronic module (Albuterol eMDPI)
!
dispense Albuterol eMDPI to patients in the DS group
!
reimburse or dispense voucher to patients in the concurrent control (CC) group
2. Procedures for Treatment Period (Day 1 through Day 84)
The following procedures and assessments will be performed during the Treatment Period:
!
resupply Albuterol eMDPI, if necessary
3. Procedures for End of Treatment/Early Termination Visit (Visit 2, Day 84 + up to 
7 days)
The following procedures and assessments will be performed at Visit 2:
!
conduct adverse events and adverse device effects inquiry
!
conduct concomitant medication inquiry
!
measure vital signs
!
iHCP asks Asthma Management questions
                                                
2 Patients may be enrolled up to 7 days after screening.
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!
administer ACT to all patients and BMQ and BIPQ, to patients, 18 years of age or 
older
!
administer System Usability Scale (SUS) to patients in the DS group, 18 years of age 
or older, and investigational center personnel
!
perform Albuterol eMDPI collection and accountability
!
remove the App from the patient’s smart device
4. Procedures for Clinically Driven Assessment(s) (If Necessary)
A Clinically Driven Assessment, which can either be via telephone or an on-site visit, may be 
performed at any time during the study at the patient’s request and as deemed necessary by 
the investigator. For DS patients, the investigator will have access to information from the 
Albuterol eMDPI on the patient’s SABA use and inhalation technique through the dashboard. 
If the investigator meets with or calls the patient as a result of an interaction with the 
dashboard, this will be captured as a Clinically Driven Assessment. 
The date and reason for the Clinically Driven Assessment (eg, treatment step up, treatment 
step down, adherence discussion, treatment for an asthma exacerbation, or other clinical 
encounters generated by the data from the Albuterol eMDPI), as well as any other data 
obtained from procedures and assessments, will be recorded in the patient’s source 
documents and the case report form (CRF) for patients in both groups, during the 12-week 
treatment period.
The following procedures and assessments will be performed at a Clinically Driven 
Assessment: 
!
conduct adverse events and adverse device effects inquiry
!
conduct concomitant medication inquiry
!
iHCP asks Asthma Management questions
!
dispense Albuterol eMDPI, as needed (if on-site and necessary)
Other procedures and assessments may be performed at the discretion of the investigator.
5. Procedures for an Unscheduled Investigational Medicinal Product Dispensing Visit
The following procedures and assessments will be performed at an unscheduled IMP 
dispensing visit:
!
conduct adverse events and adverse device effects inquiry
!
conduct concomitant medication inquiry
!
perform Albuterol eMDPI collection and accountability
!
dispense test investigational medicinal product (IMP) to DS group patients
6. Procedures for Follow-up Telephone Call (Day 98 + 7 days)
The following procedures and assessments will be performed at the follow-up telephone call:
!
conduct adverse events and adverse device effects inquiry
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!
conduct concomitant medication inquiry 
!
for DS group patients, confirm that the patient has returned to previous asthma 
treatment
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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/Institutional Review Board (IEC/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 Deviations
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 deviation. Protocol deviations may include nonadherence on the part of the 
patient, the investigator, or the sponsor to protocol-specific inclusion and exclusion criteria, 
primary objective variable criteria, or Good Clinical Practice (GCP) guidelines; noncompliance 
to investigational medicinal product (IMP) administration; or use of prohibited medications. 
Protocol deviations will be identified and recorded by investigational center personnel in the 
CRF. All protocol deviations will be reported to the responsible IEC/IRB, as required.
When a protocol deviation is reported, the sponsor will determine whether to withdraw 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 investigational center personnel learn that a patient who did not meet protocol 
inclusion and exclusion criteria was entered in a study, they must immediately inform the 
sponsor of the protocol deviation. If such patient has already completed the study or has 
withdrawn early, no action will be taken but the violation will be recorded.
Information to Study Personnel
The investigator is responsible for giving information about the study to all personnel members 
involved in the study or in any element of patient management, both before starting the study and 
during the course of the study (eg, when new personnel become involved). The investigator must 
ensure that all study personnel are qualified by education, experience, and training to perform 
their specific task. These study personnel members must be listed on the investigational center 
authorization form, which includes a clear description of each personnel member’s 
responsibilities. This list must be updated throughout the study, as necessary.
The study monitor is responsible for explaining the protocol to all study personnel, including the 
investigator, and for ensuring they comply with the protocol.
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Study Monitoring
To ensure compliance with GCP guidelines, the study monitor or representative is responsible 
for ensuring that patients have signed the informed consent form (ICF) and the study is 
conducted according to applicable Standard Operating Procedures (SOPs), the protocol, and 
other written instructions and regulatory guidelines.
The study monitor is the primary association between the sponsor and the investigator. The main 
responsibilities of the study monitor(s) are to visit the investigator before, during, and after the 
study to ensure that there is 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(s) 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 
documents 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.
In case of an emergency situation (eg, the COVID-19 pandemic), where study monitors may not 
be able to access the investigational centers for on-site visits, investigational centers will be 
monitored remotely, where allowed, and in accordance with local regulations.
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.
In case of an emergency situation (eg, the COVID-19 pandemic), where auditors may not be able 
to access the investigational centers for on-site visits, investigational centers will be monitored 
remotely, where allowed, and in accordance with local regulations.
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APPENDIX D. ETHICS
Informed Consent/Assent
For patients ≥18 years of age, 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 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 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.
For patients ages ≥13 to <18 years of age, the investigator, or a qualified person designated by 
the investigator, should fully inform the patient and parent/legally acceptable representative of 
all pertinent aspects of the study, including the written information approved by the IEC/IRB. All 
written and oral information about the study will be provided in a language as nontechnical as 
practical to be understood by the parent/legally acceptable representative and the patient. The 
patient and parent/legally acceptable representative should be given ample time and opportunity 
to inquire about details of the study and to decide whether or not to participate in the study. The 
above should be detailed in the source documents.
A personally signed and dated ICF 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.
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Competent Authorities and Independent Ethics Committees/Institutional Review Boards
Before this study starts, the protocol will be submitted to the national competent authority and to 
the respective IEC/IRB for review. As required, the study will not start at a given investigational 
center before the IEC/IRB and competent authority (as applicable) for the investigational center 
give written approval or a favorable opinion.
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. 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, 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 F.
PRODUCT COMPLAINTS
I.
Clinical Product Complaints/Device Deficiency 
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 
clinical.productcomplaints@tevapharm.com within 48 hours of becoming aware of the issue.
For complaints involving a device/combination product or other retrievable item, it is required 
that the device/combination product (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.
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.
Handling of Investigational Medicinal Product(s) and Devices 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 or devices, the sponsor will 
provide the information needed to handle the return.
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, if 
applicable.
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).
Documenting a Product Complaint
The investigator will record in the source documentation a description of the product complaint, 
the initial determination whether the deficiency could have led to a serious adverse event 
(Section II), 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.
II.
Assessment of Device Performance
Device performance will be assessed by device deficiencies and product complaints.
A device deficiency is defined as any inadequacy of an investigational medical device with 
respect to its identity, quality, durability, reliability, safety, or performance (Appendix Figure 1). 
This definition includes malfunctions, use errors, inadequate labeling (eg, unintelligible label, 
incorrect expiry date), and product complaints that are related to the eMDPI.
The investigator should use Appendix Table 1 and Appendix Table 2 to help make an initial 
determination whether the device deficiency could have led to a serious adverse event and notify 
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the sponsor by completing the product complaint form provided by Teva and emailing it to 
clinical.productcomplaints@tevapharm.com. 
Device deficiencies with potential serious adverse device effect are defined as deficiencies that 
might have led to a serious adverse device effect if (Appendix Figure 1):
!
suitable action had not been taken (or)
!
intervention had not been made (or)
!
circumstances had been less fortunate
Appendix Figure 1: Decision Tree for Device Deficiencies
IEC=Independent Ethics Committee; IRB=Institutional Review Board; SAE=serious adverse event.
Appendix Table 1: Potential Use-Related Deficiencies That Could Lead to Serious Adverse 
Events
Use Step
Use Error
Potential Hazard Situation
Potential Harm
Setup App (first 
use)
User thinks they need to use App 
to use inhaler
Continuous use - no dose
Worsening of condition
Preparing the 
inhaler
User opens cap with inhaler in 
upside down position/ User does 
not apply directional force to 
open cap
Continuous use - no dose
Worsening of condition
Inhalation
User does not understand the 
importance of not breathing into 
the inhaler / User does not 
realize inhaler is breath activated
Continuous use - no dose
Worsening of condition
Close cap after 
use
User does not apply directional 
force to close cap
Continuous use - no dose
Worsening of condition
End of life
User continues using inhaler 
when 0 inhalations remaining
Continuous use - no dose
Worsening of condition
Cleaning
User washes device in water
Continuous use - no dose
Worsening of condition
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Appendix Table 2: Potential Design-Related Deficiencies That Could Lead to Serious 
Adverse Events
Device Component
Failure Mode
Potential Hazard Situation
Potential Harm
Dose counter
Undercounting, dose counter 
displays doses remaining 
after the inhaler has 
dispensed 200 doses
Continuous use - no dose
Worsening of condition
Dustcap
Dustcap broken/ 
detached/misaligned
Continuous use - no dose
Worsening of condition
Other internal 
components
Drug not delivered
Continuous use - no dose
Worsening of condition
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Appendix G.
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 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 (eg, clinical laboratory, central 
image center, or electronic diary data), 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, IEC/IRB, and inspectors from competent 
authorities (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 (US) 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 (eg, central laboratory, bioanalytical laboratory, central 
image center, electronic diary data, electronic patient-reported outcome [ePRO] tablet), 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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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
122
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 
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, national and local laws, including, but not limited to:
!
full case histories
!
signed ICFs
!
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, electronic diary)
!
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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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
123
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 the 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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Parallel-group, Controlled Study - Asthma
Clinical Study Protocol with Amendment 04
Study ABS-AS-40138
124
Appendix H.
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” (International Committee of Medical Journal Editors [ICMJE] 
Recommendations 2017). 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 ICMJE 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.
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SAP_001.pdf: 
 
 
 
 
Statistical Analysis Plan 
 
 
CONNected Electronic Inhalers Asthma Control Trial 1 (“CONNECT 1”), a 12-
Week Treatment, Multicenter, Open-Label, Randomized, Parallel Group 
Comparison, Feasibility Study to Evaluate the Effectiveness of the Albuterol eMDPI 
Digital System, to Optimize Outcomes in Patients at Least 13 Years of Age or Older 
with Asthma 
 
 
Study Number ABS-AS-40138 
 
 
NCT03890666 
 
 
SAP Approval Date: 13 October 2021 


Parallel-group, Controlled Study - Asthma
Statistical Analysis Plan
Study ABS-AS-40138
1
 
Statistical Analysis Plan
Study Number ABS-AS-40138
CONNected Electronic Inhalers Asthma Control Trial 1 (“CONNECT 1”), a 12-Week 
Treatment, Multicenter, Open-Label, Randomized, Parallel Group Comparison, Feasibility Study 
to Evaluate the Effectiveness of the Albuterol eMDPI Digital System, to Optimize Outcomes in 
Patients at Least 13 Years of Age or Older with Asthma
Short title: A 12-Week Treatment Study to Evaluate the Effectiveness of Albuterol eMDPI DS in 
Patients 13 Years or Older with Asthma
Lay person title: A Study to Test if Using the Albuterol eMDPI System is Effective in Getting 
Better Control of Asthma in Patients at Least 13 Years of Age Compared to Usual Care
Feasibility Study
IND number: 104532;     NDA number: Not applicable;     BLA number: Not applicable;
EudraCT number: Not applicable
Approval Date: 13 October 2021
Sponsor
Teva Branded Pharmaceutical 
Products R&D, Inc.
145 Brandywine Parkway
West Chester, PA 19380
United States
Prepared by:
Teva Global Statistics
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Parallel-group, Controlled Study - Asthma
Statistical Analysis Plan
Study ABS-AS-40138
2
STATISTICAL ANALYSIS PLAN APPROVAL
Study No.:
CONNected Electronic Inhalers Asthma Control Trial 1 (“CONNECT 1”), a 
12-Week Treatment, Multicenter, Open-Label, Randomized, Parallel Group 
Comparison, Feasibility Study to Evaluate the Effectiveness of the Albuterol 
eMDPI Digital System, to Optimize Outcomes in Patients at Least 13 Years of 
Age or Older with Asthma
Study Title:
ABS-AS-40138
Statistical Analysis Plan for:
Interim Analysis
Integrated Summary of Efficacy
Final Analysis
Integrated Summary of Safety
Amendment: Not applicable
Author:
Teva Global Statistics
______________________________________________________________________________
Approver:
Date
______________________________________________________________________________
Approver:
Date
Executed signature pages are maintained separately within the Trial Master File
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Parallel-group, Controlled Study - Asthma
Statistical Analysis Plan
Study ABS-AS-40138
3
TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
STATISTICAL ANALYSIS PLAN APPROVAL..........................................................................2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................................7
INTRODUCTION ...........................................................................................................................9
1.
STUDY OBJECTIVES AND ENDPOINTS..............................................................10
1.1.
Primary and Secondary Study Objectives and Endpoints ..........................................10
1.2.
Exploratory Objectives and Endpoints.......................................................................11
2.
STUDY DESIGN .......................................................................................................12
2.1.
General Design ...........................................................................................................12
2.2.
Randomization and Blinding......................................................................................13
2.3.
Data Monitoring Committee.......................................................................................13
2.4.
Sample Size and Power Considerations .....................................................................13
2.5.
Sequence of Planned Analyses ...................................................................................14
2.5.1.
Planned Interim Analyses...........................................................................................14
2.5.2.
Final Analyses and Reporting.....................................................................................14
3.
ANALYSIS SETS ......................................................................................................15
3.1.
Intent-to-Treat Analysis Set........................................................................................15
3.2.
Modified Intent-to-Treat Analysis Set........................................................................15
3.3.
Safety Analysis Set.....................................................................................................15
4.
GENERAL ISSUES FOR DATA ANALYSIS..........................................................16
4.1.
General........................................................................................................................16
4.2.
Specification of Baseline Values................................................................................16
4.3.
Handling Withdrawals and Missing Data...................................................................16
4.4.
Study Days and Visits.................................................................................................16
5.
STUDY POPULATION.............................................................................................18
5.1.
General........................................................................................................................18
5.2.
Patient Disposition......................................................................................................18
5.3.
Demographics and Baseline Characteristics...............................................................18
5.4.
Medical History ..........................................................................................................18
5.5.
Prior Therapy and Medication....................................................................................18
5.6.
Study Protocol Deviations..........................................................................................18
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Parallel-group, Controlled Study - Asthma
Statistical Analysis Plan
Study ABS-AS-40138
4
6.
DATA ANALYSIS ....................................................................................................19
6.1.
General........................................................................................................................19
6.2.
Primary Endpoint and Analysis..................................................................................19
6.2.1.
Definition....................................................................................................................19
6.2.2.
Primary Analysis ........................................................................................................19
6.2.3.
Sensitivity Analysis ....................................................................................................20
6.3.
Secondary Endpoints and Analysis ............................................................................21
6.3.1.
Secondary Endpoint #1 – Description of Asthma Management Actions by 
the Investigational Center Healthcare Providers ........................................................21
6.3.1.1.
Definition....................................................................................................................21
6.3.1.2.
Analysis ......................................................................................................................22
6.3.2.
Secondary Endpoint #2 – Evaluation of Short-Acting Beta2 Agonists Usage ...........22
6.3.2.1.
Definition....................................................................................................................22
6.3.2.2.
Analysis ......................................................................................................................22
6.3.3.
Secondary Endpoint #3 – Usability and Acceptability of the Digital System............23
6.3.3.1.
Definition....................................................................................................................23
6.3.3.2.
Analysis ......................................................................................................................23
6.3.4.
Secondary Endpoint #4 – Assessment of Behavioral Correlates of 
Responsiveness to Digital Health Technology...........................................................23
6.3.4.1.
Definition....................................................................................................................23
6.3.4.2.
Analysis ......................................................................................................................24
6.4.
Exploratory/Other Endpoints Analysis.......................................................................24
6.4.1.
Definition....................................................................................................................24
6.4.2.
Analysis ......................................................................................................................24
7.
MULTIPLE COMPARISONS AND MULTIPLICITY ............................................25
8.
SAFETY ANALYSIS ................................................................................................26
8.1.
General........................................................................................................................26
8.2.
Duration of Exposure to IMP .....................................................................................26
8.3.
Inhalation Flow Parameters........................................................................................26
8.4.
Adverse Events ...........................................................................................................27
8.5.
Deaths .........................................................................................................................27
8.6.
Vital Signs ..................................................................................................................27
8.7.
Concomitant Medications or Therapies......................................................................28
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Parallel-group, Controlled Study - Asthma
Statistical Analysis Plan
Study ABS-AS-40138
5
9.
TOLERABILITY VARIABLES AND ANALYSIS..................................................29
10.
STATISTICAL SOFTWARE ....................................................................................30
11.
CHANGES TO ANALYSES SPECIFIED IN THE STUDY PROTOCOL..............31
12.
REFERENCES ...........................................................................................................32
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Parallel-group, Controlled Study - Asthma
Statistical Analysis Plan
Study ABS-AS-40138
6
LIST OF TABLES
Table 1:
Criteria for Potentially Clinically Significant Vital Signs..........................................28
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Parallel-group, Controlled Study - Asthma
Statistical Analysis Plan
Study ABS-AS-40138
7
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
ACT
Asthma Control Test
App
smart device application
BIPQ
Brief Illness Perception Questionnaire
BMI
body mass index
BMQ
Beliefs about Medicines Questionnaire
CAE
clinical asthma exacerbation
CC
concurrent control
CI
confidence interval
CRF
case report form
CSR
clinical study report
DHP
Digital Health Platform
DS
Digital System
ED
emergency department
ET
early termination
eMDPI
multidose dry powder inhaler with integrated electronic module
GERD
gastroesophageal reflux disease
GINA
Global Initiative for Asthma 
HCP
healthcare provider
iHCP
investigational center healthcare provider
IMP
investigational medicinal product
ITT
intent-to-treat 
LAMA
long-acting muscarinic antagonist
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MI
multiple imputation
MIF
maximal inhalation flow
mITT
modified intent-to-treat 
R&D
Research and Development
RTSM
Randomization and Trial Supply Management
SABA
short-acting beta2 agonist
SAP
statistical analysis plan
SD
Standard Deviation
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Parallel-group, Controlled Study - Asthma
Statistical Analysis Plan
Study ABS-AS-40138
8
Abbreviation
Term
SE
Standard Error
SOC
system organ class
SOP
standard operating procedure
SUS
System Usability Scale
WHO
World Health Organization
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Parallel-group, Controlled Study - Asthma
Statistical Analysis Plan
Study ABS-AS-40138
9
INTRODUCTION
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for Teva 
Branded Pharmaceutical Products Research and Development (R&D) study ABS-AS-40138 
(CONNected Electronic Inhalers Asthma Control Trial 1 (“CONNECT 1”), a 12-Week 
Treatment, Multicenter, Open-Label, Randomized, Parallel Group Comparison, Feasibility Study 
to Evaluate the Effectiveness of the Albuterol eMDPI Digital System, to Optimize Outcomes in 
Patients at Least 13 Years of Age or Older with Asthma), and was written in accordance with
GSD_SOP_702 (SAP).
The reader of this SAP 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 SAP is intended to be in agreement with the protocol, especially with regards to the primary 
and all secondary endpoints and their respective analyses. However, the SAP may contain more 
details regarding these particular points of interest, or other types of analyses (e.g. other 
endpoints). When differences exist in descriptions or explanations provided in the study protocol 
and this SAP, the SAP prevails; the differences will be explained in the Clinical Study Report
(CSR).
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Parallel-group, Controlled Study - Asthma
Statistical Analysis Plan
Study ABS-AS-40138
10
1.
STUDY OBJECTIVES AND ENDPOINTS
1.1.
Primary and Secondary Study Objectives and Endpoints
The primary and secondary study objectives and endpoints are:
Objectives
Endpoints
The primary objective of this 
study is to demonstrate the 
effectiveness of the Digital
System (DS) compared to a 
concurrent control (CC) group. 
The primary endpoint is the proportion of patients for the DS and CC
groups achieving meaningful improvement, which is defined as an 
Asthma Control Test (ACT) score greater than or equal to 20 at the 
end of the 12-week treatment period or an increase of at least 3 units 
on the ACT score from baseline at the end of the 12-week treatment 
period.
The secondary objective (#1)
is to describe the asthma 
management actions by 
investigational center healthcare 
providers (iHCPs) for all 
patients in both groups.
This secondary endpoint will describe the frequency and types of 
interventions done to improve asthma control including:
!
number of discussions between patient and healthcare provider 
(HCP) regarding inhaler technique or adherence
!
number of adjustments of therapy including:
o
increased or decreased doses of inhaled medication
o
change to different inhaled medication
o
additional inhaled medication
o
addition of a systemic corticosteroid medication 
for asthma or another controller, including a long-
acting muscarinic antagonist (LAMA) or 
biologics
!
frequency of intervention to manage comorbid conditions 
associated with poor asthma control (gastroesophageal reflux 
disease [GERD], sinusitis, etc.)
The secondary objective (#2) 
is to evaluate short-acting beta2
agonist (SABA) usage and the 
number of SABA-free days in 
the DS group.
This secondary endpoint is the change from baseline in the mean 
weekly SABA usage and the change from baseline in the number of 
SABA-free days over the 12-week treatment period for the DS group.
The secondary objective (#3)
is to assess the usability and 
acceptability of the DS by 
patients in the DS group and the 
investigational center personnel.
This secondary endpoint is the assessment of the DS (eMDPI, App and 
dashboard) acceptability and usability, utilizing the System Usability 
Scale (SUS), completed by the patients in the DS group, 18 years of 
age or older, and the investigational center personnel at the end of the 
study.
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Parallel-group, Controlled Study - Asthma
Statistical Analysis Plan
Study ABS-AS-40138
11
Objectives
Endpoints
The secondary objective (#4)
is to assess behavioral correlates 
of responsiveness to digital 
health technology among 
patients for all patients in both 
groups.
This secondary endpoint is the assessment of patients’ beliefs and 
perceptions about their disease and treatment, utilizing the Beliefs 
about Medicines Questionnaire (BMQ) and the Brief Illness 
Perception Questionnaire (BIPQ) to both the DS and CC groups, 
patients 18 years of age or older, describing their behavioral profile at 
baseline and at the end of the study.
The secondary objective (#5)
is to evaluate the safety of 
Albuterol eMDPI.
This secondary endpoint is the reporting of adverse events related to 
Albuterol eMDPI at participating investigational centers.
The safety endpoints for this study include the following for all 
patients in both groups:
!
adverse event data
!
adverse device effect data
Notes: The Digital System (DS) group will include eligible study population patients who will use the DS (eMDPI, 
App, DHP [Cloud solution], and dashboard) during the treatment period. The concurrent control (CC) group will 
include eligible patients who will be treated with their standard of care albuterol-administering rescue inhalers and 
will not use the DS during the treatment period.
1.2.
Exploratory Objectives and Endpoints
Exploratory objectives and endpoints are as follows:
 
 
 
 
 
 
 
 
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Parallel-group, Controlled Study - Asthma
Statistical Analysis Plan
Study ABS-AS-40138
12
2.
STUDY DESIGN
2.1.
General Design
This is a 12-week treatment, multicenter, open-label, randomized, parallel group comparison 
feasibility study to evaluate the effectiveness of the Albuterol eMDPI DS, including inhaler, 
App, Digital Health Platform (DHP, Cloud solution), and dashboard, to optimize outcomes in 
patients at least 13 years of age or older with asthma.
The study will consist of a screening visit, a 12-week open-label treatment period, and a follow-
up telephone call (2 weeks following treatment completion).
Patients with suboptimal asthma control will be enrolled in the study and randomized in a 1:1 
ratio to 1 of 2 parallel groups stratified by investigational center: DS group patients utilizing the 
Albuterol eMDPI DS, including inhaler, App, DHP (Cloud solution), and dashboard, and CC 
group patients who will be treated with their standard of care albuterol-administering rescue 
inhalers and will not use the DS during the treatment period. Similar data will be collected 
regarding outcomes for the CC group: ACT after 12 to 14 weeks, BMQ and BIPQ responses, and 
the frequency of CAEs.
All patients will have a screening/baseline visit, at which they will be asked if they use a smart 
device and use different applications on their smart devices. A baseline ACT score for all 
patients, and BMQ and BIPQ responses for patients 18 years of age or older, will be collected. 
Once randomized, patients in the DS group will be trained on the use of the Albuterol eMDPI DS 
(including instructions on how to use both the eMDPI and the App) and, upon demonstrating 
competency, will receive 2 Albuterol eMDPI devices for use as rescue bronchodilators to replace 
their rescue treatment during the study. Additional Albuterol eMDPI devices may be supplied 
during the treatment period, based on patients’ needs. Patients in the CC group will be 
reimbursed or given a voucher to use to purchase their existing rescue medications.
Investigational centers will also receive similar instruction regarding features of the App, as well 
as features of the associated dashboard, which mirrors the digital information obtained from the 
eMDPI and App, including frequency and times of SABA rescue use and associated inspiratory 
flow parameters measured by the eMDPI with each inhalation.
The CC group will be followed according to the clinical judgment of the investigator; the asthma 
of patients in the CC group will be managed in a manner consistent with the clinical judgment of 
the investigator and based on asthma management guidelines (eg, GINA). Similar to the 
management of the CC group, the DS group patients will be followed by the investigational 
centers with the addition of objective information on Albuterol eMDPI usage being available to 
both patients and investigational centers through the App and the dashboard, respectively. The 
iHCPs will check the dashboard at least once a week and use this information, as per their 
clinical judgment, to modify patients’ asthma management. Clinically Driven Assessments for 
both groups, if necessary, should be arranged per the clinical judgment of the iHCP managing 
the patient and can be via a telephone call or an on-site visit.
For all patients, at Visit 2 and at each Clinically Driven Assessment, if necessary, the iHCP will 
record answers to Asthma Management questions regarding what interventions occurred as a 
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Parallel-group, Controlled Study - Asthma
Statistical Analysis Plan
Study ABS-AS-40138
13
consequence of the Clinically Driven Assessment, including discussions regarding adherence, or 
inhaler technique, treatment adjustments, or additions of new treatments, including biologic 
medication usage. Additionally, for patients in the DS group, the iHCP will be asked whether or 
not the contact with the patient was originated from the iHCP interaction with the dashboard.
At the end of the treatment period (12 weeks), final assessments of the DS and CC group patients 
will be made, as specified in Table 3 of the study protocol. A follow-up telephone call will be 
made by the investigational center to all patients, 2 weeks later, and will confirm the DS group 
patients have returned to previous asthma treatments.
It should also be noted that no specific clinical decisions are being mandated. One secondary 
objective of this study is to describe how clinicians actually use the information provided by the 
DS to manage their patients.
Study procedures and assessments with their timing are summarized in Table 3 of the study
protocol.
2.2.
Randomization and Blinding
This is an open-label study and patients will be randomly assigned to the DS group or CC group 
in a 1:1 ratio stratified by investigational center, using a Randomization and Trial Supply 
Management (RTSM) system. Since this an open-label study, blinding is not applicable.
2.3.
Data Monitoring Committee
There will be no Data Monitoring Committee for this study.
2.4.
Sample Size and Power Considerations
Sample size estimates are based upon the assumption that the absolute differences between the 
DS and CC group and the associated operational characteristics will be similar to the absolute 
differences and operational characteristics of the DS and CC groups noted in the sample size 
rationale for the study design.
The recommended sample size for the study is 150 evaluable patients per group (30 
investigational centers with each investigational center enrolling at least 10 patients), 300 
patients in total. Accounting for a dropout rate of 10%, this leads to a recommended total number 
of 330 enrolled patients.
With this sample size and assuming a true absolute difference in proportions (treatment effect as 
the estimated response rate for the CC group is 60% and for the DS group is 73%) between the 
groups of at least 13%, the probability that the posterior probability will be at least 95% is 0.77 
(power) (analogous to 1-sided p-value < 0.05) (Merchant et al 2016). Assuming no treatment 
effect (difference in proportions between the groups is 0%, ie, Type 1 error) then the probability 
is 0.05 that posterior probability will be at least 95% is 0.05.
It should be noted that both power and Type 1 error are dependent on the absolute difference 
between the DS and the CC groups as illustrated in Figure 5 of the study protocol by the 
operational characteristics calculated for the study design.
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Parallel-group, Controlled Study - Asthma
Statistical Analysis Plan
Study ABS-AS-40138
14
2.5.
Sequence of Planned Analyses
2.5.1.
Planned Interim Analyses
There will be no formal interim analysis for this study.
2.5.2.
Final Analyses and Reporting
All analyses identified in this SAP will be performed after the end of study as defined in the 
study protocol.
This SAP and any corresponding amendments will be approved before database lock, in 
accordance to SOP GBP_RD_702 (SAP).
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Parallel-group, Controlled Study - Asthma
Statistical Analysis Plan
Study ABS-AS-40138
15
3.
ANALYSIS SETS
3.1.
Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set will include all randomized patients. In the ITT analysis set,
treatment will be assigned based on the treatment to which patients were randomized, regardless 
of which treatment they actually received. This analysis population will be used for 
summarization of patient disposition and demographic and baseline characteristics, as 
appropriate.
3.2.
Modified Intent-to-Treat Analysis Set
The modified intent-to-treat (mITT) analysis set is a subset of the ITT analysis set including only 
patients who receive at least 1 dose of investigational medicinal product (IMP) (IMP is albuterol 
eMDPI for the DS group and standard-of-care albuterol-administering rescue medication for the 
CC group) and at least 1 postbaseline assessment on any of the study endpoints (primary, 
secondary, or exploratory). 
In the mITT analysis set, treatment will be assigned based on the treatment to which patients 
were randomized, regardless of which treatment they actually received. This analysis will be 
used for all primary, secondary, and exploratory endpoint analyses. 
3.3.
Safety Analysis Set
This analysis set will include all patients in the DS group who receive at least 1 dose of IMP and 
all patients in the CC group. In the safety analysis set, treatment will be assigned based on the 
treatment patients actually received, regardless of the treatment to which they were randomized, 
unless otherwise specified. This analysis set will be used for all safety analyses.
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4.
GENERAL ISSUES FOR DATA ANALYSIS
4.1.
General
Descriptive statistics for continuous variables include n, mean, standard deviation (SD), standard 
error (SE), median, minimum, and maximum. Descriptive statistics for categorical variables 
include patient counts and percentages, missing category will be displayed as appropriate.
Treatment dates are defined as follows:
!
Treatment start date: date of randomization/the screening/baseline visit date.
!
Treatment end date: the end of treatment/early termination (ET) visit date. If the end of 
treatment/ET date is missing then the last contact date will be used.
4.2.
Specification of Baseline Values
Baseline is the data observed at that screening/baseline visit, unless otherwise specified.
4.3.
Handling Withdrawals and Missing Data
For the primary endpoint, patients who discontinue early due to technology failure, disliking the 
digital platform, disease worsening, adverse experience or disliking the IMP will be counted as 
treatment failures. For those who discontinue early not to these reasons, the ACT value assessed 
at ET visit will be used. Those who discontinue early and do not have an ET visit will be counted 
as treatment failures. 
For the SUS items 1, 3, 5, 7, and 9, if response to 1 item is missing, the missing item will be 
replaced by the average of the remaining 4 responses. For items 2, 4, 6, 8, and 10, if response to 
1 item is missing, the missing item will be replaced by the average of the remaining 4 responses. 
If response to 2 or more of items 1, 3, 5, 7, and 9 are missing, or 2 or more of items 2, 4, 6, 8, 
and 10 are missing, the overall SUS score will be set to missing.
For the BMQ subscales, if response to 1 item within a subscale is missing, the missing response 
will be replaced with the average of the remaining responses within the subscale. If response to 2 
or more items within a subscale are missing, the missing responses will not be replaced and the 
subscale score will be set to missing.
For the BIPQ cognitive subscale, if response to 1 item within the subscale is missing, the missing 
response will be replaced with the average of the remaining responses within the subscale. If 
response to 2 or more items within the subscale is missing, the missing responses will not be 
replaced and the subscale score will be set to missing. For the emotional subscale, if 1 of the 
responses is missing then the subscale will be set to missing.
4.4.
Study Days and Visits
Study days are numbered relative to the treatment start date (ie, ..., –2, –1, 1, 2, ...; with day 1 
being the treatment start date and day –1 being the day before the treatment start date).
Weeks are defined in 7-day intervals (days 1 to 7, 8 to 14, …, 78 to 84). Day 1 is defined as the 
treatment start date (i.e., date of randomization/Visit 1 visit date).
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By-visit (or by-week) summaries will include baseline, and the end of treatment and ET visits.
The ET visit will be summarized as a separate visit.
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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. 
Summaries will be presented by treatment group and for all patients.
5.2.
Patient Disposition
Patients screened and screened but not randomized (with reason not randomized) will be 
summarized only for all patients using patient counts. Patients in the ITT analysis set, ITT 
analysis set who did not attempt to download the App, ITT analysis set who did not use the 
inhaler, safety analysis set, and mITT analysis set, patients who completed and withdrew from 
treatment (with reason for withdrawing), and patients who completed and withdrew from the 
study (with reason for withdrawal) will be summarized using descriptive statistics. The summary 
will be based on all patients. The denominator for calculating the percentages will be the number 
of patients in the ITT analysis set.
5.3.
Demographics and Baseline Characteristics
The continuous variables of patient age, weight, height, and body mass index (BMI) will be 
summarized using descriptive statistics. The categorical variables of subject sex, race, and 
ethnicity will be summarized using descriptive statistics for each category. Missing categories 
will be presented if necessary.
5.4.
Medical History
All medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The incidence of medical history abnormalities will be summarized using 
descriptive statistics by system organ class (SOC) and preferred term. Patients are counted only 
once in each SOC category, and only once in each preferred term category.
5.5.
Prior Therapy and Medication
Any prior therapy or medication a patient is taking at the screening/baseline visit will be 
recorded on the CRF. All prior therapies and medications will be coded using the World Health 
Organization (WHO) drug dictionary (WHO Drug).
The incidence of prior therapies and medications will be summarized using descriptive statistics 
by therapeutic class and preferred term. Patients are counted only once in each therapeutic class 
category, and only once in each preferred term category. Prior therapies and medications will 
include all medications taken and therapies administered before the treatment start date.
5.6.
Study Protocol Deviations
Data from patients with any important protocol deviations during the study will be summarized 
overall and for each category using descriptive statistics.
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6.
DATA ANALYSIS
6.1.
General
The efficacy of the drug product will not be evaluated in this study. The focus of this study is the 
engagement of the patient with the Albuterol eMDPI DS.
The mITT analysis sets will be used for all data analyses. Summaries will be presented by 
treatment group, as randomized.
6.2.
Primary Endpoint and Analysis
6.2.1.
Definition
The Asthma Control Test (ACT) is a simple, patient-completed tool used for the assessment of 
overall asthma control. The 5 items included in the ACT assess daytime and nighttime asthma 
symptoms, use of rescue medication, and impact of asthma on daily functioning. Each item in the 
ACT is scored on a 5-point scale, with summation of all items providing scores ranging from 5 to 
25. The scores span the continuum of poor control of asthma (score of 5) to complete control of 
asthma (score of 25), with a cutoff score of 19 and below indicating patients with poorly 
controlled asthma (Schatz et al 2006).
The primary endpoint is the proportion of patients reaching well-controlled asthma as defined by 
an ACT score of greater than or equal to 20 or a clinically important improvement in asthma 
control as defined by an increase of at least 3 units on the ACT score from baseline at the end of 
the 12-week treatment period (responder analysis of DS versus CC group with responders 
defined by an ACT score of greater than or equal to 20 or an increase by greater than or equal to 
3 units on the ACT score).
6.2.2.
Primary Analysis
To analyze the primary endpoint, the following estimand framework will be used:
1.
Analysis will be performed on the mITT analysis set. 
2.
A binary distribution is assumed for the primary endpoint. Patients who discontinue early 
due to technology failure, disliking the digital platform, disease worsening, adverse experience 
or disliking the IMP will be counted as treatment failures. For those who discontinue early not 
due to these reasons, the ACT value assessed at the ET visit will be used.
3.
Summary measure: A successful differentiation between the 2 groups will be determined 
by a Bayesian posterior probability for  > 0 greater than 0.95 (1-sided). The following 
statistical methods will be utilized:
Logistic regression model allowing for different response rates at enrolling investigational 
centers will be used for testing the hypothesis :  = 0, :  > 0 in the following model:
    ln(

) =  +  +   
+  !"
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where xi = treatment group i , pij = response proportion of treatment group i at Center j, Centerj = 
random center effect of center j. 
Non-informative priors will be assumed for all coefficients. Estimates of mean response rate and 
corresponding 95% credible intervals for individual proportions, histograms of the posterior 
response rates, odds ratio with corresponding 95% credible intervals for DS versus CC, and 
probability of ( > 0) and probability of (#$$ % & > clinical meaningful value) will be 
presented.
The SAS code for the primary analysis is as follows:
proc mcmc data = x nbi = 1000 nmc = 500000 thin = 20 seed = 159 outpost = 
post1 monitor = (beta0-beta2 sigma2 beta1_gt0 pi pi0 pooled or) 
statistics=(summary intervals);
  parms beta0-beta2 0;
  parms sigma2 1;
  prior beta0-beta2 ~ normal(mean = 0, var = 1000);
  prior sigma2 ~ igamma(shape = 0.001, scale = 0.001);
  random b0 ~ normal(mean = 0, var = sigma2) subject = CENTER;
  eta = beta0 + b0 + beta1*trt + beta2*y0;
  pi = logistic(eta);
  pi0 = logistic(beta0 + b0 + beta2*y0);
  model count ~ binomial(n = total, p = pi);
  array or[<# of sites>];
  or[CENTER] = exp(b0 + beta1);
  pooled = exp(beta1);
  beta1_gt0 = beta1 > 0;
run;
    where   count = number of responders and total = number of patients.
To include study center into the model, the study centers may be pooled according to the number 
of patients enrolled at each center by keeping the largest centers intact and pooling the remainder 
of the larger sites with smaller sites to form pooled sites. A final plan for pooling will be made 
and documented in Statistical Data Review meeting minutes prior to database lock. In addition, 
summary statistics for the ACT score will be presented at baseline, and the end of treatment and 
ET visits. ACT score values and changes from baseline to each visit will be summarized using 
descriptive statistics.
6.2.3.
Sensitivity Analysis
Sensitivity analysis will be performed for the primary analysis by imputing missing ACT values
using the multiple imputation (MI) method assuming missing at random (MAR). Those who
discontinue early due to technology failure, disliking the digital platform, disease worsening, 
adverse experience or disliking the IMP will be considered having missing data. For those who 
discontinue early not due to these reasons, the ACT value assessed at the ET visit will be used.
Those who discontinue early and do not have an ET visit will be considered having missing data.
The following steps will be performed for the analysis:
!
Create complete datasets using imputation. The SAS code is as follows:
proc mi data = yy out = yy2 seed = 4192 nimpute = 500 minimum = 5 maximum = 25;
  class trt;
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  var trt actbase v2;
  monotone regpmm;
run;
!
For each dataset, the clinically important improvement in asthma control variable will be 
derived for each patient as defined in Section 6.2.1.
!
Analyze each dataset using the model described below for the primary endpoint.
ods output Diffs = dif LSMeans = lsm;
  proc genmod data = indata;
    by _imputation_;
    class trt;
    model y = trt actbase / dist = binomial;
    lsmeans trt/pdiff cl diff exp;
  run;
ods output close;
!
The output datasets from the above analysis will contain odds ratio estimates from each 
of the 500 datasets. An overall estimate will be generated using PROC MIANALYZE . 
The SAS code is as following:
proc mianalyze data=zz;
  modeleffects estimate;
  stderr stderr;
  ods output paramestimates=or;
run;  
6.3.
Secondary Endpoints and Analysis
6.3.1.
Secondary Endpoint #1 – Description of Asthma Management Actions by the 
Investigational Center Healthcare Providers
6.3.1.1.
Definition
Secondary endpoint #1 will describe the frequency and types of interventions done to improve 
asthma control including:
!
number of discussions between patient and HCP regarding inhaler technique or 
adherence
!
number of therapy adjustments including:
o
increased or decreased doses of inhaled medication
o
change to different inhaled medication
o
additional inhaled medication
o
addition of a systemic corticosteroid medication for asthma or another controller, 
including a LAMA or biologics
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!
frequency of intervention to manage comorbid conditions associated with poor asthma 
control (GERD, sinusitis, etc.)
6.3.1.2.
Analysis
Frequency and types of interventions during the 12-week treatment period will be summarized as 
count data using descriptive statistics. In addition, similar Bayesian analysis specified for 
primary endpoint will be performed for those variables separately using Poisson regression. The 
suggested SAS code for the analyses is as follows:
proc mcmc data = x nbi = 1000 nmc = 100000 thin = 20 seed = 159 outpost = post2
  monitor = (beta0-beta3 sigma2 beta1_gt0 lambda lambda0 pooled) statistics=(summary 
intervals);
  parms beta0-beta3 0;
  parms sigma2 1;
  prior beta0-beta3 ~ normal(mean = 0, var = 1000);
  prior sigma2 ~ igamma(shape = 0.001, scale = 0.001);
  random b0 ~ normal(mean = 0, var = sigma2) subject = CENTER;
  eta = beta0 + b0 + beta1*trt + beta2*logt + beta3*y0;
  lambda = exp(eta);
  lambda0 = exp(beta0 + b0 + beta2*logt + beta3*y0);
  model hosp ~ poisson(lambda);
  array lmda[<# of sites>];
  lmda[CENTER] = exp(b0 + beta1 + beta2*logt + beta3*y0);
  pooled = exp(beta1);
  beta1_gt0 = beta1 < 0;
run;
6.3.2.
Secondary Endpoint #2 – Evaluation of Short-Acting Beta2 Agonists Usage 
6.3.2.1.
Definition
Secondary endpoint #2 is the change from week 1 in the mean weekly SABA usage and the 
change from week 1 in the number of SABA-free days over the 12-week treatment period for the 
DS group. SABA usage and SABA-free days. Weekly average SABA use will be defined as 
((number of inhalations in a week)*90 ug/7) and change from week 1 in weekly average SABA 
use will be defined as (week i – week 1). Weekly SABA-free days will be defined as number of 
days a patient does not use the rescue medication in a week. If no inhalations done for any week, 
the amount of the SABA use will be 0 and SABA-free days for week will 7.
6.3.2.2.
Analysis
Weekly average SABA use, change from week 1 in weekly average SABA use and weekly 
SABA-free days will be summarized using descriptive statistics.
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6.3.3.
Secondary Endpoint #3 – Usability and Acceptability of the Digital System
6.3.3.1.
Definition
The SUS is used to explore device acceptability and usability for patients in the DS group. It is a 
10-item tool that provides a composite measure of the overall usability of the system being 
studied. Responses for each item range from 1 (strongly disagree) to 5 (strongly agree). To 
calculate the SUS score, first sum the responses from each item. Each item's contribution will 
range from 0 to 4. For items 1,3,5,7, and 9 the score contribution is the response minus 1. For 
items 2,4,6,8 and 10, the score contribution is 5 minus the response. Multiply the sum of the 
scores by 2.5 to obtain the overall SUS score. SUS scores have a range of 0 to 100.
Secondary endpoint #3 is the assessment of the DS (eMDPI, App and dashboard) acceptability 
and usability, utilizing the SUS, completed by the patients in the DS group, 18 years of age or 
older, and investigational center personnel at the end of the study. The SUS will be completed 
after all other questionnaires.
6.3.3.2.
Analysis
The SUS score (completed by patients and investigator sites) at the end of treatment and ET 
visits will be summarized as continuous data using descriptive statistics. 
6.3.4.
Secondary Endpoint #4 – Assessment of Behavioral Correlates of 
Responsiveness to Digital Health Technology
6.3.4.1.
Definition
The BMQ is used to assess cognitive representations of medicine. The BMQ-Specific 
(BMQ-S11) is an 11-item questionnaire that assesses representation of medication prescribed for 
personal use. The specific necessity subscale is the sum of items 1, 3, 5, 7, and 10, and the 
specific concern subscale is the sum of items 2, 4, 6, 8, 9, and 11. The BMQ should be the 
second questionnaire completed during a study visit following the ACT.
The BIPQ is a 9-item questionnaire designed to rapidly assess cognitive and emotional 
representations of illness. The BIPQ uses a single-item scale approach to assess perception on a 
0-10 response scale. The BIPQ comprises 5 items on cognitive representation of illness 
perception: consequences, timeline, personal control, treatment control, and identity. There are 2 
items on emotional representation: concern and emotions; one item is on illness 
comprehensibility. The last item is on perceived cause of illness, in which respondents list the 3 
most important causal factors in their illness. The cognitive subscale is the sum of items 1 to 5, 
and the emotional representation subscale is the sum of items 6 and 7. The BIPQ should be the 
third questionnaire completed during a study visit following the BMQ.
Secondary endpoint #4 is the assessment of patients’ beliefs and perceptions about their disease 
and treatment, utilizing the BMQ and the BIPQ for both the DS and CC groups, patients 18 years 
of age or older, describing their behavioral profile at baseline and at the end of the study.
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6.3.4.2.
Analysis
Summary statistics for the BMQ and BIPQ subscales will be presented at baseline, and the end 
of treatment and ET visits. BMQ and BIPQ subscales values and changes from baseline to each 
visit will be summarized using descriptive statistics.
6.4.
Exploratory/Other Endpoints Analysis
6.4.1.
Definition
The exploratory endpoints are:
 
 
 
 
 
 
 
 
 
  
  
  
  
  
  
  
 
 
 
 
 
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7.
MULTIPLE COMPARISONS AND MULTIPLICITY
No multiplicity adjustment is needed since there is no hypothesis testing in this study, Bayesian 
methods for primary endpoint and secondary endpoint #1 and descriptive nature of all other 
endpoints. 
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8.
SAFETY ANALYSIS
8.1.
General
In this study, safety will be assessed by qualified study personnel by evaluating reported adverse 
events, adverse device effects, vital signs measurements, and use of concomitant medications.
No clinical laboratory tests, physical examinations, and ECGs are scheduled to be performed 
during this study.
The safety analysis set will be used for all safety analyses. Summaries will be presented by 
treatment group and for all patients.
8.2.
Duration of Exposure to IMP
Since the dosing of the test IMP is on an as-needed basis, there is no set maximum exposure. 
Duration of exposure to IMP is the number of days from date of the 2nd dose (since the 1st dose is 
used for testing at the study site on date of randomization) to date of last dose of IMP (last dose 
of IMP date – 2nd dose of IMP date + 1). If the 1st dose is not used on date of randomization, the 
duration of exposure to IMP will be calculated as last dose of IMP date – 1st dose of IMP date + 
1 assuming no testing is done at study site for the patient. Number and percent of patients will be 
summarized by duration of exposure to IMP categories ≤ 1 week, >1 to ≤2 weeks, …, >11 to ≤12 
weeks, and > week 12. Duration of exposure to IMP (days) and number of inhalations will also 
be summarized as continuous data using descriptive statistics.
The number of days a patient takes IMP will be summarized as continuous data using descriptive 
statistics. If a patient takes more than 1 IMP treatment on the same day, the patient will be 
counted only once in the summary; if a patient does not take any IMP treatment on a given day 
the patient will be counted as zero on that day.
8.3.
Inhalation Flow Parameters 
Inhalation flow parameters (peak inhalation flow [PIF], inhalation volume, inhalation duration, 
and time to PIF) values will be calculated for each week in the treatment period. 
The inhalation parameters for each week are defined as the values from the inhalation with the 
median value of PIF during each week. If the number of inhalations is an even number, the later 
of the two inhalations in the middle will be deemed as the inhalation for the week. If no 
inhalations are done in a week, no inhalation parameters are defined for the week. Similarly the 
inhalation parameters for the entire 12-week treatment period are the values from the inhalation 
with the median PIF during the entire 12-week treatment period. Any inhalation with PIF > 120 
L/min will be excluded from derivations.  
Summary statistics for inhalation flow parameters will be presented by week in the treatment 
period, and the entire 12-week treatment period. Actual values and changes from week 1 to each 
week and overall will be summarized using descriptive statistics.
Statistical analyses of inhalation flow parameters will be performed outside of the scope of this 
SAP. The big data team will analyze this date and a separate SAP will be devolved for this.
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8.4.
Adverse Events
All adverse events will be coded using the MedDRA. Adverse events occurring on or after the 
treatment start date will be included in the summary tables while all of the adverse events will be 
listed in data listings. 
A summary will be presented for adverse events in the following categories: all adverse events, 
adverse events determined by the investigator to be related to study drug, severe adverse events, 
serious adverse events, adverse events leading to withdrawal from the study, non-serious adverse 
events, device-related adverse events (DS group only), asthma related adverse events, and CAE 
related adverse events. The incidence of patients with an adverse event in each category will be 
summarized using descriptive statistics. 
Summaries will be presented for all adverse events (overall and by severity), adverse events 
determined by the investigator to be related to study drug (overall and by severity), serious 
adverse events, adverse events leading to withdrawal from the study, non-serious adverse events, 
and device-related adverse events (DS group only).
The incidence of adverse events will be summarized using descriptive statistics by SOC and 
preferred term (all AEs overall will also be presented by just preferred term category). Patients 
are counted only once in each SOC category, and only once in each preferred term category. For 
the summaries by severity, patients are counted at the greatest severity. Adverse events with the 
missing flag indicating serious will be excluded from the summary of serious adverse events but 
included in the summary of non-serious adverse events.
8.5.
Deaths
If any patient dies during the study, all relevant information will be discussed in the patient’s 
narrative included in the CSR.
8.6.
Vital Signs
Summary statistics for vital signs (pulse, systolic and diastolic blood pressure, and respiratory 
rate) will be presented at baseline, and the end of treatment and ET visits. Vital signs values and 
changes from baseline to each visit will be summarized using descriptive statistics.
Summaries of potentially clinically significant abnormal values will include all postbaseline 
values (including scheduled, unscheduled, and early termination visits). The incidence of 
potentially clinically significant abnormal values will be summarized using descriptive statistics 
with the criteria specified in Table 1. 
Table 1 specifies the criteria for identifying vital signs as potentially clinically significant 
abnormal values. Note that in order to qualify as potentially clinically significant abnormal, a 
value needs to meet both criteria below: ie, have a value beyond the criterion value and a change 
of at least the magnitude specified in the change relative to baseline column.
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Table 1:
Criteria for Potentially Clinically Significant Vital Signs
Vital Sign
Criterion value
Change relative to baseline
Pulse
∀120 bpm
Increase of ∀15 bpm
#50 bpm
Decrease of ∀15 bpm
Systolic blood pressure
∀180 mm Hg
Increase of ∀20 mm Hg
#90 mm Hg
Decrease of ∀20 mm Hg
Diastolic blood pressure
∀105 mm Hg
Increase of ∀15 mm Hg
#50 mm Hg
Decrease of ∀15 mm Hg
Respiratory rate
<10 breaths/min
8.7.
Concomitant Medications or Therapies 
Concomitant medications and therapies, 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.
The incidence of concomitant medications and therapies will be summarized using descriptive 
statistics by therapeutic class category and preferred term. The incidence of concomitant 
medications for asthma at baseline will also be summarized using descriptive statisics by 
therapeutic class category and preferred term. Patients are counted only once in each therapeutic 
class, and only once in each preferred term category. Concomitant medications will include all 
medications taken from the day of treatment start through the end of treatment.
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9.
TOLERABILITY VARIABLES AND ANALYSIS
Tolerability is not applicable to this study.
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10.
STATISTICAL SOFTWARE
All data listings, summaries, and statistical analyses will be generated using SAS® version 9.4 or 
later.
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11.
CHANGES TO ANALYSES SPECIFIED IN THE STUDY 
PROTOCOL
There are no changes to analyses specified in the study protocol.
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Parallel-group, Controlled Study - Asthma
Statistical Analysis Plan
Study ABS-AS-40138
32
12.
REFERENCES
Merchant, RK, Inamdar R, Quade, RC. Effectiveness of population health management using the 
Propeller Health Asthma Platform: a randomized clinical trial. J Allergy Clin Immunol Pract. 
2016 May-Jun;4(3):455-63.
Schatz M, Sorkness CA, Li JT, Marcus P, Murray JJ, Nathan RA, et al. Asthma Control Test: 
reliability, validity, and responsiveness in patients not previously followed by asthma specialists. 
J Allergy Clin Immunol 2006;117(3):549-56.
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