Utilizing Advances in Digital Inhaler Technology to Understand Heterogeneous Treatment Responses to Biologics in Severe Asthma
Phase: PHASE4
Conditions: Asthma
Sponsor: University of Michigan

TEVA Asthma Predictive Analytics Study 
NCT04997304  
Date of Actual IRB Approval: 12/17/2024 

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TEVA Asthma Predictive Analytics Study 
Unique Protocol Identification Number: HUM00189756 
National Clinical Trial (NCT) Identified Number: 04997304 
Principal Investigator: Njira Lugogo 
Co-Investigators: Stewart Wang, Michael Sjoding 
TEVA Collaborators: Tanisha Hill, Amanda Boe 
IND/IDE Sponsor: TEVA Branded Pharmaceutical 
Funded by: TEVA Branded Pharmaceutical 
 
Protocol Version: 1- 10 August 2020 
Protocol Version: 2- 01 October 2021 
Protocol Version 3 – 01 November 2024 
 
 
Summary of Changes from Previous Version: 
 
Affected Section(s) 
Summary of Revisions Made 
Rationale 
 Throughout Document Updated Versioning 
  
Section 1.1 Synopsis 
Clarified Endpoints and Objectives 
and updated Exploratory Objectives 
Section 3. Objectives 
and Endpoints 
Clarified Endpoints and Objectives 
and updated Exploratory Objectives 
 
 
 
 
 

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Table of Contents 
Statement of Compliance ............................................................................................................................. 4 
1 Protocol Summary...................................................................................................................................... 5 
1.1 Synopsis ............................................................................................................................................................... 5 
1.2 Schema ................................................................................................................................................................ 7 
1.3 Schedule of Activities (SoA) ................................................................................................................................. 8 
2 Introduction ............................................................................................................................................... 9 
2.1 Study Rationale & BACKGROUND ........................................................................................................................ 9 
2.3 Risk/Benefit Assessment.................................................................................................................................... 11 
2.3.1 Known Potential Risks ................................................................................................................................. 11 
2.3.2 Known Potential Benefits ........................................................................................................................... 11 
2.3.3 Assessment of Potential Risks and Benefits ............................................................................................... 11 
3 Objectives and Endpoints ........................................................................................................................ 13 
4 Study Design ............................................................................................................................................. 17 
4.1 Overall Design .................................................................................................................................................... 17 
4.2 Scientific Rationale for Study Design ................................................................................................................. 17 
4.3 Justification for Dose ......................................................................................................................................... 18 
4.4 End of Study Definition ...................................................................................................................................... 18 
5 Study Population ...................................................................................................................................... 19 
5.1 Inclusion Criteria ................................................................................................................................................ 19 
5.2 Exclusion Criteria ............................................................................................................................................... 19 
5.3 Lifestyle Considerations ..................................................................................................................................... 20 
5.4 Screen Failures ................................................................................................................................................... 20 
5.5 Strategies for Recruitment and Retention ......................................................................................................... 20 
6 Study Intervention ................................................................................................................................... 21 
6.1 Study Intervention(s) Administration ................................................................................................................ 21 
6.1.1 Study Intervention Description ................................................................................................................... 21 
6.1.2 Dosing and Administration ......................................................................................................................... 21 
6.2 Preparation/Handling/Storage/Accountability .................................................................................................. 21 
6.2.1 Acquisition and accountability .................................................................................................................... 21 
6.2.2 Formulation, Appearance, Packaging, and Labeling ................................................................................... 22 
6.2.3 Product Storage and Stability ..................................................................................................................... 22 
6.2.4 Preparation ................................................................................................................................................. 22 
6.3 Measures to Minimize Bias: Randomization and Blinding ................................................................................. 22 
6.4 Study Intervention Compliance ......................................................................................................................... 23 
6.5 Concomitant Therapy ........................................................................................................................................ 23 
6.5.1 Rescue Medicine ......................................................................................................................................... 23 
7 Study Intervention Discontinuation and Participant Discontinuation/Withdrawal ................................ 24 
7.1 Discontinuation of Study Intervention .............................................................................................................. 24 
7.2 Participant Discontinuation/Withdrawal from the Study .................................................................................. 24 
7.3 Lost to Follow-Up ............................................................................................................................................... 24 
8 Study Assessments and Procedures ......................................................................................................... 26 
8.1 Efficacy Assessments ......................................................................................................................................... 26 
8.1.1 Study Visits.................................................................................................................................................. 26 
8.1.2 Study Procedures ........................................................................................................................................ 27 

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8.2 Safety and Other Assessments .......................................................................................................................... 30 
8.3 Adverse Events and Serious Adverse Events ..................................................................................................... 30 
8.3.1 Definition of Adverse Events (AE) ............................................................................................................... 30 
Adverse Event ...................................................................................................................................................... 31 
8.3.2 adverse device effect and reporting ........................................................................................................... 31 
8.3.3 Definition of Serious Adverse Events (SAE) ................................................................................................ 32 
8.3.4 Serious Adverse Event Reporting................................................................................................................ 33 
8.3.5 Reporting Events to Participants ................................................................................................................ 34 
8.3.6 Events of Special Interest ........................................................................................................................... 34 
9 Statistical Considerations ......................................................................................................................... 35 
9.1 Statistical Hypotheses ........................................................................................................................................ 35 
9.2 Sample Size Determination................................................................................................................................ 35 
9.3 Populations for Analyses ................................................................................................................................... 35 
9.4 Statistical Analyses............................................................................................................................................. 36 
9.4.1 General Approach ....................................................................................................................................... 36 
9.4.2 Analysis of the Primary Efficacy Endpoint(s) .............................................................................................. 36 
9.4.3 Analysis of the Secondary Endpoint(s) ....................................................................................................... 36 
9.4.4 Safety Analyses ........................................................................................................................................... 37 
9.4.5 Baseline Descriptive Statistics .................................................................................................................... 37 
9.4.6 Planned Interim Analyses ........................................................................................................................... 37 
9.4.7 Sub-Group Analyses .................................................................................................................................... 37 
9.4.8 Tabulation of Individual Participant Data ................................................................................................... 38 
9.4.9 Exploratory Analyses .................................................................................................................................. 38 
10 Supporting Documentation and Operational Considerations ............................................................... 39 
10.1 Regulatory, Ethical, and Study Oversight Considerations ................................................................................ 39 
10.1.1 Informed Consent Process ........................................................................................................................ 39 
10.1.2 Study Discontinuation and Closure ........................................................................................................... 39 
10.1.3 Confidentiality and Privacy ....................................................................................................................... 39 
10.1.4 Future Use of Stored Specimens and Data ............................................................................................... 40 
10.1.5 Key Roles and Study Governance ............................................................................................................. 40 
10.1.6 Safety Oversight ........................................................................................................................................ 40 
10.1.7 Clinical Monitoring .................................................................................................................................... 40 
10.1.8 Quality Assurance and Quality Control ..................................................................................................... 41 
10.1.9 Data Handling and Record Keeping .......................................................................................................... 41 
10.1.10 Protocol Deviations................................................................................................................................. 41 
10.1.11 Publication and Data Sharing Policy ....................................................................................................... 42 
10.1.12 Conflict of Interest Policy ........................................................................................................................ 42 
10.2 Additional Considerations ............................................................................................................................... 42 
10.3 Abbreviations ................................................................................................................................................... 42 
10.4 Protocol Amendment History .......................................................................................................................... 44 
11 References ............................................................................................................................................. 45 
 
 
 
 

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STATEMENT OF COMPLIANCE 
 
Provide a statement that the trial will be conducted in compliance with the protocol, International 
Council on Harmonization Good Clinical Practice (ICH GCP) and applicable state, local and federal 
regulatory requirements. Each engaged institution must have a current Federal-Wide Assurance (FWA) 
issued by the Office for Human Research Protections (OHRP) and must provide this protocol and the 
associated informed consent documents and recruitment materials for review and approval by an 
appropriate Institutional Review Board (IRB) or Ethics Committee (EC) registered with OHRP. Any 
amendments to the protocol or consent materials must also be approved before implementation. Select 
one of the two statements below. If the study is an intramural NIH study, use the second statement 
below: 
The trial will be conducted in accordance with International Council on Harmonization Good 
Clinical Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), and 
the [specify NIH Institute or Center (IC) [ Terms and Conditions of Award. The Principal 
Investigator will assure that no deviation from, or changes to the protocol will take place 
without prior agreement from the funding agency and documented approval from the 
Institutional Review Board (IRB), and the Investigational New Drug (IND) or Investigational 
Device Exemption (IDE) sponsor, if applicable, except where necessary to eliminate an 
immediate hazard(s) to the trial participants. All personnel involved in the conduct of this study 
have completed Human Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form(s) must be obtained before any participant is consented. Any amendment to the protocol 
will require review and approval by the IRB before the changes are implemented to the study. 
All changes to the consent form(s) will be IRB approved; a determination will be made regarding 
whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 

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1 PROTOCOL SUMMARY 
1.1 SYNOPSIS 
Title: 
Utilizing Advances in Digital Inhaler Technology to Understand Heterogeneous 
Treatment Responses to Biologics in Severe Asthma  
Study Description: 
This real-world study aims to determine baseline inhalation parameters and 
patterns of use in patients receiving treatment with TEVA digital inhalers, and to 
develop predictive models for asthma exacerbations and response to biologics 
using data collected from these devices. 
Objectives: 
Primary Objective: 
To determine the baseline inhalation parameters and patterns of use of 
both the maintenance (AirDuo®) Digihaler™ and rescue (ProAir®) 
Digihaler™ in patients with severe persistent asthma who are being treated 
with biologics. 
 
Secondary Objectives:  
1. To determine the predictive value of inhalation parameters, including 
peak inspiratory flow (PIF), inspiratory time and volume, and number of 
inhaled doses on asthma exacerbations in a population of severe 
asthma patients on biologics. 
 
2. To determine whether inhalation measurements can serve as 
surrogates of standard expiratory flow measurements. Specifically, to 
determine the correlation between PIF with FEV1 and identify 
thresholds for changes in PIF that are associated with a clinically 
meaningful increases or decreases (10%) in lung function as measured 
by conventional spirometry (e.g., FEV1). 
 
3. To determine the impact of variable degrees of adherence to 
maintenance therapy on outcomes to biologics. The Digihaler™ will 
allow us to collect accurate information on adherence that will be 
utilized to divide patients into groups and to assess asthma outcomes 
such as change in mean FEV1, exacerbations, oral steroid reduction, 
and asthma control (using the asthma control test scores over time) in 
patients receiving biologic therapies.  
 
4. To determine the impact on inhalation parameters on categorical 
response to biologics. Response will be categorized as non-response, 
partial and complete response on the basis of six factors: a 50% 
reduction in exacerbations, any reduction in maintenance OCS dose, 
change of at least 10% in FEV1, improvement of 3 points in ACT score, 
and patient perception of global improvement in asthma.  
 
 
 
 

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Exploratory Objectives  
5. To evaluate the asthma control and health care utilization of 
subjects as measured by the number of exacerbations (acute 
worsening of asthma requiring at least 3 days of corticosteroids 
or a doubling dose of maintenance steroids), Emergency and 
hospitalization encounters, and patient-reported perceptions of 
asthma control. 
6. To employ machine learning techniques to a robust well characterized 
cohort with clinical, biological, and digital markers to develop a 
predictive algorithm aimed at identifying responders to biologics. In 
addition, we would aim to develop an algorithm that can detect early 
changes in measured parameters that can predict long-term 
improvements in asthma control and exacerbations when biologics are 
initiated. The latter objective will be achieved by focusing on the sub-
group of patients initiating biologics for the first time or switching 
between biologics due to perceived inadequate response.  
 
Endpoints: 
Primary Endpoint:  
Mean and median number of (daily) doses of ProAir® Digihaler™ and 
AirDuo® Digihaler™ utilized at baseline, temporal patterns in rescue and 
controller medication utilization, and within-patient parameter mean, 
median, and variance per-inhalation to establish baselines. 
 
Secondary Endpoints: 
1. Proportion of patients with different rates of adherence. 
2. Proportion of Patients achieving non-response, partial-responses, and 
complete response to biologics.  
3. Change in Main Peak Inspiratory volume from baseline up to one year. 
4. Change in Mean Inspiratory Time from baseline up to one year. 
5. Change in mean peak inspiratory flow (PIF) from baseline up to one 
year. 
6. Change in mean forced expiratory volume in one second (FEV1) from 
baseline up to one year. 
Exploratory Endpoints 
7. Number of exacerbations from baseline up to one year. 
8. Number of hospitalizations. 

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9. Number of emergency room visits. 
10. Mean Asthma Control Test (ACT) scores. 
11. Algorithm that produces a daily asthma exacerbation probability given 
a set of baseline and current inhalation parameters.  A confusion 
matrix summarizing the algorithm’s performance on training dataset 
and from which performance statistics (accuracy, sensitivity, specificity, 
etc.) can be computed.  
12. Machine learning model developed for predicting responders to 
biologics (developed in collaboration with the University of Michigan 
Morphomic Analysis Group). Reporting key factors in the model that 
are associated with response, using inhalation parameters (digital 
markers), clinical factors, and biomarkers. 
Study Population: 
Adults > 18 years of age or older with severe persistent asthma as defined by 
ERS/ATS criteria that are currently receiving or awaiting approval for biologic 
therapies for asthma.  
Phase: 
Open Label Real World Study 
Description of Sites 
Enrolling 
Participants: 
All patients will be recruited from the Michigan Medicine Severe Asthma Clinics. 
Description of Study 
Intervention: 
Maintenance inhaler (AirDuo® Digihaler™) and two rescue inhalers (ProAir® 
Digihaler™) use in Severe Asthma patients currently receiving or awaiting 
approval for biologic therapies for asthma.  
Study Duration: 
2 years, including approximately 3-month start-up, 6 months’ recruitment 
period, 12 months follow-up of the last subject in (LSI), 3-month data cleaning 
and analysis.  
Participant Duration: 12 months  
 
1.2 SCHEMA 
 
 
Visit 0 
(Screening/Baseline) 
Inclusion/Exclusion 
Review, Informed Consent, 
Medical History, 
Medications, FeNO, CBC, 
IgE, Device Teaching 
 
“Good Control” 
30% of Participants 
ACT ≥ 19  
“Poor Control” 
70% of Participants 
ACT < 19  
Visit 1 – Visit 12 
(Treatment Period) 
Review of Concomitant Medications, 
Dispensation of Inhalers, Adverse Event 
Assessment, Review of Asthma 
Exacerbations 
Visit 3, 6, 9, 12 will be onsite visits. 
All others will be phone contact only. 

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1.3 SCHEDULE OF ACTIVITIES (SOA) 
Study Visit 
Screening/ 
Baseline 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 Visit 7 
Visit 8 Visit 9 Visit 10 Visit 11  Visit 
12/EOS 
Follow 
Up 
Study Week1 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
52 
Location 
Clinic 
Phone 
Phone 
Clinic 
Phone 
Phone 
Clinic 
Phone Phone Clinic 
Phone 
Phone 
Clinic 
Phone 
Informed Consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
Enrollment to MiAsthma Registry 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
Inclusion/Exclusion Review 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking/Tobacco Use History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History- General/Asthma 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
Conmeds- General/Asthma 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exacerbations/Healthcare Utilization X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient Reported Outcomes (PRO)2 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
FeNO (Clinical)3 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
 
CBC w. Differential (Clinical)3 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
 
Immunoglobulin (IgE) (Clinical)3 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
 
Inhaler Teaching 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
Dispense Digihaler™ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Registration/Onboarding App 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
Home Spirometry Teaching 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
Dispense Home Spirometer 
X 
  
  
  
  
  
  
  
  
  
  
  
  
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subject Fee/Stipend 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
 
Phone Call 
  
X 
X 
  
X 
X 
  
X 
X 
  
X 
X 
  
X 
Ship Drug (As Needed) 
  
X 
X 
  
X 
X 
  
X 
X 
  
X 
X 
  
 
1 Study visits have a ± 7 Day window. 
2 Patient Reported Outcomes include the Asthma Control Test (ACT), AIRQ, and the St. George’s Respiratory Questionnaire 
3 Clinical activities will be captured if they are available but will not be done specifically for the study. 
 

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2 INTRODUCTION 
2.1 STUDY RATIONALE & BACKGROUND 
Severe asthma affects 10% of the adult population and these patients suffer an increased number of 
exacerbations and subsequent accelerated decline in lung function.  Asthma exacerbations are poorly 
understood and the ability to predict exacerbations is limited.  The factors associated with an increased 
risk of exacerbations include a prior history of exacerbations, elevated type 2 markers, lower lung 
function and increased short acting beta agonist (SABA) use.  The ability to predict the onset of each 
isolated exacerbation event and to thus intervene is hampered by a lack of access to real-time 
information about both SABA use and lung function parameters. The Digihaler™ has demonstrated 
changes in both PIF and SABA doses surrounding acute asthma events (TEVA, unpublished data). The 
clinical utility of this information will be tested in future trials that aim to examine the impact of data 
from the Digihaler™ on clinical decision making.  The data from the Digihaler™ coupled with clinical 
characteristics and biomarkers could be utilized to revolutionize how asthma is monitored and how 
exacerbations are detected.  
 
Two-thirds of patients with severe asthma have evidence of type 2 inflammation that is targeted by five 
approved biologics for asthma. In clinical trials biologics have demonstrated significant impacts on 
exacerbation reduction, oral steroid sparing effects and improvements in quality of life. In all the clinical 
trials patients were required to remain on their maintenance inhaled (background) therapies and use of 
rescue bronchodilators was reported using patient self-report in symptom diaries. Little is known about 
how patients use their maintenance and rescue medications for asthma following the initiation of 
biologics and whether these patterns of use impact their response to these therapies. Furthermore, 
information about inhalation parameters such as peak inspiratory flow and inspiratory time and the 
importance of variability in these parameters that are measured in the Digihaler™ are lacking. The TEVA 
Digihaler™ offers an opportunity to obtain granular data about inhaler use in patients with severe 
asthma.  Importantly, this data will be incorporated with clinical, biomarker, and digital data from the 
cohort, and machine learning methods will be utilized to determine if predictive algorithms can be 
developed to not only identify exacerbations but also provide a priori prediction of likelihood of 
response to biologics. These models will enhance our understanding of disease variability and 
characteristics, enable us to perform future trials testing the hypothesis that “baseline characteristics 
and early changes in lung function parameters and medication use will provide early and accurate 
predictions of future outcomes when biologics are initiated,” and could provide the basis for early 
discontinuation of ineffective therapies, saving money and time for patients who are currently subjected 
to long trials with biologics prior to switching or discontinuation.  
 
Asthma is a highly prevalent disease that affects 30 million people in the United States. The vast 
majority of asthma patients are well controlled with conventional asthma therapies; however, 10% of 
patients have severe disease that is associated with significant comorbidity and exposure to high doses 

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of oral corticosteroids (OCS). This exposure to OCS increases the odds of developing co-morbid diseases 
such as diabetes, hypertension, cardiac disease and cataracts1. Severe asthma is associated with an 
increased risk of acute events/exacerbations that result in accelerated lung function decline2 and 
increased morbidity and mortality. Exacerbations are difficult to characterize and what is currently 
known about the changes in lung function prior to, during, and after exacerbations is predominantly 
focused on expiratory flow and highly reliant on patient diaries and peak flow meters. The variability in 
inspiratory flow parameters during acute events is not well characterized and may significantly impact 
inhaled drug delivery.  The Digihaler™ data could enable the development of next-generation asthma 
action plans and novel real-time asthma control monitoring. Furthermore, this technology will allow the 
development of novel methods to monitor asthma and enable earlier detection of acute asthma 
exacerbations. The early detection of asthma attacks would enable clinicians and empower patients to 
intervene and perhaps change the trajectory of illness. 
 
The rapid development of new biologics approved for the management of severe asthma with type II 
inflammation has led to a revolution in asthma care 3-5. The term "type II inflammation” refers to an 
increase in the levels of type II cytokines including interleukin IL-4, IL-5 and IL-13, which results in 
downstream production of IgE and eosinophils. Sixty percent of severe asthma patients have evidence 
of type II inflammation6 7. Surrogate biomarkers including peripheral eosinophils, fraction of exhaled 
nitric oxide (FeNO) and total IgE levels are used to phenotype patients with severe asthma and to guide 
biologic drug selection8. Eosinophils have been shown to predict response to IL5 and IL4 targeted 
therapies and FeNO is a predictor of response to anti-IL4 therapy9 10. 
 
The response to targeted biologic therapies is heterogeneous despite the use of biomarkers to select 
potential responders. Unfortunately, even when patients with a high likelihood of response are selected, 
10-15% have complete non-response in all clinical parameters, 40% have a robust and complete 
response to therapy, and the remainder of patients have a partial response. This is likely related to the 
presence of overlapping inflammatory pathways, co-morbid eosinophilic diseases that affect response 
to therapy, possible sub-optimal dosing of drug, and the lack of highly specific biomarkers. 
 
Little is known about how biologics impact the use of inhaled asthma therapies and whether the 
heterogeneity in responses to biologics could be partially attributed to nonadherence with maintenance 
therapies once biologic therapy is initiated. Data collection on use of both maintenance and inhaled 
therapies is based primarily on patient self-reporting. The Digihaler™ presents a unique opportunity to 
gain invaluable insights into both patterns of use of inhaled therapies and changes in inspiratory flow 
parameters in patients with severe asthma who are treated with biologics. In addition, coupling the 
maintenance and rescue Digihaler™ will allow the collection of a significant amount of information both 
about baseline therapies and exacerbations. Furthermore, the granular data collected from these 
inhalers will be invaluable in determining the impact of inhalation parameters on predicting asthma 
outcomes and in determining whether these measurements can serve as surrogates of expiratory flow 
measurements that are the cornerstone of asthma management but often challenging to obtain in real 
world settings. Coupling digital biomarkers from the inhaler with biological and clinical characteristics in 
a cohort of severe asthma patients will lead to an enhanced ability to not only understand the impact of 

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maintenance therapies on asthma outcomes but will also provide us with the opportunity to use 
machine learning algorithms to develop predictive models that may enhance our ability to predict 
response to biologics. 
  
Precision medicine approaches to severe asthma are in their infancy and the application of complex 
techniques to help guide therapy are urgently needed. Currently, patients that are partial responders or 
non-responders to given therapies are switched between available biologics, and clinical response is 
assessed 4-6 months after the new therapy is initiated. This represents an inefficient approach that is 
both time consuming and costly to patients and payers. 
  
We propose that variability in patterns of inhaler use, inhalation parameters, and overall medication 
adherence will significantly impact response to biologics in patients with severe asthma. Furthermore, 
the additive impact of predictive biomarkers, digital markers, and clinical characteristics will allow the 
development of a predictive algorithm that will help identify responders and enhance our 
understanding of the heterogeneous responses to therapy. 
2.3 RISK/BENEFIT ASSESSMENT 
2.3.1 KNOWN POTENTIAL RISKS 
There is a risk of loss of PHI which will be mitigated by use of secure servers at the University of 
Michigan campus. The cloud that receives digital information from the inhalers is HIPAA compliant and 
under the control of TEVA. TEVA collaborating investigators will partner with a cross-functional internal 
team and principal investigator/sponsor to determine the appropriate AE/SAE reporting requirements 
and reporting structure.] 
  
Clinical Safety: A total of 1289 subjects were treated with PROAIR® RESPICLICK during the clinical 
development program. The most common adverse reactions (≥1% and >placebo) were back pain, pain, 
gastroenteritis viral, sinus headache, and urinary tract infection. In a long-term study of 168 patients 
treated with PROAIR® RESPICLICK for up to 52 weeks (including a 12-week double-blind period), the 
most commonly reported adverse events ≥5% were upper respiratory infection, nasopharyngitis, 
sinusitis, bronchitis, cough, oropharyngeal pain, headache, and pyrexia. In a small cumulative dose 
study, tremor, palpitations, and headache were the most frequently occurring (≥5%) adverse events. 
2.3.2 KNOWN POTENTIAL BENEFITS 
Participants in this study will receive free asthma maintenance and rescue inhalers and access to 
information in the Digihaler™ app that may have a positive impact on their health behaviors.  
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
This is a minimal risk study that will focus on real world use of approved medications with an emphasis 
on understanding patterns of use, inhalational parameters, and changes in these measurements during 
acute episodes of asthma. Patients will be encouraged to follow the clinical guidance that is provided by 
the treating physician. 

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The ProAir® Digihaler™ is a rescue/reliever agent that includes an eModule on top of the approved 
PROAIR® RESPICLICK inhaler. The system consists of the ProAir® Digihaler™, the App, the cloud solution, 
and the dashboard. The ProAir® Digihaler™ 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 Digihaler™ 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). 
Furthermore, the steps to take a dose of ProAir® Digihaler™ 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. In summary, the benefit and risk assessment for ProAir® 
Digihaler™ is favorable following review of the outlined data.  
 
 

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3 OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
To determine the baseline inhalation 
parameters and patterns of use of 
both the maintenance (AirDuo®) and 
rescue (ProAir®) Digihaler™ in 
patients with severe persistent 
asthma who are being treated with 
biologics from baseline through the 
duration of the 12-month treatment 
period 
• 
Mean number of daily doses 
of ProAir® Digihaler™ 
• 
Mean number of daily doses 
of AirDuo® Digihaler™  
• 
Median number of daily doses 
of ProAir® Digihaler™ 
• 
Median number of daily doses 
of AirDuo® Digihaler™ 
 
The number of inhalations 
of rescue and maintenance 
bronchodilator use varies 
amongst and within patients 
with severe asthma and is 
impacted by changes in 
asthma control. This is a 
clinically meaningful 
measurement that is 
included in assessments of 
disease activity and control. 
PIF, inspiratory time and 
volume vary with changes in 
baseline asthma control and 
may be important in 
identifying acute 
exacerbations of asthma.  
 
Maintenance therapies can 
impact asthma control and 
confound the response to 
biologics. In addition, the 
patterns of use of 
maintenance therapies and 
the potential discordance 
with rescue inhaler use 
would be important to 
delineate in this severe 
asthma population.  
Secondary 
To determine the impact of variable 
degrees of adherence to 
maintenance therapy on outcomes 
to biologics. The Digihaler™ will allow 
us to collect accurate information on 
adherence that will be utilized to 
divide patients into groups and to 
assess asthma outcomes such as 
change in mean FEV1, exacerbations, 
oral steroid reduction, and asthma 
control (using the asthma control 
• 
Proportion of patients with 
different adherence rates.  
 
Tests: Summary, chi-squared test, 
and Tukey’s HSD test statistics of 
asthma outcomes by adherence 
group. 
Adequate understanding of 
adherence is essential for 
guiding treatment decisions 
in clinical asthma care. It 
may impact response to 
biologics particularly in 
patients that are partial 
responders to targeted 
therapies. The degree of 
asthma control while on 
biologics may be altered by 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
test scores over time) in patients 
receiving biologic therapies.  
 
Definitions: Adherence rates will be 
defined as: high (>80% of puffs), 
moderate (50-80% of puffs) and low 
levels (<50% of puffs) of adherence 
to maintenance inhalers (assuming 
an expected baseline usage of two 
puffs per day).  
 
non-adherence to inhaled 
therapies and lead to 
incorrect conclusion that the 
biologic is not effective. In 
addition, little is known 
about how patients with 
severe asthma utilize their 
inhalers once biologics are 
initiated and more 
importantly if it is safe to 
discontinue these therapies 
altogether. 
To determine the impact on 
inhalation parameters on categorical 
response to biologics. Response will 
be categorized as non-response, 
partial and complete response on the 
basis of six factors: a 50% reduction 
in exacerbations, any reduction in 
maintenance OCS dose, change of at 
least 10% in FEV1, improvement of 3 
points in ACT score and patient 
perception of global improvement in 
asthma.  
• 
Proportion of patients 
achieving non-response, 
partial and complete response 
to biologics.  
 
 
Tests: Summary, chi-squared test, 
and Tukey’s HSD test statistics of 
inhalation parameters by response 
group. 
Response to biologics is 
heterogeneous, and it is 
unclear if inhalational 
parameters measured by 
the Digihaler™ are 
correlated with degree of 
response. 
To determine whether inhalation 
measurements can serve as 
surrogates of standard expiratory 
flow measurements. Specifically, to 
determine the correlation between 
PIF with FEV1 and identify thresholds 
for changes in PIF that are associated 
with a clinically meaningful increases 
or decreases (10%) in lung function 
as measured by conventional 
spirometry (e.g., FEV1). 
• 
Change in Main Peak 
Inspiratory volume from 
baseline up to one year 
• 
Change in Mean Inspiratory 
Time from baseline up to 
one year 
• 
Change in mean peak 
inspiratory flow (PIF) from 
baseline up to one year 
• 
Change in mean forced 
expiratory volume in one 
second (FEV1) from baseline 
up to one year 
 
Tests: Correlation coefficients, 
regression equations, and regression 
summary statistics (e.g., R-squared, 
FEV1 is a well-established 
and accepted measure of 
lung function in asthma. 
Changes in FEV1 are noted 
during acute episodes and 
clinically meaningful 
changes have been 
established. Little is known 
about the correlation 
between FEV1 and PIF and 
whether change in PIF could 
serve as a surrogate for 
change in FEV1. 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
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mean absolute error) for PIF vs. 
FEV1, PIF vs. FVC. Identification of 
change in PIF thresholds (increase 
and decrease thresholds) that are 
clinically meaningful. 
Univariate/multivariate regression 
statistics between inhalation 
parameters and asthma outcomes 
such as asthma control score, 
number of exacerbations, and 
number of hospitalizations.  
Reported confusion matrix for 
change in PIF versus asthma 
exacerbations and poor asthma 
control. 
Exploratory  
To evaluate the asthma control and 
health care utilization of subjects as 
measured by the number of 
exacerbations (acute worsening of 
asthma requiring at least 3 days of 
corticosteroids or a doubling dose of 
maintenance steroids), Emergency 
and hospitalization encounters, and 
patient-reported perceptions of 
asthma control.  
 
• 
Number of exacerbations 
from baseline up to one 
year 
• 
Number of hospitalizations 
• 
Number of emergency room 
visits 
• 
Mean Asthma Control Test 
(ACT) scores 
Understanding the 
healthcare utilization and 
perceptions of asthma 
control can help researchers 
better understand 
how/whether the digihalers 
are helping the patients 
achieve better asthma 
control.    
To determine the predictive value of 
inhalation parameters, including 
peak inspiratory flow (PIF), 
inspiratory time and volume, and 
number of inhaled doses on asthma 
exacerbations in a population of 
severe asthma patients on biologics. 
To determine the impact on 
inhalation parameters on categorical 
response to biologics. Response will 
be categorized as non-response, 
partial and complete response on the 
basis of six factors: a 50% reduction 
in exacerbations, any reduction in 
maintenance OCS dose, change of at 
least 10% in FEV1, improvement of 3 
points in ACT score and patient 
Algorithm that produces asthma 
exacerbation probability given a set 
of baseline and current inhalation 
parameters.  A confusion matrix 
summarizing the algorithm’s 
performance on training dataset and 
from which performance statistics 
(accuracy, sensitivity, specificity, 
etc.) can be computed.Proportion of 
patients achieving non-response, 
partial and complete response to 
biologics. Summary, chi-squared 
test, and Tukey’s HSD test statistics 
of inhalation parameters by 
response group. 
PIF, inspiratory time and 
volume are expected to vary 
within a patient over time; 
however, significant changes 
in these variables may 
indicate the development of 
acute exacerbations of 
asthma during the early 
phase when interventions 
may help change the 
progression of these 
events.Response to biologics 
is heterogeneous, and it is 
unclear if inhalational 
parameters measured by 
the Digihaler™ are 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
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perception of global improvement in 
asthma.  
correlated with degree of 
response. 
To employ machine learning 
techniques to a robust well 
characterized cohort with clinical, 
biological and digital markers to 
develop a predictive algorithm aimed 
at identifying responders to 
biologics. In addition, we would aim 
to develop an algorithm that can 
detect early changes in measured 
parameters that can predict long-
term improvements in asthma 
control and exacerbations when 
biologics are initiated. The latter 
objective will be achieved by 
focusing on the sub-group of patients 
initiating biologics for the first time 
or switching between biologics due 
to perceived inadequate response.  
Machine learning model developed 
for predicting responders to 
biologics (developed in collaboration 
with the University of Michigan 
Morphomic Analysis Group). 
Reporting key factors in the model 
that are associated with response, 
using inhalation parameters (digital 
markers), clinical factors, and 
biomarkers. 
Predictive analytics have 
been utilized in many 
diseases to develop robust 
ways to identify response, 
and the use of machine 
learning methods has 
enhanced our ability to 
identify responders to 
antibiotics, predict those 
with a risk of poor surgical 
outcomes, and identify 
those likely to have disease 
progression. We will use our 
experience with machine 
learning to develop new 
predictive models that can 
help us to shift the 
treatment paradigm, 
improving our ability to 
make early predictions of 
therapeutic response in 
patients receiving biologics 
for asthma. 

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4 STUDY DESIGN 
4.1 OVERALL DESIGN 
This is an open-label real world study that has been designed to determine the patterns of use and 
impact of inhalation parameters on both predicting asthma exacerbations and response to biologics in 
patients with severe asthma. The digital inhalers used in this trial are unique in their ability to seamlessly 
record multiple parameters as the patients use their inhalers. There are no external devices required for 
device use recording. We aim to leverage the information collected by the digital inhaler to understand 
the impact of exacerbations on inhalation parameters, to determine the clinically meaningful differences 
in these measurements, and to determine their correlation to FEV1, which is the most widely accept 
measure of airflow in patients with severe asthma. Home spirometry is challenging and expensive and if 
inspiratory flow measures can be used as surrogates of expiratory flow, this would revolutionize our 
ability to track lung function in patients with severe asthma. The digital parameters will be incorporated 
with clinical, digital, and biological markers in an attempt to identify predictive algorithms that can 
identify responders to biologics early in the treatment course, facilitating decisions about continuation 
or discontinuation of therapy.  
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
We designed an open label, single site study and intend to enroll patients in a sequential manner via 
screening of the EMR system for patients currently receiving biologics or with a pending approval for 
biologics for asthma. The open label design was selected as we are interested predominantly in 
inhalation parameters that are collected without any specific actions from participants, thus decreasing 
any potential changes in medication utilization. We intend to educate the patients on the use of the 
inhaler and how it has been prescribed but will make no efforts to intervene to encourage compliance 
with medication utilization, as we are interested in patient behavior and interaction with the 
device.  The application that collects information about inhaler use will be stored on the patients’ smart 
phone, and therefore they may choose to review the information and make changes in their adherence. 
We will not require patients to utilize the application and will passively record whether patients report 
using the app or not. We will design a questionnaire that determines patients’ opinions of the app if 
they are utilizing it. All clinical parameters will be collected from the EMR.  
 
Our main objective is to determine baseline inhalation parameters (e.g., peak inspiratory flow) using 
sample means.  According to one study (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328129/) the 
PIF mean was 115 and standard deviation was 15. Assuming a 100 patient sample, the 95% CI of our 
estimate of the PIF sample mean would be plus or minus 3, e.g., 115 (95% CI 112 – 118), which we deem 
to be of sufficient power for our analysis (http://statulator.com/SampleSize/ss1M.html).  
Our secondary objective includes training a machine learning model, and one common measure to 
evaluate model performance is discrimination, assessed by an area under the ROC curve (AUROC).  
Again, assuming a 100 patient sample and a 50% event rate, we would have adequate power to 
conclude that a model with an AUROC performance of >0.65 has confidence intervals that won’t cross 
0.5 (which would be a model that is no better than chance) 
(http://www.biosoft.hacettepe.edu.tr/easyROC/). 

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4.3 JUSTIFICATION FOR DOSE 
We intend to use the approved dosage of the IMP. No changes to therapy were warranted in this study.  
4.4 END OF STUDY DEFINITION 
There are no formal rules for early termination of this study. During the conduct of the study, serious 
adverse events will be reviewed as they are reported from the study site 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. 
 
 

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5 STUDY POPULATION 
5.1 INCLUSION CRITERIA 
1. A history of severe persistent asthma as defined by ERS/ATS criteria which includes the presence of 
poor asthma control on high dose ICS/LABA OR the need for high dose ICS/LABA to maintain asthma 
control OR oral steroids for maintenance therapy for more than 50% of the prior year. 
  
2. Age >18 years of age or older. 
  
3. Presence of current biologic use or planned initiation of biologics following study enrollment. 
  
4. Patients will be categorized on the basis of asthma control (ACT< 19 will be considered poor asthma 
control). We will cap the patients with good asthma control at 30% and will no longer enroll those 
patients once the strata have been fully enrolled.  
  
5. Willingness to switch maintenance inhalers to AirDuo® Digihaler™ and/or to use ProAir® Digihaler™ 
for rescue therapy. Use of nebulized albuterol will be discouraged but not prohibited. We will require 
patients to document nebulizer use.  Patients that discontinue Pro-Air will be asked to document use of 
their rescue inhalers in their diaries. 
  
6. 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 study application.  If their smart device is not compatible with the 
study software; willingness to use an alternative device that will be provided by the study team. 
  
7. Ability to provide informed consent. 
  
8. 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. 
5.2 EXCLUSION CRITERIA 
1. Clinically important pulmonary disease including COPD, primary bronchiectasis, idiopathic 
pulmonary fibrosis, cystic fibrosis and interstitial lung disease. 
2. Any disorder that is either not stable or could in the opinion of the investigator affect the ability 
of the subject to safely participate in the study or could adversely affect study results. 
3. History of HIV or other primary immunodeficiency syndrome. 

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4. Malignancy other than skin cancer that has occurred within the past year and that will impact 
survival thus limit participation in the clinical trial. 
5. Current documented alcohol abuse or drug use.  Patients with a history of abuse and are in 
remission are eligible to enroll. 
6. Any life-threatening diseases that will impact the patient’s ability to complete the 12-month 
study period. 
7. Inability to provide informed consent. 
5.3 LIFESTYLE CONSIDERATIONS 
There are no lifestyle considerations for this study. 
5.4 SCREEN FAILURES 
Patients will - be removed from the study if they do not get started on a biologic or if they discontinue 
therapy with biologics for any reason.  
 
Patients who screen fail do not need to be replaced to reach the target enrollment number. 
5.5 STRATEGIES FOR RECRUITMENT AND RETENTION 
Patients will be recruited from the Severe Asthma Clinics at the University of Michigan. The program 
currently has 300 patients receiving biologics for asthma. We will also recruit patients from other clinics 
that are receiving biologics as long as the providers are willing to obtain and document detailed 
information on biologic response to therapy.  
 
 

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6 STUDY INTERVENTION 
6.1 STUDY INTERVENTION(S) ADMINISTRATION 
6.1.1 STUDY INTERVENTION DESCRIPTION 
The Teva Digihaler™ System consists of 4 devices. Device 1 is the ProAir® Digihaler™, which is the test 
IMP. The 3 investigational medical devices are: Device 2 - Patient-facing App; Device 3 - DHP (cloud 
solution); and Device 4 - Provider-facing dashboard. Patients will receive 2 ProAir® Digihaler™ devices at 
the face-to-face visits and can request additional devices if these devices have been completely used. A 
three-month supply of maintenance AirDuo® Digihaler™ will be provided at each in person visit and only 
after verification that data from the previous device has been downloaded. Patients will receive 
instructions for using the ProAir® Digihaler™ and AirDuo® Digihaler™ from the investigational center 
personnel. Patients will be instructed to return all inhalers to the investigational center at the end of 
treatment visit or at early termination.  These devices will be brought to the in-person visits and the 
data download will be confirmed, after which the devices will be discarded.  
6.1.2 DOSING AND ADMINISTRATION 
Patients will receive the ProAir® Digihaler™ 90mcg and the AirDuo® Digihaler™ at a dose that is 
equivalent to the patients current inhaled therapy dose. Most patients will likely require the high dose 
inhaler: 232/14 device. This medication will be administered twice daily. The ProAir® Digihaler™ will be 
utilized up to six times per day as needed for acute asthma symptoms.  
6.2 PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
Each IMP shipment will include a packing slip listing the contents of the shipment, return instructions, 
and any applicable forms.  
 
The research pharmacy 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.  
 
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 the final visit or at early termination. 

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The investigator, institution, or the head of the medical institution (where applicable) is responsible for 
IMP accountability, reconciliation, and record maintenance (i.e., 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 (i.e., 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 Reference Manual. 
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
The prescribed dose of ProAir® Digihaler™ used in this study (i.e., 90 mcg, 1 to 2 inhalations every 4 to 6 
hours, as needed) was selected based on the prescribing information for PROAIR® RESPICLICK, which has 
the same drug delivery design as ProAir® Digihaler™. The prescribed dose of AirDuo® Digihaler™ is based 
on current FDA approval for the AirDuo® inhaler. The inhaler used in this study will have the digital 
interface for data collection, and this should not impact the drug delivery in any way. The digital inhaler 
is longer than the conventional inhaler but is otherwise used similarly.  
  
Supplies of IMP will be labeled according to the current International Council for Harmonization (ICH) 
guidelines on Good Clinical Practice (GCP) and Good Manufacturing Practice and will include any locally 
required statements. 
6.2.3 PRODUCT STORAGE AND STABILITY 
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 drug (IDS) pharmacy at the University of Michigan will be 
responsible for acknowledging receipt of the IMP. All study drug will be dispensed by the IDS pharmacy.  
6.2.4 PREPARATION 
There is no medication preparation required.  
6.3 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
There is no randomization in this study. Subjects will be pre-screened prior to clinical visits and all 
eligible subjects will be approached. Once the controlled strata have been filled then we will no longer 
approach patients that do not meet criteria for poor asthma control (ACT >/=19). 
 
 

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6.4 STUDY INTERVENTION COMPLIANCE 
We will determine medication compliance by assessing the data collected from the inhaler. These 
inhalational parameters and medication use data will be transferred from the Digihaler™ to the patients’ 
phone app and then to the server powering the dashboard. If a patient switches to ProAir® Digihaler™ 
/Airduo™ and determines that one of the inhalers is ineffective they can switch back to their original 
inhaler and remain in the study.  The patient will need to agree to use at least one of the two digital 
inhalers to remain in the study (ie either the rescue or maintenance inhaler) as this will allow us to 
obtain the inspiratory parameters required in this study.  We also ask that all non-digital inhaler use be 
documented in the patient diary.  We will allow a maximum of 10% of the study population to switch 
their medications during the study.   
6.5 CONCOMITANT THERAPY 
  
6.5.1 RESCUE MEDICINE 
The patients will utilize the ProAir® Digihaler™ for rescue. Nebulized albuterol and atrovent will be 
allowed for severe symptoms during exacerbations and patients will be required to report when these 
medications were utilized. We will encourage preferential use of the inhaler if symptoms are not severe 
enough to warrant nebulized medications.  
  
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.  
 
 

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7 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 DISCONTINUATION OF STUDY INTERVENTION 
Patients will be discontinued from study intervention if they are no longer willing or able to comply with 
study procedures or if they withdraw consent.  If a patient switches to ProAir® Digihaler™ /Airduo™ and 
later has a preference for their original controller or short-acting beta agonist, then switches will be 
allowed as long as the patient remains on at least one of the two digihaler devices.  The patient will 
need to agree to use at least one of the two digital inhalers to remain in the study (ie either the rescue 
or maintenance inhaler) as this will allow us to obtain the inspiratory parameters required in this study.  
7.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
1. Patient withdraws consent or withdrawal from the study for any reason 
2. 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. 
3. Patient develops an illness that would interfere with his/her continued participation. 
4. Patient is noncompliant with the study procedures and assessments in the opinion of the 
investigator. 
Patients should be treated with standard of care after withdrawal from or termination of the study as 
appropriate.  We will 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. 
7.3 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 

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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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8 STUDY ASSESSMENTS AND PROCEDURES 
8.1 EFFICACY ASSESSMENTS 
The efficacy of the drug product will not be evaluated in this study.  The focus of this study is the current 
behavior of severe asthmatics with regard to their inhaler use. 
8.1.1 STUDY VISITS 
8.1.1.1 SCREENING/BASELINE VISIT (V0) 
 
Patients will be pre-screened and recruited as they attend standard of care visits in the Severe Asthma 
Clinic at Michigan Medicine.  The following events will take place during the screening/baseline visit: 
• 
Informed Consent 
• 
Enrollment into the MiAsthma Registry 
• 
Review of Inclusion/Exclusion Criteria 
• 
Collection of Medical and Procedure History 
• 
Collection of Smoking/Tobacco Use History 
• 
Review of Past and Current Medications 
• 
Review of Asthma Exacerbations and Healthcare Utilization 
• 
Collection of Clinical Variables (if available) including FeNO, CBC w. Differential, and 
Immunoglobulin E (IgE) Levels 
• 
Dispensation of Inhaler 
o Education on Inhaler Use and Registration to Inhaler Application 
• 
Dispensation of Home Spirometer 
o Education on Use of Home Spirometer 
• 
Collection of Patient Reported Outcomes 
o Asthma Control Test (ACT), AIR-Q, SGRQ 
 
8.1.1.2 IN PERSON/CLINICAL VISITS (V3, V6, V9, V12) 
 
Patients will return to clinic every three months to check in with the study team and to provide-
additional inhalers for the study.  During the in-person visits the following events will take place: 
• 
Review of Current Medications 
• 
Review of Asthma Exacerbations and Healthcare Utilization 
• 
Collection of Clinical Variables (if available) including FeNO, CBC w. Differential, and 
Immunoglobulin E (IgE) Levels 
• 
Dispensation of Inhaler 
• 
Adverse Event Assessment 
• 
Collection of Patient Reported Outcomes 

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o Asthma Control Test (ACT), AIR-Q, SGRQ 
• 
Device Re-Education (As Needed) 
8.1.1.3 INTERIM PHONE CONTACT (V1, V2, V4, V5, V7, V8, V10, V11) 
 
Patients will be contacted monthly between in person visits to assess the following: 
• 
Review of Current Medications 
• 
Review of Asthma Exacerbations and Healthcare Utilization 
• 
Shipping of Inhaler (As Needed) 
• 
Adverse Event Assessment 
• 
Device Re-Education (As Needed) 
 
8.1.2 STUDY PROCEDURES 
8.1.2.1 ENROLLMENT INTO MIASTHMA REGISTRYSCREENING/BASELINE VISIT (V0) 
 
All clinical data elements will be abstracted from the EMR and entered into an existing asthma registry 
at the University of Michigan (MiAsthma Registry) that focuses on severe asthma.  A separate consent is 
required for entry into the database and will be obtained at the same time as initial consent for this 
study.  Variables captured in the MiAsthma Registry include medical and procedure history, review of 
past and current medications (both asthma and non-asthma related) and collection of clinically assessed 
PRO’s.  Relevant medical history may include any of the following:  asthma history, co-morbid conditions 
such as nasal polyps, allergic rhinitis, hives, eosinophilic disease other than asthma, obesity and sleep 
apnea, age of asthma onset, number of exacerbations in the past year, lifetime hospitalizations, yearly 
ER visits, oral steroid dependence, history of life-threatening asthma as indicated by prior intubation 
and mechanical ventilation. 
8.1.2.2 CLINICAL VARIABLES AND BIOLOGICAL MARKERS 
 
When available FeNO, peripheral eosinophils (the three highest values in the past 12 month) collected 
via CBC with Differential, total IgE, presence or absence of positive specific IgE results will also be 
recorded.  Prior lung function measurements and spirometry data (all available within 12 months prior 
to initiation of biologic therapy) will be abstracted via the MiAsthma Registry when available.  No study 
specific testing will take place (with the exception of home spirometry). 
8.1.2.3 ASTHMA EXACERBATIONS 
 
During the study, an asthma exacerbation will be defined as a worsening of asthma symptoms (defined 
below) that leads to any of the following: 

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• 
Administration of a bolus/burst of systemic corticosteroids (one dose of IV or IM steroids or at 
least consecutive three days of oral corticosteroids). 
• 
An emergency room or urgent care visit for asthma related symptoms that required oral/IV/IM 
corticosteroids. 
• 
An inpatient hospitalization (defined as admission to an inpatient facility and/or evaluation and 
treatment in a healthcare facility for ≥ 24hrs) due to asthma. 
For the protocol, the start date of the exacerbation will be based on the day of ER, urgent care visits or 
hospitalization. For those that did not experience one of these events, the day of the first dose of OCS 
will be used as the initial day of the exacerbation. The last day of systemic corticosteroids will be used as 
an end date of the exacerbation. If less than 7 days has elapsed between the end of the first 
exacerbation and the beginning of new symptoms, then this will be considered a relapse of the initial 
episode rather that a new episode. Subjects that experience exacerbations post enrollment will be 
treated per standard of care by the patient's physician.  
8.1.2.4 DIGIHALER™, TEACHING, AND ONLINE APPLICATION 
 
Education for the appropriate use of the Digihaler™ will be provided at the Screening/Baseline visits and 
again as needed throughout the study.  The study team will assist in registering for the digital inhaler 
application and periodically check to ensure data is being captured appropriately. 
 
Inhalation parameters and number of doses will automatically be collected using the Digihaler™. 
  
Application 
The software App is a user facing software/focused smart device application for patients using the 
Digihaler™ product.  The smart device app is used to track medication usage and allow users to self-
assess their respiratory symptoms on a daily basis, share information on local environmental conditions, 
and produce user reports to review 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 health data automatically from the inhaler devices via Bluetooth on a smart device.  
The smart device camera will be used for scanning and pairing.  The data will allow the patient to track 
their usage of medication, inhalation results, and self-assessments related to their asthma.  The App will 
get environmental information from 1 or more web services. 
 
TEVA Digital Health Platform 
The TEVA DHP is a system that stores and transfers health data collected from the App.  The cloud 
solution automatically synchronized with the App after events and/or at predetermined time 
periods/intervals.  An internet connection to the smart device (e.g., wireless or cellular phone network) 
is required in order for communication to be established between the App and the cloud solution. The 

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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. 
8.1.2.5 SPIROMETRY 
 
Home spirometry will be performed with the Go Spiro device that is coupled with an avatar that 
provides coaching and real time feedback about whether the testing has met ATS criteria. Patients will 
be asked to perform spirometry a least three days per week, at least one of which occurs on the 
weekend.  Patients will be asked to make a maximum of three attempts to obtain data.  Patients will be 
encouraged to complete more than three readings per week whenever possible. The spirometry should 
be obtained at approximately the same time of each day. 
  
The vendor providing central spirometry services will be responsible for assuring that the spirometer 
used by patients at home meets ATS/ERS criteria and that study staff educating participants on home 
spirometry have been properly certified to provide this training.  
  
Subjects should be instructed to follow the required restrictions below prior to performing spirometry. If 
the required restrictions have not been adhered to the visit should be rescheduled to the earliest 
possible time to maintain the visit windows. 
  
Home Spirometry Testing 
An electronic hand-held spirometer will be provided to the subject at the screening visit. Subjects will be 
trained on how to obtain at home PEF and FEV1 measurements at the screening visit. Training should 
include explanation of the device functionality and proper use of the PEF meter. 
  
Home PEF measurements will be taken in the morning (prior to taking morning medications) and/or in 
the evening at bedtime (prior to taking pm medications for asthma) on the days that spirometry is done. 
FEV1 will be measured at home using accepted ATS/ERS criteria via the use of an avatar guided 
maneuver. Subjects should perform 3 successive maneuvers while sitting or standing but in the same 
position at every testing. Adherence to peak flow measurements must be checked by the study 
coordinator at every in-person visit. A low compliance trigger will be sent to the study site if the subject 
had completed less than 80% of the expected measurements over a seven-day period. 
  
8.1.2.6 PATIENT REPORTED OUTCOMES 
 
Asthma Control Test (ACT) 

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The ACT captures asthma symptoms and short acting bronchodilator usage. Questions will be weighted 
equally and scored per the standardized questionnaire (REF). An ACT score of <19 is consistent with 
uncontrolled asthma.  
 
Asthma Impairment and Risk Questionnaire (AIRQ) 
The AIRQ™ is a patient assessment tool intended to help identify patients 12 years of age and older 
whose health may be at risk because of uncontrolled asthma. This assessment is based on a series of 
patient-facing questions about asthma medications, respiratory symptoms, and utilization of health care 
resources. Depending on the patient’s responses to these questions, the patient will receive a score 
reflecting their level of asthma control. 
 
St. George’s Respiratory Questionnaire 
The St. George’s Respiratory Questionnaire (SGRQ) is a patient reported questionnaire designed to 
measure impact on overall health, daily life, and perceived well-being in patients with obstructive 
airways disease.  Scores range from 0 to 100 with higher scores indicating more limitations. 
 
8.2 SAFETY AND OTHER ASSESSMENTS 
In this study, safety will be assessed by qualified study personnel by evaluating reported adverse events, 
device safety (as assessed by adverse device effects and serious adverse device effects), and use of 
concomitant medications.   
8.3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Safety Considerations: The external sponsor/collaborator shall have the sole responsibility for the 
collection and recording of all reported Adverse Events (AEs),Serious Adverse Events (SAEs), 
Pregnancies, Adverse Device Effects and Serious Adverse Device Effects throughout the entire study.  In 
keeping with good clinical practice or good pharmacovigilance practice, and 21 C.F.R. Part 314 as the 
case may be, the external sponsor/collaborator will be required to report and notify the FDA, 
Institutional Review Boards (IRBs), Teva Pharmaceuticals (Teva), and any other 
collaborators/investigators of all situations mentioned below, within twenty-four (24) hours from 
receiving information of the situation.  The event will be reported to Teva by submitting the collected 
information to the Teva Local Safety Officer. 
(a) 
All related Serious Adverse Events 
(b) 
All Serious Adverse Device Effects. 
(c)  
Any medical event which may reasonably be believed to impair the integrity, validity or 
ongoing viability of the Study  

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Pharmacovigilance approved definitions of AEs and SAEs and reporting and recording procedures will be 
followed as noted below. 
In this study, safety will be assessed by qualified study personnel by evaluating reported adverse events 
and device safety (as assessed by adverse device effects and serious adverse device effects).  The 
external sponsor/collaborator will be responsible for the collection and recording of all reported 
Adverse Events (AEs), Serious Adverse Events (SAEs) Pregnancies, Adverse Devise Effects and Serious 
Adverse Device Effects throughout the entire study. 
Definitions: 
Adverse Event  
An adverse event (AE) 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 or 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.  
 
 8.3.2 ADVERSE DEVICE EFFECT AND REPORTING 
 
An adverse device effect is an adverse event related to the use of an investigational medical device or 
combination product. This includes adverse events resulting from insufficient or inadequate instructions 
for use, deployment, implantation, installation, operation, or any malfunction of the investigational 

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medical device, including any event resulting from user error or from intentional misuse of the 
investigational medical device. 
A serious adverse device effect is an adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event as described in section 8.3.3. 
  
AE=adverse event; ADE=adverse device effect; SADE=serious adverse device effect; SAE=serious adverse 
event. 
8.3.3 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
Serious Adverse Event 
A serious adverse event (SAE) 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 (i.e., 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 

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• 
absence of initial findings of cholestasis (i.e., 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 non-serious adverse event. 
8.3.4 SERIOUS ADVERSE EVENT REPORTING 
In keeping with good clinical practice or good pharmacovigilance practice, and 21 C.F.R. Part 314 as the 
case may be, the external sponsor/collaborator will be required to report and notify the FDA, 
Institutional Review Boards (IRBs), Teva Pharmaceuticals (Teva), and any other 
collaborators/investigators of all situations mentioned below, within twenty-four (24) hours from 
receiving information of the situation.  The event will be reported to Teva by submitting the collected 
information to the Teva Local Safety Officer. 
(a) 
All related Serious Adverse Events 
(b) 
All Serious Adverse Device Effects 
 (c)  
Any medical event which may reasonably be believed to impair the integrity, validity or 
ongoing viability of the Study  
Adverse Event.  Sponsor/collaborator acknowledges that Company is required to comply fully and 
promptly with all regulatory safety reporting requirements regarding its products. The investigator being 
the sponsor of the study has sole responsibility for reporting of adverse events to the FDA, IRBs and/or 
investigators. For informational purposes any correspondence to the FDA regarding adverse events or 
other safety issues will be simultaneously copied to the Company via email 
(us.clinops.sae@tevapharm.com) or facsimile (215-795-4243). The Investigator will communicate the 
occurrence of any serious adverse events which he or she believes to be definitely, likely, possibly or 
probably related to the Study Product, and any exposure of a pregnant study participant to the Study 
Product, within 24 hours of becoming aware of the event. In the case of non-interventional studies, the 
Investigator also will communicate all related, non-serious adverse events to Company within 24 hours 
of becoming aware of the event.  Please note that the reporting period begins when a patient signs the 
informed consent, and ends 30 days after the discontinuation of dosing or completion of the patient’s 
participation in the Study if the last scheduled visit occurs at a later time. In addition, the Investigator 
must notify Company of any serious adverse events that may occur after this time period which he or 
she believes to be definitely, likely, possibly or probably related to the Study Product.   
 
The MedWatch 3500A form should be utilized to report serious adverse events to the FDA.   
 
A serious adverse event or reaction is any untoward medical occurrence that at any dose:  
 
• 
Results in death;  
• 
Is life-threatening (meaning that the patient was at immediate risk of death as the 
event occurred, but not including events that could cause death if they occurred in a 
more severe form); 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization; 
• 
Results in a persistent or significant disability/incapacity; 
• 
Is a congenital anomaly or birth defect; 

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• 
Results in the development of drug dependency or drug abuse;  
• 
An important medical event that may not result in death, be life threatening, or require 
hospitalization, but may jeopardize the patient and require medical intervention to 
prevent one of the outcomes listed above.  
 
For the purpose of this Agreement, these terms shall have the same meaning as the terms used in the 
provisions of the Code of Federal Regulations governing drug and biologic safety reporting.  See 21 CFR 
314.80(a); 600.80(a).  Additionally, pregnancy exposure and any safety information as reasonably 
requested by Company, will also be deemed to be adverse events for purposes of this Agreement. 
Investigator shall use his/her judgment to determine the relationship between the serious adverse event 
and the Study Product. In the event the IRB requests additional safety information from Investigator, 
Investigator shall notify Company of such request within one (1) business day.  
 
Investigator and Institution further agree to report all Adverse Events in compliance with all applicable 
legal and regulatory requirements, and in accordance with any requirements provided by Company.   
 
8.3.5 REPORTING EVENTS TO PARTICIPANTS 
 
Events that involve device failure that will affect drug delivery as noted by the sponsor or any other new 
safety requirements that may be required by the FDA will be reported to participants.  
8.3.6 EVENTS OF SPECIAL INTEREST 
 
There are no events of special interest anticipated in this study.  
 
 
 
 

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9 STATISTICAL CONSIDERATIONS 
9.1 STATISTICAL HYPOTHESES 
• 
Primary Efficacy Endpoint(s): Establish group-level daily/weekly baseline normative values for: 
(1) mean and median number of doses of ProAir® Digihaler™ and AirDuo® Digihaler™, and per-
inhalation baseline normative values for (2) peak inspiratory flow (PIF), (3) inspiratory time and 
(4) volume.  We will test the hypothesis that patient-specific baseline usage values are 
significantly different from usage values collected during or leading up to exacerbation events.   
• 
Secondary Efficacy Endpoint(s):  1. Test the hypothesis that imminent exacerbation events can 
be predicted using Digihaler™ inhalation parameter measurements.  2. Test the hypothesis that 
PIF is linearly (or non-linearly) related to FVC and FEV1. Test the hypothesis that there exists a 
threshold for change in PIF that is associated with a clinically meaningful change (>10%) in lung 
function. 3. Test the hypothesis that patients with low, moderate, and high adherence to 
maintenance inhalers have significantly different asthma outcomes.  4. Test the hypothesis that 
non-responders, partial, and complete responders have significantly different Digihaler™ 
inhalation parameters.  5. Test the hypothesis that future response to biologics can be predicted 
using clinical, biological, and digital (inhalation) markers.  
9.2 SAMPLE SIZE DETERMINATION 
Sample size calculations were based on peak inspiratory flow measurements.  
 
Based on population-based estimates of peak inspiratory flow: 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328129/ The mean was 115 and standard deviation 
was 15. With a 100-patient sample, 95% CI of our estimate of the mean would be plus or minus 3, e.g. 
115 (95 CI 112 – 118).  
 
The machine learning model will be performed based on the most common measure to evaluate 
performance which is discrimination that is assessed by an AUROC.  If we have a 100-patient sample and 
assume a 50% event rate (http://www.biosoft.hacettepe.edu.tr/easyROC), we would have adequate 
power to conclude that a model with an AUROC performance of > 0.65 has confidence intervals that 
won’t cross 0.5 (which would be a model that is no better than chance). 
9.3 POPULATIONS FOR ANALYSES 
University of Michigan patients currently receiving biologics or with a pending approval for biologics for 
asthma.  
 

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9.4 STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
We will perform a retrospective analysis of prospectively enrolled patient data. Following completion of 
the study’s data collection period, data from the Digihaler™ asthma inhalers will be downloaded to 
secure servers, joined to clinical data from the electronic medical record (including exacerbation event 
data) and patient questionnaire responses, and analyzed using R statistical analysis software.  The 
University of Michigan Morphomics Analysis Group will collaborate with the TEVA analytics team to 
produce a rigorous and reproducible research result. An alpha level of 0.05 will be used to determine 
“statistical significance” with a Bonferroni correction (alpha / # tests) applied to account for multiple 
testing when appropriate.   
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
To establish normative baseline values, summary statistics (mean, standard deviation, median, IQR) will 
be computed for the number of doses taken per individual, stratified by type of inhaler (maintenance, 
rescue), and aggregated per day and for particular times of day (morning, midday, afternoon, evening, 
overnight).  Per-inhalation summary statistics will be computed for PIF, inspiratory time, and inspiratory 
volume.  Inhalation data within +/- 14 days of an acute exacerbation event will be identified and 
excluded from normative baseline calculations.  
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
1. To develop an algorithm that can identify probable imminent exacerbation events using Digihaler™ 
inhalation parameter measurements, we will compare the performance of several different machine 
learning regression models.  Since we expect our training set to be relatively small with a low event rate, 
we plan to use the entire inhalation parameter dataset for model training but will employ repeated k-
fold cross-validation to reduce variance (over-fitting) and include non-linear features to reduce bias 
(under-fitting). Examples of features that could be computed and included in this model include but are 
not limited to: difference between current value and patient-specific 7-day moving average, difference 
between current value and patient-specific 24-hour moving average, 7-day sample entropy, 24-hour 
sample entropy, difference in Min-Max over last 24 hours, etc. 
 
 A logistic regression model would treat the outcome (exacerbation) as a binary (Yes/No) event.  The 
output of this model would be a daily probability between 0 and 1 that an exacerbation event will occur 
within a certain period of time. Different models will be fit for different periods of time (e.g., 24, 48, 72 
hours) and the performance of each model assessed and compared to others.   A recurrent event 
survival model would treat the exacerbations as discrete events in time.  The output of this model would 
be the predicted time (e.g., in decimal days or hours) until the next event.  Other models may include 
convolutional and/or recurrent neural networks (RNN) with LSTM or GRU architecture with varied 
numbers of hidden layers. 
 
2. To determine whether and how PIF is associated with FEV1 and FVC, we assess the linearity and 
strength of the relationship using scatter plots, calculate the paired correlations (Pearson, Kendall, and 
Spearman), and compute univariate linear regression equations with PIF as the predictor and FEV1 or 

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FVC as the response. If non-linearity is found, we will determine the appropriate PIF transformation or 
polynomial term to use in the regression. Regression summary statistics (e.g., R-squared, Mean Absolute 
Error, Coefficients, and p-values) will be reported.  
 
3. Patients will be assigned to one of three adherence groups (low, moderate, high) based on Digihaler™ 
inhalation usage parameters over the previous month.  We will use the Chi-squared test to determine if 
group differences exist for each asthma outcome over the next month, and Tukey’s Honest Significant 
Difference test to determine which groups are significantly different. 
 
4. Patients will be assigned to one of three biologics response groups (non, partial, complete) based on 
six asthma factors (described earlier).  We will use the Chi-squared test to determine if group differences 
exist for each inhalation parameter, and Tukey’s Honest Significant Difference test to determine which 
groups are significantly different. 
 
5. To develop an algorithm that can predict patients that will respond to biologics regression or 
classification models.  Since we expect our training set to be relatively small with a low event rate, we 
plan to use the entire inhalation parameter dataset for model training but will employ repeated k-fold 
cross-validation to reduce variance (over-fitting) and include non-linear features to reduce bias (under-
fitting).  We do not know a priori whether regression or classification would be the appropriate 
approach to this question so we will test models using both approaches. The classification approach can 
be formulated as either a two-class problem – Non vs. Partial or Complete responders, or Non or Partial 
vs. Complete responders – or a three-class problem – Non vs. Partial vs. Complete. The regression 
approach requires a two-class formulation using logistic regression. Different models will be fit for 
different formulations and the performance of each model assessed and compared to others. 
9.4.4 SAFETY ANALYSES 
 We will track and document safety events related to the device during the clinical trial.  
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 Count, mean, standard deviation, median, IQR will be computed for continuous variables and 
percentages for categorical variables – daily, time-of-day, and per-inhalation parameters, exhalation 
spirometer variables, clinical and demographic variables, asthma outcomes, radiographic variables.  
Summaries will be computed for males vs. females, adherence group, and response group. 
9.4.6 PLANNED INTERIM ANALYSES 
We will perform the initial analysis once 50% of the study population has completed six months of 
follow-up within the study. 
9.4.7 SUB-GROUP ANALYSES 
 See secondary endpoints #3 (adherence groups) and #4 (responder groups). 

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9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
We do not plan to tabulate or report individual participant data, except in the case where we determine 
that one or more participant’s data would be useful for explaining a general concept or idea, or is 
representative of an overall trend, and as such may be displayed (without any identifying information) in 
a data graphic or visualization with or without an accompanying data table.  
9.4.9 EXPLORATORY ANALYSES 
We plan to conduct extensive exploratory analyses including but not limited to: data cleaning and 
aggregation, outlier analysis, multicollinearity (correlation) analysis, sex effect analysis, age effect 
analysis, time series analysis, unsupervised cluster analysis, univariate testing (T-tests, Fisher’s Exact 
Test, Wilcoxon Test, Chi-Squared Test, Tukey’s Honest Significant Difference (HSD) Test), multivariable 
linear and non-linear regression, feature creation and selection for machine learning models, feature 
scaling and centering, training machine learning models using repeated k-fold cross-validation, and 
extensive data visualization for correlations and time series analysis.   
 
 

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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
It is the responsibility of the named investigator to assure that all study subjects undergo an appropriate 
process of written informed consent that has been reviewed and approved by their local Institutional 
Review Board. The investigators will inform all subjects as to the nature, aims, duration, potential 
hazards, and procedures to be performed during the study and that his/her medical records and study-
related documents may be reviewed by the FDA or sponsoring companies in a manner designed to 
protect their confidentiality.  This protocol must receive approval by the Institutional Review Board at 
each participating site prior to implementation of the study at that site. Investigators must also disclose 
to subjects any existing conflicts of interest and explain that patients are completely free to refuse to 
enter the study or to withdraw from it at any time without prejudice to their medical care.  
  
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Consent will be copied and provided to the patient after it has been signed. The documentation will 
then be scanned into the EMR per University of Michigan protocol.  
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
The protocol will be discussed in detail with all potentially eligible patients and the essential 
components of the informed consent process personally confirmed by a responsible investigator before 
the consent is signed and countersigned. The subject will sign the informed consent document prior to 
any procedures being done specifically for the study. All revisions of the protocol must be reviewed by 
the IRB and reflected in the consent form. Patients will receive copies of all consent documents and 
HIPAA forms for their records and these documents will detail emergency contact numbers for the study 
and independent reporting numbers for the local IRB in the event that they have any concerns or 
questions about the process of consent or the handling of human subjects. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
The investigators and/or sponsor reserve the right to terminate the study at any time. If this becomes 
necessary, appropriate procedures for continuing long-term follow-up and assuring the adequate 
treatment and safety of the participating subjects will be arranged after review and approval by the 
study sponsor, Institutional Review Boards and the FDA. 
10.1.3 CONFIDENTIALITY AND PRIVACY 
Every participating clinical site will maintain appropriate medical and research records for this trial, in 
compliance with ICH E6 and regulatory and institutional requirements for the protection of 
confidentiality of subjects. Participating clinical sites will also obtain institutional authorization for 
external monitoring by the Sponsor, Data Coordinating Center and the FDA to examine (and when 

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permitted by applicable law, to copy) clinical records for the purposes of quality assurance reviews, 
audits, and evaluation of the study safety, progress, and data validity. 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA 
Source data are defined as all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples of these 
original documents and data records include, but are not limited to, hospital records, clinical and office 
charts, laboratory notes, memoranda, subject’s memory aids or evaluation checklists, pharmacy 
dispensing records, recorded audio tapes, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, photographic 
negatives, microfilm x-rays, and subject files and records kept at the pharmacy, at the laboratories, and 
medico-technical departments involved in the clinical trial. It is acceptable to use CRFs as source 
documents when the data is collected and recorded there as the primary source of information, but 
CRFs will not constitute the only form of source document information for this trial. 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Principal Investigator 
Medical Monitor 
   Njira Lugogo, MD 
 Not applicable 
 Co-Investigators 
  
   Stewart Wang, MD 
  
   Mike Sjoding, MD 
  
    
  
  
10.1.6 SAFETY OVERSIGHT 
DSMB will not be required for this study. Safety events will be tracked in a log and reviewed by the 
principle investigator on a monthly basis. These safety events will also be reviewed with the sponsor 
during monthly calls.  
10.1.7 CLINICAL MONITORING 
No clinical monitoring will be required for this study. Oversight for the accuracy of data entry will be the 
responsibility of the Clinical Research Project Manager that will be overseeing the coordinator working 
on this study.  
  
The clinical research project manager will ensure that: 
• 
Data collected and entered into the database are verifiable against source documents for the 
subjects.  
• 
Appropriate consent is obtained for each subject prior to study procedures. 
• 
The rights and well-being of subjects are being protected. 

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• 
The study is conducted in accordance with the currently approved protocol (including study 
treatment being used in accordance with the protocol), with any other study agreements, with 
GCP and with applicable regulatory requirements. 
• 
Will work with the research pharmacy on drug accountability and will review logs on a 
bimonthly basis.  
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
The clinical trial site has established a set of standard operating procedures (SOPs) governing the 
processes used to ensure patient privacy and data confidentiality, including the use of anonymous 
subject IDs on CRFs and in reports. Redcap® enables compliance with Good Clinical Practice (GCP) and 
regulatory requirements by providing differentiated user roles and privileges, password and user 
authentication security, electronic signatures, SSL encryption, and comprehensive auditing to record and 
monitor access and data changes. 
10.1.9 DATA HANDLING AND RECORD KEEPING 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
PI. The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of 
the data reported.  In addition to the protocol, the DCC will prepare a Manual of Operations will 
provides additional detail on data collection procedures, including source documentation, eCRF 
completion guidelines, data handling procedures and procedures for data monitoring and quality control 
that ensure these data are accurate, consistent, complete and reliable and in accordance with ICH 36.  
10.1.9.2 STUDY RECORDS RETENTION 
Study documents are to be retained for a minimum of at least 6 years have elapsed since the formal 
discontinuation of clinical development of the investigational product for the studied purpose. These 
documents should be retained for a longer period, however, if required by local regulations. No records 
will be destroyed without the written consent of the sponsor, if applicable. It is the responsibility of the 
sponsor to inform the investigator when these documents no longer need to be retained. 
10.1.10 PROTOCOL DEVIATIONS 
A protocol deviation is any noncompliance with the clinical trial protocol requirements. The 
noncompliance may be either on the part of the subject, the investigator, or the study site staff.   It is 
the responsibility of the site to use continuous vigilance to identify and report deviations per local IRB 
and DCC reporting requirements after identification of the protocol deviation or scheduled protocol-
required activity.  The investigator will work with the research project manager to ensure that all 
protocol deviations are documented and addressed in a timely fashion.  

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10.1.11 PUBLICATION AND DATA SHARING POLICY 
The study will comply with Section 801 of the Food and Drug Administration Amendments Act of 2007, 
and this clinical trial will be registered in ClinicalTrials.gov, a freely available public registry sponsored by 
the National Library of Medicine. 
  
In addition, an explicit goal of this study is to present the primary and related outcomes of this study at 
Scientific Meetings and to publish, as possible, in peer-reviewed Scholarly Journals to assure 
dissemination of the findings. The authority to do so resides with the subject investigators and not with 
any sponsor. 
  
10.1.12 CONFLICT OF INTEREST POLICY 
The investigators and sponsors will comply with the FDA regulations governing financial disclosure by 
clinical investigators, 21 CFR part 54, in case a new drug application should be filed in conjunction with 
the work supported by this clinical trial. As per the regulations, applicants will certify the absence of 
certain financial interests and arrangements of clinical investigators that could affect the reliability of 
data submitted to FDA, or alternatively disclose those financial interests and arrangements to the 
agency and identify steps taken to minimize the potential for bias (21 CFR § 54.4(a)). 
  
In addition to FDA regulations, Investigators at the University of Michigan will follow institutional 
Conflicts of Interest and Conflicts of Commitment policies (https://research-compliance.umich.edu/coi-
policies).   
• 
Conflicts of Interest and Conflicts of Commitment standard practice guideline  
• 
Policy for Identification and Management of Conflicts of Interest in Research, Sponsored 
Research, and Technology Transfer - includes outside interest disclosure requirements for 
individual or personal COI.  
• 
Unit Policies - Michigan Medicine Outside Interests and Conflicts of Interest Policy, 01-04-003 
• 
Policy for Institutional Conflicts of Interest in Research - U-M Office of President policy (effective 
July 1, 2018) includes oversight requirements when U-M, as an institution, has financial interests 
that may affect/appear to affect research.  
 
10.2 ADDITIONAL CONSIDERATIONS 
 
None 
10.3 ABBREVIATIONS 
ACT 
Asthma Control Test 
AE 
Adverse Event 
AIRQ 
Asthma Impairment and Risk Questionnaire 
ANCOVA Analysis of Covariance 

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CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LSMEANS Least-squares Means 
MedDRA Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH 
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 

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SAP 
Statistical Analysis Plan 
SGRQ 
St George’s Respiratory Questionnaire 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
 
10.4 PROTOCOL AMENDMENT HISTORY 
Version 
Date 
Description of Change  
Brief Rationale 
 2 
01OCT2021 
Updates to exclusion criteria and 
expectations for use of spirometry 
and rescue inhalers. 
Provide clarity for inclusion and 
to lessen study burden on 
patients to improve compliance 
with protocol procedures. 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 

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