Conditions: Asthma Bronchial Diseases Respiratory Tract Infections Lung Diseases, Obstructive Lung Diseases Respiratory Hypersensitivity Immune System Diseases
Keywords: asthma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 103
Healthy volunteers: no

Brief summary:
This is a patient level randomized trial for teenagers and adults with asthma who will be randomized to four arms - enhance usual care, rescue inhaled corticosteroids, azithromycin and both rescue inhaled corticosteroids and azithromycin. Participants in all arms will be offered access to an online asthma symptom monitoring system.

Detailed description:
Design. Current activities consist of a Feasibility study to test all activities prior to the full study. The Feasibility study will involve only 5 centers and each participant will be involved for only 3 months. The study will consist of a four arm, patient level randomized trial (N=125). Comparators: Rescue Inhaled Corticosteroids (R-ICS) versus azithromycin versus R-ICS plus azithromycin versus enhanced usual care patients. All arms will include home monitoring of asthma symptoms using various approaches. R-ICS therapy will consist of a corticosteriod/formoterol inhaler, or a stand-alone ICS inhaler used with usual rescue therapy or when available a combination corticosteroid/albuterol inhaler, the initial azithromycin dose will be 500mg (10mg/Kg) three times a week and may be titrated down to 250mg (10mg/Kg) three times per week for side effects. Exacerbations will be blindly adjudicated. Individuals who experience three exacerbations in \< 12 months in the full study will have their treatments "stepped-up,"unless in the dual treatment arm; control participants going to R-ICS and single therapy participants to dual therapy. In the full study, after a step-up participants will be followed for an additional 12 months. There will be no step-up during the Feasibility phase. Individuals completing either of the azithromycin arms will be offered 6 additional months of follow-up after stopping the azithromycin only.

Arms:
arm 1: Participants will be asked to use an online Asthma Symptom Monitoring tool to enhance communication with the medical team as well as self-awareness of their asthma symptoms. There are no "study drugs" in this arm. All 4 arms of the study will use these tools arm 2: Participants in this arm will either have budesonide/formoterol (Symbicort) or mometasone/formoterol (Dulera), or a stand-alone ICS (beclomethasone/QVAR, or budesonide/Pulmicort, or fluticasone Flovent HFA, Flovent Diskus, ArmonAir RespiClick, Arnuity Ellipta, or mometasone, Asmanex HFA, Asmanex Twisthaler or ciclesodine Alvesco HFA) added to the participants usual treatment or a combination inhaler of corticosteroid and albuterol (AirSupra) that was recently approved arm 3: Participants will use azithromycin (Zithromax) 500mg three times a week (10mg.kg for participants under 50Kg) which can be dropped to 250 mg three times a week for dose related side effects arm 4: This arm includes both the inhaled corticosteroid comparator and the azithromycin comparator as described in those two arms Participants in this arm will either have budesonide/formoterol (Symbicort) or mometasone/formoterol (Dulera), or a stand-alone ICS (beclomethasone/QVAR, or budesonide/Pulmicort, or fluticasone Flovent HFA, Flovent Diskus, ArmonAir RespiClick, Arnuity Ellipta, or mometasone, Asmanex HFA, Asmanex Twisthaler or ciclesodine Alvesco HFA) added to the participants usual treatment or a combination inhaler of corticosteroid and albuterol (AirSupra) that was recently approved AND Participants will use azithromycin (Zithromax) 500mg three times a week (10mg.kg for participants under 50Kg) which can be dropped to 250 mg three times a week for dose related side effects

Interventions: intervention 1: Asthma Symptom Monitoring online tools intervention 2: Inhaled Steroids intervention 3: Azithromycin Pill
Intervention descriptions: intervention 1: All participants will be provided access to the Asthma Symptom Monitoring tools and 3/4's will be randomized to one of the other three arms above intervention 2: participants will use either a combination of budesonide/formoterol or mometasone/formoterol as both controller and rescue therapy or a stand alone inhaled steroid (beclomethasone, budesonide, fluticasone, mometasone, ciclesodine) of their choice with their current reliever therapy or be converted to budesonide/albuterol as rescue therapy intervention 3: Participants will take 500mg of azithromycin three times a week or 10mg/kg if under 50Kg which may be reduced to 250mg/Kg for side effects

Protocol document:
Prot_SAP_003.pdf: 
PROTOCOL NUMBER: 23-10-462
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Protocol Amendment – Summary of Changes Table
Individualizing Treatment of Asthma in Primary Care (iTREAT-PC)
BRANY File # 23-10-462 Master File
Summary of Changes from Protocol Number: 23-10-462, Version Date: 11_22_2023
to Protocol 23-10-462, Version Date: 07_23_2024
Page #, Section #, and Title
Change Description (all changes are in 
tracked changes)
Rationale/Justification
Page 112. Appendix 9.
1.
We would like to email a follow-
up message to participants that 
were not administered the last 
question(s) in their Month 3 
survey to complete the remaining 
question(s).  Message is provided 
in Appendix 9 (page 112). 
The last questions in the IRB approved 
Month 3 survey were not activated in the 
REDCap system until July 16, 2024. This 
includes item #30 (pages 93-94) for the R-
ICS, AZ, and AZ + R-ICS intervention 
groups, and items #29-#31 (page 94) for 
the ASM only group.  
Page 113. Appendix 10.
2.
We would like to email 
participants a message to let 
them know they have completed 
the study following the 
completion of their 3-month 
(final) survey. 
End of study message informs 
participants that they have completed 
the study, thanks them, and directs them 
to talk with their doctor if they are taking 
study medications, to discuss whether to 
continue study medications. 
 
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STUDY (PROTOCOL) TITLE
Individualizing Treatment for Asthma in Primary Care 
1) OBJECTIVES
Feasibility Aims: 
Specific Aim 1: Establish the final protocol for the study, in conjunction with all stakeholder groups, 
including recruitment, implementation support, safety reviews, data collection/adjudication and 
IRB approval. 
Specific Aim 2: Recruit up to 125 eligible individuals into a four-month “Vanguard” pilot study to 
include all data collection activities, across 5 participating sites, with qualitative feedback from 
participants, clinicians, staff, and research teams. Recruit up to 65 individuals at the remaining 
five sites to complete the active symptom monitoring activities for 4 to 6 weeks each, with 
qualitative feedback from up to 25 participants and up to 20 clinicians and staff. 
Specific Aim 3:  Adjust protocol based on the findings of specific aim 2 and feedback from all 
stakeholders and submit IRB protocol amendments for the full project. 
Full Study Aims: 
Specific Aim 1: Implement and evaluate 3 interventions, inhaled corticosteroids (ICS) as part of 
rescue therapy (Rescue ICS or R-ICS pronounced “RICKS”), prolonged azithromycin usage, and the 
combination of the two, compared to control individuals using Asthma Symptom Monitoring 
(ASM), in a patient-level randomized trial, among people with different asthma phenotypes, with 
annualized asthma exacerbation rate as the primary outcome. 
Specific Aim 2: Analyze the impact on secondary outcomes of asthma control, asthma quality of life, 
and missed days of school or work across the 3 effector arms, and multiple asthma phenotypes, 
compared to control participants as well as head-to-head comparisons between arms.
Specific Aim 3: Using the PRISM (updated RE-AIM) framework evaluate the 3 different interventions 
for overall use with “eligible individuals,” willingness of practices to engage with the 
interventions, fidelity of implementation by clinicians and participants, and maintenance of the 
interventions by participants and practices. 
2) BACKGROUND
Impact of Asthma. Twenty-five million people have asthma in the US.1 [See Appendix 3 for reference 
list.] Asthma exacerbations (AEX) cause the largest number of lost days from school or work for 
children and young adults, 1/3 of all days.2, 3 Despite new medications,4, 5 new drug regimens,6-11 and 
evolution of treatment guidelines12-14 the number of people with exacerbations in the previous year 
has decreased only slightly over the past 20 years, from 51.6% to 46%.15, 16 Deaths from asthma have 
fallen by a 1/3 the past 15 years, dropping from 15 per million people with asthma to 10 per million; 
but asthma still accounts for over 3,500 deaths per year.17 Asthma is also a disease with a high 
degree of disparities in outcomes. Blacks have exacerbation and death rates that are 2-2.5 times 
higher than Caucasians and Asians,18 while Hispanics, particularly Caribbean Hispanics, have 2 times 
the rate of exacerbations and 1.5 times the rate of death.19, 20 Thus, there is an ongoing need to 
expand and improve treatment approaches for individuals with asthma. 
While asthma therapy is becoming more individualized based on asthma phenotypes,12-14, 21-
23 other than eosinophil counts for biologics, we know little about how to tailor newer therapies to 
individuals. Inhaled corticosteroid (ICS) medications are the foundation of care for all individuals 
with persistent asthma.24 But ICS use is not without possible long term side effects, i.e., increased 
bone loss in pre-menopausal women,25 transient growth retardation in children,26 increased risk of 
carriage of Streptococcus pneumoniae in children,27, 28 and pneumonia and adrenal suppression at 
higher doses.29-33   
 
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Treatment Options to be Studied: 
We will compare two currently available approaches to reduce AEX in primary care patients: (1) use 
of inhaled corticosteroids (ICS) as part of rescue therapy, also known as SMART therapy (Single 
Maintenance And Reliever Therapy) or PARTICS therapy (Patient Activated Reliever Trigger Inhaled 
Corticosteriods) combined referred to as R-ICS, and (2) use of azithromycin (AZ) as a preventive 
therapy, both individually and in combination.  
Evidence for ICS as part of Reliever Therapy 
Inhaled corticosteroids (ICS) are the mainstay for treatment of persistent asthma.34 While 
the steroid molecules have been tweaked and delivery systems improved, the basic construct of use 
on a regular basis as a “controller” medication had not changed until recently. A number of studies 
have demonstrated the efficacy of ICS as part of rescue therapy. These studies enrolled tens of 
thousands of individuals and included both ICS plus a short acting beta agonist (ICS SABA)32, 33, 35 as 
well as an ICS plus a long-acting beta agonist (ICS LABA).36-38 Across efficacy and pragmatic trials the 
approaches have reduced exacerbations from 7% to 50%. Three years ago the Global Initiative for 
Asthma (GINA)12 added ICS LABA therapy for rescue therapy as the preferred approach in steps 3 
and 4 (see Figure 1) as did the new US guidelines released in December, 2020.24 Based on recent 
studies, GINA recently expanded ICS LABA to all steps as rescue therapy.12 Neither guideline has 
officially addressed ICS SABA rescue therapy, though a number of randomized controlled trials 
showed positive results.32, 33, 39 Our completed pragmatic PREPARE study using ICS SABA in 
participants of African American/Black race or Hispanic/Latinx ethnicity 35 demonstrated a 13% 
reduction in exacerbations, improved ACT scores by over 3 points and ASUI scores by almost 1 point 
at the population level (both greater than the patient MID) and decreased lost days of school or 
work by 20%, all statistically significant.40 These changes are equivalent to the combined impact of 
SMART therapy across the studies used by the National Asthma Education and Prevention Program 
Coordinating Committee (NAEPPCC) Expert Work Group 4 in making their recommendation for 
SMART.32, 33, 35-39 SMART therapy is internationally recognized as a reasonable treatment option, 
though currently it is only recommended in the US in two care steps, and has not been studied with 
nebulizer users. In talking with GINA committee members their recommendation for nebulizer users 
is to have them stop using nebulizers. In our PREPARE study 60% of participants used nebulizers 
intermittently and 40% used nebulizers weekly. In a survey conducted during the study, regular 
users felt their nebulizers were more effective than metered dose medications and indicated they 
had no interest in stopping nebulizer use.  The PARTICS approach is entirely compatible with 
nebulizer use, in fact, nebulizer users had a greater response to PARTICS than the full population.35 
Thus, the addition of PARTICS as a treatment option alongside SMART solves the nebulizer problem 
without forcing people to make yet another change in their usual therapy.
 
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Figure 1. Asthma Treatment Steps from 2020 US Asthma Guidelines Update
The full scope of whom to treat with SMART therapy, including which combinations of 
medications and what to use with nebulizer users is not fully elucidated.14 Several factors complicate 
the dissemination of SMART therapy. First, the package insert for inhalers containing formoterol (the 
LABA that must be used for rescue therapy) specifically state: “not indicated for the relief of acute 
bronchospasm.”41 Many primary care clinicians and patient stakeholders have told us they are 
concerned about using a medication in direct contradiction to the package insert. Second, many 
insurance carriers do not cover SMART therapy in the US. Third, a large percentage of people with 
asthma use nebulizers (60% were nebulizer users in our PREPARE study), and integrating ICS as 
rescue therapy with nebulizer use has not been demonstrated until our PREPARE study. The first 
issue is not likely to be addressed soon as formoterol is now generic and thus no pharmaceutical 
company has an incentive to apply for a New Drug Indication. The second is progressing as payers 
are considering the new guidelines. The third requires additional study. Some of these concerns can 
be addressed by offering patients and clinicians another option for delivering ICS as part of rescue 
therapy, the PARTICS approach. PARTICS adds a stand-alone medium strength ICS to a patient’s 
current therapy. This approach overcomes several of the concerns expressed above: 1) stand-alone 
ICS medications do not have language as part of their package insert indicated they should not be 
used during episodes of bronchospasm; 2) an additional stand-alone ICS has generally been covered 
by pharmacy benefits programs, furthermore these medications are typically tier 1 and thus have 
lower patient co-pays; 3) PARTICS is easily matched with nebulizer use. On the other hand, the 
current PARTICS approach requires the user to carry two different inhalers and thus does not “force” 
the use of ICS with the beta-agonist as the SMART approach does. A combined, single inhaler may 
work better for selected individuals that have difficulty in remembering their therapy and are not 
nebulizer users, for instance SMART may make more sense for many teenagers. Also, formoterol has 
a longer half-life which may have some impact on outcomes. The two approaches compare similarly 
in a meta-analysis performed by the PREPARE team thus, at this point both appear to be logical 
options where patient and clinician preferences can guide the therapy choice. 
 
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Table 1 – Equivalent ICS Preparations for PARTICS Use
Furthermore, dissemination of SMART or PARTICS is further complicated by another part of the US 
guidelines which recommends against “increasing ICS at the time of onset of an exacerbation.”24  
Many clinicians report these two recommendations appear incongruent, though they are distinctly 
different. The ROUTINE use of ICS as part of rescue therapy is a different intervention than a short-
term increase in the ICS dose with worsening asthma symptoms.24  Additionally, not all asthma 
patients are steroid responsive. Patients with non-eosinophilic asthma (non-Type 2 inflammation) 
and smokers, among others, may respond less to increases in ICS, regardless of delivery.42-45 Thus, 
our current, one size fits all guidelines are not congruent with the developing nuances of asthma 
treatment.  Therefore, the latest US asthma guidelines as well as GINA and others call for ongoing 
research into the role of ICS as part of rescue therapy.12, 24 This project will address these research 
needs by studying the extension of SMART or PARTICS treatment into steps 2 and 5 as presented by 
the US Asthma treatment guidelines, as well as adding options for use with nebulizers. For ease of 
reading from here on the use of ICS as part of rescue therapy whether as SMART or PARTICS therapy 
will be referred to as R-ICS, except when the two approaches are being evaluated individually. 
Evidence for Long Term Use of Azithromycin 
Azithromycin (AZ), an azalide macrolide antibiotic with anti-inflammatory properties, 
demonstrates efficacy in reducing asthma exacerbations,46, 47 though who will respond best to 
treatment is not clear.13 Some individuals treated with AZ have been able to stop ICS use for 
prolonged periods.48, 49 Some individuals have remained symptom-free for years after completing 6-
12 months of AZ.48, 49 
The mechanism of action for macrolide therapy for asthma is currently unknown. Two 
mechanisms have been postulated: (1) macrolides have intrinsic immunomodulatory/anti-
inflammatory activity that may be more specific for neutrophil-mediated inflammation;50 and (2) 
macrolides have anti-microbial activity against persistent intracellular infections, particularly 
mycoplasma and chlamydia organisms.51-54 Both mechanisms may be at play in reducing asthma 
severity across individuals.50 While the anti-inflammatory effects are currently the most widely 
believed mechanism, this does not explain the long-term impact of macrolide therapy even after 
treatment has stopped.55 Our primary research question (Which asthma phenotypes are helped the 
most with AZ treatment?) is mechanism agnostic. Our secondary heterogeneity of treatment effect 
(HTE) indices include C. pneumoniae (Cp) and M. pneumoniae biomarkers to explore the infectious 
construct and a Challenge sub-study after stopping AZ. A recent meta-analysis found that the 
population-attributable risk (PAR) of Cp-IgE for chronic asthma was 47% (39%-55%).56 This large PAR, 
along with the recommendations of the recent Cochrane review57 are strong justification for 
inclusion of infectious biomarkers in our study to investigate: (1) the predictive value of infectious 
biomarkers for positive AZ treatment responses;58 and (2) whether infectious biomarkers predict 
prolonged improvements/remissions in asthma after completion of AZ treatment courses.48, 49 
The AMAZES study,46 an AZ-based intervention, demonstrated a 40% decrease in 
exacerbations using AZ. There were no sub-group differences, suggesting broad patient benefit for 
 
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AZ. A smaller study,  AZISAST59, showed an impact from AZ only in individuals with total eosinophil 
counts < 200/µl.49, 55  Thus, whether the effect is more pronounced in non-Type 2 asthma is unclear. 
The guidelines from GINA,60 European Respiratory Society/American Thoracic Society (ERS/ATS),61 
and British Thoracic Society (BTS)62 all include use of AZ as a treatment option for severe asthma. A 
narrative review,63 a systematic review/meta-analysis,56 the recently released Cochrane review 57 
and the GINA guidelines12 highlight critical gaps in evidence for AZ in asthma and recommend 
performance of pragmatic trials such as iTREAT-PC.  The varying recommendations and current lack 
of research across a broad group of people affected by asthma highlight the GINA call for further 
head-to-head research including macrolide therapy. The Cochrane review recommends: 1) 
clarification of responsive phenotypes; 2) study of infectious biomarkers related to AZ 
responsiveness; 3) clarification of side effects from long term AZ; 4) and whether effects persist 
after therapy is stopped. Should trials indicate positive results that provide clear implementation 
direction, adoption of AZ for uncontrolled asthma would be simple and scalable because prescribing 
AZ is familiar to many clinicians and AZ is a fraction of the cost of ICS/LABA or biologics.
Evidence for Asthma Symptom Monitoring for all participants 
Multicomponent asthma interventions that improve asthma self-management have 
repeatedly been shown to decrease exacerbations and improve quality of life.64 One component, 
Asthma Symptom Monitoring (ASM), is supported by dozens of RCTs showing an effect, by raising 
patients’ awareness of worsening symptoms earlier so that treatment can be adjusted in time to 
avoid exacerbations.65-69 Informed by this evidence, US asthma guidelines call for clinicians to 
monitor patients’ asthma symptoms.24 Driven by the COVID-19 pandemic, primary care settings have 
rapidly switched to remote care, and many are monitoring symptoms through apps or patient 
portals.70 Various drivers, including ASM recommendations,71, 72 pandemic “new normal” remote 
care, and the movement toward value-based purchasing should substantially increase ASM in the 
near future,73, 74 moving towards the standard of care.
ASM can be performed with various tools, however, smart phone applications are likely the 
optimal solution because they can offer engaging and interactive functionality and have been 
demonstrated to be an effective, low-cost way to sustain engagement.71, 75-77 Over 85% of the 
population uses smart phones, and there are no longer major differences in use based on income, 
race, or geography.78 Our existing app successfully implemented asthma symptom monitoring 
between visits.76, 77 The clinically integrated app monitors asthma weekly and allows patients 
communication with their clinic according to specific logic rules.  Based on an iterative user-centered 
design process,76 consistent with best practices,79 the app integrates well into clinical workflows, 
emphasizes simplicity, and is highly scalable.80, 81 We have demonstrated its ability to effectively 
implement ASM in primary82  and specialty care.76, 77 See Appendix 4 for details on the app.
We will require ASM in all arms of the study with the app as our preferred approach but will 
allow similar approaches built into EHR patient portals or a stand-alone version built in REDCap. Our 
patient stakeholders are very enthusiastic about the possibility of ASM minimizing steroid bursts. 
This approach will allow us to evaluate our asthma interventions in context of where we believe 
ASM will be seven years from now when this study would be completed. Our team has experience 
implementing all of the above ASM options.83-85 
Summary of Treatment Options to be Studied
Table 2 – Treatment Arms
Treatment Arms
(1) R-ICS therapy
+ Asthma Symptom Monitoring 
(ASM)
(2) Azithromycin (AZ) 
+ ASM
(3) R-ICS + AZ
+ ASM
(4) ASM only
The two treatment options, resulting in 3 different treatment combinations (R-ICS, AZ, R-ICS+AZ) 
provide alternatives to achieve control prior to starting biologics, which are only effective in ~50% of 
 
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individuals, increase the risk of life-threatening infections and perhaps some cancers, and are very 
costly. R-ICS therapy and AZ appear to address asthma from different mechanisms so they can be 
logically combined. They cover a wide spectrum of persistent asthma severity, as seen in primary 
care. Both appear to decrease overall steroid burden49, 86 while reducing AEX, improving quality of 
life and decreasing lost days of school, work or usual activities.36-38, 46, 59  These outcomes have been 
consistently endorsed by our patient stakeholders.  
Research Questions 
The feasibility phase of the project will address multiple questions: 1) Can practices implement the 
interventions and find eligible patients who are willing to be randomized to all four arms of the 
study? 2) Will data collection systems be efficient and facile? 3) What is the impact of adjusting 
doses of AZ on participant side effects? 4) Will clinicians be willing to prescribe azithromycin if a 
central prescription system is not utilized? 5) Can all sites implement Asthma Symptom Monitoring 
(ASM) at the minimally acceptable level? and 6) What safety activities need to be in place related to 
concomitant medications used by participants in either of the azithromycin (AZ) arms? 
The feasibility phase will fully engage all stakeholder groups and recheck our randomization 
strata based on EHR queries from the participating practices. The feasibility questions are focused on 
implementation activities of the research cores and local research teams, on clinicians and staff in 
primary care practices and on participants using the therapeutic approaches, including the ASM, and 
reporting their outcomes. We will work closely with all stakeholder groups to refine, review, adjust, 
and perfect the entire research protocol during the feasibility phase. The Data Coordinating Center 
(DCC) will utilize information from the sites to refine their plans. We are confident that the feasibility 
phase will answer the implementation questions posed above. 
The feasibility phase will consist of two distinct interventional activities. The primary 
feasibility study will consist of a full implementation of the study protocol, as detailed below, in 
five different study sites: Harvard/Brigham and Women’s, Mt. Sinai, University of North Carolina, 
Rutgers, and Kelsey- Seybold. We will ask all five sites to recruit 24 eligible individuals to be 
randomized equally across the 4 study arms. These five sites will be expected to have an ASM system 
in place. The adequacy of the ASM systems for the five full implementation sites will be assessed per 
the protocol discussed below for the remaining, ASM-only, involved sites. The recruited participants 
will be asked to respond to monthly surveys instead of bi-monthly surveys for 3 months to shorten 
the overall feasibility time frame. 
Protocol Amendment (April 1, 2024)
Due to delays in patient enrollment, Drs. Wilson Pace and Dave Mauger would like to add Atrium 
Health/Wake Forest to the group of 5 full implementation feasibility sites to enroll and consent 
patients. This is to ensure that the study achieves its overall enrollment target of up to 125 
participants. The Harvard/BWH and Atrium Health/Wake Forest sites will enroll up to 24 participants 
across both sites. The minimum number of participants required of Harvard/BWH and Atrium 
Health/Wake Forest will be 6 participants each with a maximum of 18 each. 
Interviews will be conducted with a subset of participants, at a minimum: 1) a group that 
responded to 100% of surveys, 2) a group that indicated medication side-effects or intervention 
cessation, 3) a group with low survey response rates (responded to only one month of surveys), 4) a 
group on traditional SMART and 5) a group on PARTICS therapy. Participants will be allowed to 
switch their ICS therapy approach during the feasibility and full study. In discussing this, our team is 
clear that having individuals continue on some ICS as rescue therapy would be preferable to having 
participants stop this therapy entirely. Should any individuals switch from one ICS therapy to another 
during the feasibility phase we will seek to talk with all of them concerning their reasons for 
switching. As this feasibility study is fleshed out additional sub-groups may be added. These 
individuals will be asked to participate in brief (approximately 10 - 20 minutes) semi-structured 
interviews. These interviews will be analyzed on an ongoing basis to identify concerns related to the 
 
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study protocol, which will be discussed by the Operations Committee, our core intervention teams, 
our sites, and our stakeholders. The two ICS groups, SMART and PARTICS, will be asked about why 
they chose their particular therapy, if they would have participated if only the opposite ICS therapy 
were offered and information on how the two therapies were presented by their prescribing 
clinician. Participants that have side effects to AZ that are likely to be dose dependent will be able to 
cut their AZ dose in half. We will include a short set of “exit” questions as part of the 3-month survey 
of all participants related to their participation, concerns, or problems encountered.  
We will also interview four different groups of 5 clinicians each (assuming all three ICS 
groups exist): 
1) clinicians that prescribed both SMART and PARTICS to at least one participant; 
2) clinicians that prescribed only PARTICS to at least 2 participants; 
3) clinicians that prescribed only SMART to at least two participants; and 
4) clinicians that prescribed AZ. 
These interviews will focus on the clinicians shared decision-making process with participants and 
for the two groups that only prescribed one option if they were willing to use the alternative or if 
they felt strongly about the option they had used. For the AZ group we will ask about patient or 
clinician concerns with this therapy for both local clinicians or central prescribing staff at the 
research hubs. 
The remaining sites that didn’t implement the protocol as described above, Reliant Health, 
Atrium Health, University of Washington, University of Colorado and the AAFP NRN, will be asked to 
conduct a feasibility study focused on implementing Asthma Symptom Monitoring approaches. 
Asthma Symptom Monitoring will be offered to study participants AND will also be available for all 
sites to offer to any patient with asthma. As such it is considered a “standard of care” quality 
improvement project. We will consent individuals who are asked to an interview related to their 
experience with the ASM systems at the time of their interview. We are not planning on consenting 
people for use of any of the ASM systems as this is not consistent with their use across asthma 
patients in the participating practices regardless of their study participation. We will ask that each 
site recruit up to 12 people that sign a HIPAA A form, or agree to be contacted when registering to 
use the DARTNet ASM system, so that the central research team can contact them for qualitative 
interviews. Verbal consent for the interviews will be obtained at the time of the interview. From the 
participants who signed a HIPAA A form we will ask that the operators of the ASM systems provide 
names of people that completed less than 3 of the 6 weeks (or the lowest reponders if everyone is > 
3 weeks) and those that completed all 6 weeks. We have identified our initial “expectations” for 
ASM as shown in Table 3. We are in the process of interviewing all of our sites to determine their 
current implementation of ASM for any condition and for asthma specifically as well as any future 
implementation plans. We will work with existing systems or seek to support efforts that are in 
planning stages for all sites. The sites conducting just the ASM will focus on nuances of ASM that 
may be difficult for the five randomizing sites to recognize as they (the randomizing sites) will be 
focused on recruiting a larger number of participants and implementing the interventions. 
Table 3 - Asthma Symptom Monitoring component expectations
Required 
Preferred
Standardized questions 
XX
Callback request option based on questionnaire responses 
XX
Completion reminders
XX
Changes in frequency/number of questions based on responses through 
branching logic and/or dynamic question presentation
XX
Variable follow- up times based on previous response
XX
Data available in EHR with reminder to clinicians before visit to check data
XX
One data collection mode available (e.g., SMS or email link to survey)
XX
Multiple data collection modes available (app, web, email, SMS)
XX
Prior responses available in graph/chart
XX
Educational materials
XX
 
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Once these sites have an acceptable ASM system instantiated, either internally or by using 
the BWH/RAND app or a REDCap system to be set up by DARTNet if needed, we will ask them to 
recruit 8 participants (8 people that sign a HIPAA A form or agree to be contacted) to use ASM for 6 
– 8 weeks. During this time central research staff will contact some of these individuals and ask them 
to request a “call back/contact” from their practice for testing purposes. We will track with them the 
success of this ask. Other metrics we will consider across the first 8 individuals are shown in Table 4. 
We will work with sites that are not able to meet these expectations to adjust their system and have 
them recruit an additional 4 people. We will then assess these outcomes again. We will also conduct 
semi-structured interviews with regular users and low users, as above defines as those that 
completed 3 or less assessments and those that completed 6 or 6 assessments) of ASM to determine 
if adjustments would have helped the low users engage with the system. Through this process we 
hope to develop a toolbox of ideas that can be drawn upon as sites continue to fine-tune ASM 
activities into the first year of the full project. Sites may offer the ASM system to other individuals 
they care for if they wish and may continue to use the system once testing complete as they wish. 
Table 4 - ASM Success Factors and Metrics
Success Factor
Specific Metric
Recruitment/enrollment
8 participants recruited and completed baseline questionnaire
Questionnaire adherence
75% of participants completed 4 or more of the 6 weekly questionnaires
Participant experience
Interviews indicate the system is intuitive and easy to use
Callback request completed
All patients who requested a callback request were called back by clinician 
within 24 hours (test at least 3 such requests per site)
The full intervention is focused on individuals with asthma seen in primary care and includes 
individuals with moderate to severe persistent asthma who have experienced an exacerbation in the 
past year or remain in poor control, such that asthma is affecting their daily lives. Our comparisons 
will include a large portion of people with asthma (over 50% of people with asthma should be 
eligible in any given year)15, 16  and provide direct information for clinicians, individuals with asthma 
and their parents/caregivers/guardians concerning optimal approaches to address gaps in asthma 
control. The kinds of questions our stakeholders are excited to better understand include: Does the 
level of controller compliance impact R-ICS therapy outcomes? Should everyone with a history of a 
lower respiratory tract infection prior to their asthma onset receive a trial of azithromycin? For 
people not eligible for biologics, will dual therapy make a noticeable difference in days lost from 
work or school? This large pragmatic trial will address these and many other stakeholder questions. 
Our research questions result in 3 head-to-head primary and 12 secondary comparisons. 
Once heterogeneity issues and exploratory items are included, the iTREAT-PC study will include over 
22 different comparisons in the final analytical plan (see Analysis section for details). Stated briefly, 
our research questions lead to the following Hypotheses: 1) All 3 intervention arms will be superior 
to the control approach in reducing AEX. 2) Participants with high eosinophil counts will have 
significantly better outcomes on R-ICS therapy than on azithromycin. 3) Individuals with lower self-
reported controller adherence will respond better to R-ICS therapy than high adherence individuals. 
4) Smokers and people with significant secondhand smoke exposure will have better outcomes on 
AZ than on R-ICS therapy. 5) Asthma control and quality of life (as measured by the Asthma Control 
Test (ACT) and Juniper mini-Asthma Quality of Life (mini-AQLQ) instruments, respectively) will 
significantly improve over baseline in all groups but will be significantly better in the 3 
pharmacologic arms than in the control arm. 
These interventions correspond to actual healthcare options relevant to stakeholders. All 
the interventions are currently available. Single inhaler SMART therapy with an ICS/LABA is currently 
available as a generic product.41 There are multiple medium dose ICS inhalers available to use for 
PARTICS therapy (see Table 1 above.) such that at least one of these products should be a Tier 1 
medication on all insurance plans. A combined ICS/SABA product is expected to receive FDA 
Ability to enter/track peak flows
XX
Ability to enter notes/triggers
XX
 
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approval soon (all approval materials reportedly submitted and product now under review) we are 
not planning on using the product at this time. AZ is recommended currently in various guidelines13, 
62 and is used across the country in a broad set of people who appear relatively steroid resistant. 
Chart reviews of these patients’ (observational) data consistently demonstrate 50+% of people have 
a clinically important response.89, 90 AZ randomized trials consistently demonstrate a >25% reduction 
in exacerbations.47 The outcomes have been specifically vetted and endorsed by our patient 
stakeholders both for our current PREPARE study and for iTREAT. 
3) INCLUSION AND EXCLUSION CRITERIA
The population for both the feasibility phase and full-scale study will be individuals ≥ 12 years of 
age12 with persistent asthma requiring regular ICS or ICS + LABA, cared for in participating primary 
care practices. Practices will include Family Medicine, General Internal Medicine and Pediatric 
practices in urban, suburban and rural locations. General patient eligibility requirements are: 1) 
poorly controlled asthma (per the Asthma Control Test (ACT)91, 92)  OR 2) a major exacerbation 
(defined in section C, Outcomes) in the past 12 months.
Inclusion Criteria:
1.
A clinical asthma diagnosis for at least 1 year;
2.
12–75 years of age;
3.
A current ACT total score of <20 OR an exacerbation requiring 72 hours or more of systemic 
steroids or a hospitalization of at least 24 hours > 30 days and < 365 days prior to enrollment; 
4.
Able to provide consent (adolescents: assent) in English or Spanish; (i.e., cognitively impaired 
individuals are deemed not to be able to provide consent and thus do not meet inclusion 
criteria.)
5.
Patients with a coexisting clinical diagnosis of COPD are eligible if they meet any one of the 
following criteria:
(i) Never smoker without secondary lung disease causing airway obstruction.
(ii) Current or former smoker with obstruction on PFTs, but normal diffusing capacity of the 
lungs for carbon monoxide (DLCO) in the past 24 months.
Exclusion criteria: 
1.
Life expectancy <1 year (operationalized by the question to the patient’s asthma care clinician 
“Would you be surprised if this person died in the next 12 months? If yes – include, if no – 
exclude); 
2.
No ICS prescribed for the individual (does not have to be using the ICS inhaler); 
3.
Active treatment for hematological or solid organ cancer other than basal cell or skin squamous 
cell cancer;
4.
Allergy to macrolides or conditions for which macrolide administration may possibly be 
hazardous (e.g., acute or chronic hepatitis, cirrhosis, or other liver disease; end-stage renal 
disease; uncorrected hypokalemia or hypomagnesemia; clinically significant bradycardia; or 
history of prolonged cardiac repolarization and QT interval or torsades de pointes); 
5.
On daily or every other day oral steroids for any reason; 
6.
Overnight hospitalization for an asthma exacerbation in the past month (can wait and re-check 
eligibility after one month);
7.
Currently on R-ICS or or any antibiotic therapy expected to last more than 30 days. If on 
antibiotics less than 30 days, enroll after they have stopped their current antibiotic for 72 hours. 
Individuals on biologics can be enrolled if they have been on a stable dose for > 6 months and 
meet the ACT or exacerbation criteria as well as all other criteria.
 
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8.
On a medication with known risk (i.e., that is associated with prolonged QT and associated with 
torsades de pointes  even when taken as recommended) or possible risk (i.e., can cause 
prolonged QT but lacks evidence for risk of torsades de pointes when taken as recommended) – 
Full lists in Appendix 1.
9.
Specified medications for which close monitoring has been recommended in the setting of 
macrolide administration (digoxin, warfarin, theophylline, ergotamine or dihydroergotamine, 
cyclosporine, hexobarbital, phenytoin or nelfinavir).
4) VULNERABLE POPULATIONS
Pregnancy and Breast Feeding
Pregnancy is not a contraindication to asthma controller therapy, including ICS, azithromycin, or use 
of ASM. Improved asthma control has been shown to be associated with improved pregnancy 
outcomes. It is unknown if AZ is excreted in breastmilk but is assumed that it is. Out of an abundance 
of caution we will only enroll women that are pregnant or breastfeeding after their maternal or child 
care clinician approves of enrollment. We will not require a pregnancy test or effective birth control 
be used to be enrolled for women of child-bearing age but will ask that they inform us if they 
become pregnant. We will recommend that women on AZ who become pregnant (either arm) to 
stop this treatment, advise them to seek maternity care as soon as they are aware of the possibility 
of pregnancy and to inform their maternity care clinician of their study participation. Should the 
participant and her maternity care clinician feel that continued use of AZ is warranted then she may 
continue on therapy. If the participant is breastfeeding after delivery, the decision whether to 
continue azithromycin will be a shared one between the participant and the infant’s care team. 
Whether or not the participant decides to continue azithromycin or stop it during pregnancy or 
breastfeeding, she will be asked to continue in the study. Pregnant or breastfeeding women in the R-
ICS or control arms of the study will be allowed to continue without interruption.
Adolescents
Children ages 12 to 17 will be included. Individuals aged 12 – 17 will require both parental/guardian 
consent as well as participant assent to be included. Given this study involves currently approved 
medications for adolescents and for use with asthma only one parent or guardian will be required to 
provide consent. 
Prisoners
No prisoners will be enrolled in the study. 
Economically or Educationally Disadvantage Populations
Many of our recruitment sites care for economically or educationally disadvantaged individuals. We 
are not planning on screening for these factors as part of the enrollment process. We do ask about 
educational level attained as well as total household income and number of people in the household 
to be able to calculate if the individual is above or below the poverty level as part of end of study 
analyses. These data are collected after consent. We strive to develop consent forms that are 
between the 6th to 8th grade reading levels. Given the inherent complexity of some medical terms, 
such as azithromycin, some paragraphs may be hard to word within these parameters. While 
consent will mostly be conducted remotely, it will involve real time interactions with a study 
coordinator so that questions can be asked and answered until the person is comfortable with what 
they are consenting to or what they are consenting to for their adolescent. The cost of SMART 
therapy, if not covered by insurance, is prohibitive for many individuals, thus we have an alternative 
treatment approach, PARTICS, that is generally covered by insurance and much cheaper. AZ is a 
generic medication and generally covered by insurance. Even if paid for out of pocket the dose used 
in this study (500mg three times week) can be found for $12 to $20 per month at various 
 
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pharmacies. We will have staff available to assist with any appeals to pharmacy benefits managers 
should insurance coverage be an issue.
Cognitively Impaired 
Individuals that are not able to provide consent or assent in English or Spanish will not be eligible for 
the study. Primarily this is due to the fact the study outcomes are entirely dependent on 
participants’ ability to answer regularly administered surveys.
5) SETTING
Involvement of Community Advisory Board
Please see our section on community engagement, on page 40 in the community-based participatory 
research section.
American Academy of Family Physicians National Research Network
The AAFP NRN is one of the largest and most aggressive clinical trial-oriented practice-based 
research networks (PBRN) in the country. On August 16, 2023 the operations of the AAFP NRN have 
been assumed by the DARTNet Institute. The AAFP NRN will continue with the clinical activities as 
outlined in this protocol. Under Dr. Pace and now Dr. Hester, the AAFP NRN has served as the clinical 
coordinating center or major component of the clinical coordinating center for multiple large clinical 
trials including: AIM-HI,93 Asthma APGAR,94 TRANSLATE CKD,95 BELT,96 PREPARE,40 TRIPPD97 and 
numerous AHRQ task orders. The AAFP NRN works with numerous academic and private research 
organizations and has specific contractual arrangements with the University of Colorado, the 
University of Kansas and DARTNet that allows personnel and services to flow seamlessly between 
each organization and the AAFP NRN. The DARTNet Institute was split off from the AAFP NRN and 
the University of Colorado in 2011 and was initially housed at the AAFP. The AAFP NRN and DARTNet 
are highly committed to staff continuity across projects, and as such, the staff on this project have 
worked together for years, some for close to 20 years. All staff of the AAFP NRN as of August 15, 
2023 were employed by the DARTNet Institute and have continued on this project. Mr. Manning, the 
overall project manager for the clinical coordinating center has served in this role for most of the 
projects listed above. He is supported by individuals involved in many of the above studies as well. 
The research cores and implementation sites are all experienced research units. Most are PBRNs in 
their own right running their own multi-site studies.  
Penn State Department of Public Health Sciences:
This group will serve as the DCC for the project and has been described in detail throughout 
the application. It is one of the major NIH data coordinating centers in the country, with numerous 
large network-based clinical trials for which it has severed a similar function. For this project the DCC 
will focus on study methodology, data quality, and timeliness reporting, data analytics and creation 
and support of the DSMB. Actual management of the study data will be managed by the DARTNet 
Institute in keeping with the highly successful data collection processes for our current PREPARE 
grant. Penn State will maintain two key statisticians, Dr. Mauger, the dual PI for the project who will 
be blinded to all treatment assignments throughout the open phases of the project and Dr. Lan, 
senior biostatistician in the department who will be unblinded and deal with initial data curation, 
report writing, and all DSMB reports. They are supported by database and statistical analysts who 
will perform the day-to-day work of the project under direction from Drs. Mauger and Lan. Both Drs. 
Mauger and Lan have been actively involved in the study development, study outcomes, and study 
analytics, and have helped refine all aspects of this application.
The Department of Public Health Sciences has extensive resources that can be called upon if 
required to support other functions of the project including data management software and patient 
 
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directed data collection systems. The Department has a state-of-the-art data center with full suites 
of analytical software. 
Dr. Mauger is the dual PI of the project, and how he and Dr. Pace will work together is 
outlined in the Leadership section. He will have full and final authority for data analytics. He will 
work with Dr. Pace and the clinical coordinating center to develop a detailed analytical plan for all 
phases and levels of analysis, and this plan will be reviewed, refined, and accepted by the Scientific 
Committee, the Executive Committee and finally the DSMB.  
DARTNet Institute:
This organization grew out of the AAFP NRN and the University of Colorado Department of 
Family Medicine and has ongoing, close working relationships that span multiple projects and 
personnel. DARTNet will be responsible for data management for consent, randomization, 
participant-facing data collection, tracking ancillary study activities such as the CBC, biomarkers, or 
Step-up and Challenge sub-study activities, tracking all exacerbation triggers, and creating and 
maintaining a database to finalize and adjudicate exacerbations. DARTNet will also be responsible 
for the creation of the EHR data extraction, transformation and loading specifications, 
standardization of EHR data to OMOP Common Data Model v6 and support of any required OMOP 
concept ID value sets required for EHR data analytics. Dr. Amanda Ratigan, Director of Analytics, will 
serve as the site PI. She has supported a number of other large trials including the PREPARE trial, a 
large PCORI funded study, Integrated Behavioral Health in Primary Care, two NIH data coordinating 
centers, and numerous smaller trials. DARTNet handles ingestion of Giga Bytes of EHR data daily 
with automated systems for most of their transformations. DARTNet operates two patient facing 
data collection systems, the Patient Engaged Electronic Reporting System (PEERS) and REDCap. Both 
offer slightly different capabilities. The two can be linked to increase performance options. The 
REDCap software is planned to be used for the participant data collection and data management for 
iTREAT. If additional functionality is required (such as participant addressable accounts for 
educational purposes) PEERS can be linked to the REDCap system. 
RAND: 
The RAND Corporation is a research organization that develops solutions to public policy 
challenges to help make communities throughout the world safer and more secure, healthier, and 
more prosperous. RAND is nonprofit, nonpartisan, and committed to the public interest. RAND 
researchers have advanced degrees in more than 350 disciplines and apply state-of-the-art methods 
to address a broader range of issues than any other research organization. Approximately 1,800 
people from 50 countries work at RAND. For this project RAND will serve as the Research Core 
responsible for the modifications and dissemination of the ASM systems. The smartphone app has 
been developed by RAND in cooperation with Brigham and Women’s/Partners Health System. Dr. 
Rudin, the PI on the projects that have developed and tested the application, will serve as the site PI 
for RAND. His team, in collaboration with the Brigham team, will develop the implementation 
support documents, specify and oversee any modifications required for use by adolescents, and 
support the integration of ASM systems, including the smart phone application into all sites. 
DARTNet also operates ASM software that can be utilized if a site so desires. At this time, the 
DARTNet system will only be offered if other options are not available. Over the course of the study 
Dr. Rudin will serve as a key member of the clinical coordinating center research team. His team will 
provide ongoing support to all sites involved in the study. Dr. Rudin has been involved in all phases 
of the development of this project, including study design, outcomes, analytics, sample sizes, and 
Research Implementation site expectations.
University of North Carolina (UNC):
The University of North Carolina Division of Allergy and Department of Family Medicine 
(UNC DFM) are teaming up to serve as the Research Core responsible for the development and 
 
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support of the R-ICS arms of the study. Dr. Hernandez served as the site PI for the current PREPARE 
study and research staff in the UNC DFM served as the support staff for that project. UNC is a major 
research university, and the UNC DFM is recognized as one of the top research groups in that 
discipline in the country. The UNC DFM operates several practice-based research networks, and the 
one that focuses on internal primary care practices has provided a letter of support and will work 
with Dr. Hernandez to also serve as one of the Research Implementation centers. Under Dr. 
Hernandez’s guidance and with support from Dr. Israel, UNC will develop the implementation tools 
for the use of R-ICS. They will help sites implement and support sites in the ongoing use of these 
intervention arms. As a Research Implementation site, the practice-based research staff will recruit, 
train, and assist UNC primary care sites in the recruitment of participants and the use of all study 
arms. UNC recruited one of the highest number of participants for the PREPARE study, mostly from 
primary care sites. 
University of Colorado, Department of Family Medicine (CUDFM):
The University of Colorado Department of Family Medicine is another of the premier 
research departments in that discipline in the country. Dr. Kessler works extensively with the AAFP 
NRN. The CUDFM is tightly affiliated with the AAFP NRN and has worked on previous projects with 
the AAFP NRN and Dr. Hahn related to AZ use in asthma. The CU health system includes over 100 
primary care clinical sites across three states and thus should have little trouble recruiting the 10 – 
12 required for this project. The practice-based research staff at the site will work with local sites, 
assisting with implementation of all study arms as well as with participant recruitment. 
Brigham and Women’s/ Partners Health (BWH):
The Brigham and Women’s/ Partners Health site will serve as a Research Implementation 
site. As the original research site for the smart phone application they will serve as consultants to 
RAND in the development of the implementation tools for the ASM options. The Internal Medicine 
practice-based research network will support local sites in the implementation of the arms of the 
study as well as with participant recruitment. The Division of Internal Medicine at BWH is one of the 
top research groups in the discipline in the country and is particularly known for innovative 
information technology tools to support and improve care. 
Atrium Health:
Atrium Health is the second largest not-for-profit health care delivery system in the nation. 
The full system spans three states and include over 60 hospitals, thousands of ambulatory sites, and 
both private and academic sites. For this project the Department of Family Medicine (Atrium DFM) 
in the Mecklenburg County, NC, area, the home of primary care research for the organization, will 
serve as a Research Implementation site. The research team is expansive, and the informatics 
support of the organization is strong. The Atrium DFM is involved in multiple research projects at 
any given time and supports a research network of 30+ close by sites and many more across the 
entire system. The Atrium DFM will support the sites in implementing the study arms as well as in 
recruitment of participants. Atrium Health is a current PREPARE site and familiar with all systems to 
be used in this project.
Kelsey Seybold:
Kelsey-Seybold Clinic is a large multi-specialty medical organization in the Houston, TX, area 
with more than 500 physicians and allied health professionals representing 55 medical specialties. 
The Clinic provides continual care for approximately half a million Houstonians each year, with over 
one million clinic visits at 30+ locations throughout the greater Houston metropolitan area. Kelsey-
Seybold Clinic is Houston's premier multispecialty group practice, founded in 1949 in Houston’s 
Texas Medical Center. More than 650 physicians and allied health professionals practice at 35+ 
locations in the Greater Houston area.  KRF actively works with Texas Medical Center institutions, 
 
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including The University of Texas M.D. Anderson Cancer Center, UTHealth’s McGovern Medical 
School and School of Public Health, Baylor College of Medicine, Houston Methodist Hospital, CHI St. 
Luke’s Health Baylor St. Luke’s Medical Center, and the University of Houston. Medical services 
offered by Kelsey-Seybold include medical care in 65 medical specialties including primary care and 
specialty care, outpatient surgery centers, travel medicine clinics, an accredited sleep center, a 
radiation therapy center, laboratory services, advanced radiology services and other diagnostic 
services, onsite Kelsey pharmacies, and a secure web portal for patients to communicate with their 
Kelsey-Seybold doctors, get test results and schedule appointments.
Reliant Health Care:
Reliant Health is a private, integrated delivery system in central Massachusetts. The site 
includes a robust research arm and frequently works with both UMass Worcester and Harvard on 
NIH, AHRQ and other research projects. The research arm is a standalone group with a track record 
of high levels of precision in research implementation and participant recruitment. Reliant will serve 
as a Research Implementation site. 
Rutgers/Robert Wood Johnson School of Medicine:
The Robert Wood Johnson Medical School is the academic center of a large and diverse 
health care system encompassing Barnabas Health as well as the Rutgers system. The Department of 
Pediatrics Division of Population Health, Quality and Implementation is a newer organization 
designed to implement and research new health care delivery interventions and models in primary 
care with a pediatric focus. This site will serve as a Research Implementation site and work with the 
Departments of Family Medicine and General Internal Medicine in implementing the project across 
primary care offices in the system. Dr. Kleinman, the site PI, and Dr. Pace and the AAFP NRN have 
worked together over the past 10+ years and are currently working together on two NIH COVID 
studies.
University of Washington
The University of Washington Department of Family Medicine (UWDFM) is another of the 
top research departments in Family Medicine in the nation. The UWDFM has close ties with 
DARTNet and has extensive interactions with the University of Colorado. The UWDFM operates a 
successful multi-state research network and works with the University of Washington community 
clinics. For this project the UWDFM will serve as a Research Implementation site and support both 
implementation of the study interventions as well as participant recruitment. 
Mt. Sinai Health System
Mt. Sinai is an integrated delivery system and SafetyNet organization with the greater New 
York City metropolitan area. The health system and specifically the primary care division has a very 
active research division that supports and coordinates research of this type. Mt. Sinai is another 
PREPARE site and has recruited a diverse and large population of participants for that project. Mt. 
Sinai will serve as a Research Implementation site for this project. Dr. Wisnivesky, the site PI for 
iTREAT-PC, is a member of the NAEPPCC and will also serve on the Scientific Expert Panel for this 
project. The  support staff will handle local implementation of the study arms as well as support 
participant recruitment. 
RESOURCES 
All sites have dedicated research personnel and space. Most are major, academic research 
organizations. Reliant and Kesley-Seybold have dedicated research staff and space and participate in 
industry funded pharmaceutical and device studies on a regular basis. The DARTNet Institute 
operates a REDCap instance that will be used for all study consent, tracking and outcome follow up. 
Local sites will use either their local REDCap instance or local study management software to 
manage recruitment prior to consent as patient names cannot be included in the central REDCap 
 
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instance until consent. The only study procedure is phlebotomy which will be performed within the 
clinical sites, dedicated research space and may be contracted out to a commercial laboratory for 
the CBCs. Therefore, there are no specific research equipment, other than standard office 
equipment, required to conduct this study. Extensive facility documents are available if desired.
All sites have access to Collaborative Institutional Training Initiative (CITI) training through 
their local IRB or through the AAFP if the site does not have a CITI account. All research staff and 
selected practice staff in the sites using network staff to conduct the study will complete the 
requisite CITI training related to their study role. All sites will rely on BRANY as a single IRB. All sites 
are part of SMART IRB (either through a local IRB or as part of their FWA) and will sign a reliance 
agreement with BRANY to be eligible to participate. 
The consent rate for our PREPARE study was over 90% for eligible individuals. In looking at 
the number of potentially eligible individuals in a “typical” primary care office (the mean and mode 
for number of clinicians across the country in a physical primary care site are both between 4 and 5) 
each site will need a minimum of 10 clinical sites to have access to approximately 2000 potentially 
eligible individuals, a reasonable starting point for recruitment.  All Research Implementation 
organizations have 3 to over 15 times this number of potential clinical sites. Since the final sites are 
not known exact EHR data is not available, though the information below in Table 5 is derived from 
the participating clinical organizations. The Feasibility potentially eligible data and the Asthma 
Symptom Monitoring data for potentially eligible individuals comes from EHR searches in the clinical 
sites to be used for 60% of the organizations at this time. 
6)  NUMBER OF SUBJECTS
Table 5 - Recruitment, Enrollment, and Retention Plans
Feasibility Full Study Phase
Number
1. Estimated number of potentially eligible study participants and a description of how this 
number was determined (EHR data used to estimate adolescent and adult asthma 
populations across the 10 networks)
Full Feasibility – 3445
2. Total number of potentially eligible study participants expected to be screened
Full Feasibility – 800
3. Total number of screened study participants expected to be found eligible
Full Feasiblity – 500
4. Target sample size 
Full Feasibility – up to 
125
5. If applicable, total number of practices or centers that will enroll participants
5 research hubs 
5 ASM hubs will include 
participants for 
qualitative interviews
6. Projected month first participant will be enrolled (month after project initiation)
9th month 
7. Projected month last participant is expected to be enrolled (month after project 
initiation)
12th month 
8. Projected rate of enrollment (anticipated number enrolled per month of enrollment 
period)
31
9. Estimated percentage of participant dropout
10%
 
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Full Study
Number
10.Estimated number of potentially eligible study participants and a description of how this 
number was determined (EHR data used to estimate adolescent and adult asthma 
populations across the 10 networks)
46,850 
11.Total number of potentially eligible study participants expected to be screened
20,000
12.Total number of screened study participants expected to be found eligible
15,000
13.Target sample se same number stated in Milestones)
3,200
14.If applicable, total number of practices or centers that will enroll participants
10 centers 120 sites 
15.Projected month first participant will be enrolled (month after project initiation)
2nd month full study
16.Projected month last participant is expected to be enrolled (month after project 
initiation)
34th month full study
17.Projected rate of enrollment (anticipated number enrolled per month of enrollment 
period)
95
18.Estimated percentage of participant dropout
15%
Feasibility Asthma symptom monitoring only 
Number
19.Estimated number of potentially eligible study participants and a description of how this 
number was determined (EHR data used to estimate adolescent and adult asthma 
populations across the 10 networks)
4266
20.Total number of potentially eligible study participants expected to be screened
400
21.Total number of screened study participants expected to be found eligible
300
22.Target sample size (use same number stated in Milestones)
Up to 65
23.If applicable, total number of practices or centers that will enroll participants
5 centers 10 sites 
24.Projected month first participant will be enrolled (month after project initiation)
10th month 
25.Projected month last participant is expected to be enrolled (month after project 
initiation)
13th month 
26.Projected rate of enrollment (anticipated number enrolled per month of enrollment 
period)
12
27.Estimated percentage of participant dropout
10%
7) MULTI-SITE RESEARCH
Most members of the Operations Committee have conducted clinical trials together over the 
past 15 to 20 years. Through this work a robust project and site management approach/plan has 
been developed and proven successful. The research team will deploy all aspects of this plan for this 
project. The multi-component process includes a central educational and learning meeting of all site 
PIs and study coordinators. At this meeting the concepts for the project are explained so that truly 
informed consent can be obtained. The study protocol is reviewed in detail and the site versus 
central responsibilities carefully delineated. During this process sites are encouraged and expected 
to talk with each other and the research team about how to deal with recruitment challenges, 
providing prescriptions to participants, helping with tracking participants and responding to possible 
exacerbations or adverse events. The sites provide extensive feedback to the research team and 
adjustments to the protocol may be made. For this project many of these activities will also include 
all stakeholder groups as outlined in the Engagement section.  All of these groups will be expected to 
work together to review the current protocol and improve or adjust if they feel it is necessary. 
The AAFP NRN staff will begin working with each site’s study coordinator to complete any 
local IRB submissions that are required. Given the requirement to rely on a single IRB we will work 
with each local IRB, through SMART IRB, to develop a reliance agreement with the BRANY IRB, which 
 
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will be the primary IRB of record. This early work helps the local sites start to really review and 
understand the protocol which makes the ongoing group interactions more meaningful.
The AAFP NRN staff will have individual teaching sessions with each site along with teach 
backs prior to enrollment. These will include education on the REDCap study management and 
consent system, on web-based video consent processes, another review of enrollment criteria and 
how to reach a central staff or senior scientist at any time. Prior to recruitment the senior staff 
associated with the AAFP NRN (Drs. Pace, Hester, Westfall or Israel) will contact and talk with each 
site PI to be sure he or she is comfortable with all processes. 
After recruitment begins the AAFP NRN staff will schedule weekly meetings with each site 
study coordinator and help them trouble shoot issues that arise as well as maintain communication 
between sites. The senior staff will touch base with the site PIs at least monthly during the Feasibility 
recruitment and follow-up phase. Recruitment figures are reported to the Operations Committee bi-
weekly and monthly summaries are provided to the Executive Committee. The Operations 
Committee is tasked with assuring recruitment meets timelines. Other parts of the communication 
plan include the creation of a study wiki for all study coordinators and site PIs to ask questions and 
seek advice across sites as well as weekly tips that are sent to the study coordinators primarily.
Several months prior to beginning enrollment the AAFP NRN will schedule two recurrent 
meetings per month for site PI’s and study coordinators for ongoing communication. The two 
meetings are identical and each site is expected to attend one or the other. This duplicative system 
allows easier coordination of schedules across multiple sites and has worked well in previous 
studies. This meeting is used to update people on protocol changes (which are also sent via email 
and posted in the Egnyte system discussed below) as well problem solve between sites and provide 
general communication. Should a significant protocol change be required due to safety concerns this 
will be emailed to all site PIs and study coordinators with a return receipt of message included. 
Phone calls to site PIs and study coordinators will be made of there is not clear evidence that the 
protocol change has been received. Study results, interim results that can be shared, protocol and 
IRB updates and premature study closure are handled through these meetings as well. Though final 
study closure typically occurs up to 18 months or more after the last participant has exited the 
study. Thus, final closure is sent via email to site PI and study coordinator to be communicated to 
the local IRB. 
All sites will be provided at least two unique folders on the DARTNet Egnyte system which is 
HIPAA compliant and can support sharing of clinical data (one folder per site) as well as study forms 
or files that are site specific (the second folder.) This system will also have shared folders for all sites 
to access and share common documents. 
The REDCap data management system will be used to communicate ongoing project 
information at the participant level. The system will include study forms, such as exacerbation 
follow-up/confirmation forms and adverse event forms that will support direct data entry as well as 
attached documents. Most participant related communication will occur through this study 
management system. 
8) RECRUITMENT METHODS
Study Population and Research Setting(s):  The population for both the feasibility phase and 
full study will be individuals ≥ 12 years of age12 with persistent asthma requiring regular ICS or 
ICS/LABA and cared for in a primary care practice participating in the study. Eligibility and exclusion 
criteria are stated in the named section above. During the feasibility phase each of the Research 
Implementation organizations recruiting for the full study feasibility arm will recruit 24 individuals 
who will participate for up to 3 months to test all aspects of the study. The other remaining sites will 
focus on testing the Asthma Symptom Monitoring systems (ASM) by recruiting 8 to 12 individuals 
per site to test the ASM approaches. Each individual well be asked to report symptoms at least 
weekly for 6 to 8 weeks. If a site has issues completing symptom reporting with the first 8 individuals 
(i.e. less than 100% call backs occurred within 48 hours – we will ask for 3 to start with), adjustments 
 
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will be made and an additional 4 individuals will be recruited. Semi-structured interviews with 
subsets of these individuals will be conducted as noted above. Likewise, several individuals at each 
site will be specifically asked to request a call-back from the central research staff and this will be 
tracked to be sure the messaging is working. These individuals will remain eligible for the full study. 
Note, the central research team is not asking for the actual symptom monitoring data just usage 
data (less than 3 weeks vs 7 to 8 weeks for qualitative interview sampling). Of the five ASM only sites 
three will be using the DARTNet REDCap based ASM system. At this time we will only allow adults to 
access the system until we finalize parental verification for adolescent use. Individuals will be 
provided a link to the site that is specific to the clinical organization. Upon registering the individual 
will complete an End User License Agreement and then be offered an option for a possible call back. 
The individual can accept that option or reject that option and use the system without any chance of 
participating in the qualitative interview described below. If an individual accepts the offer to 
potentially be called they will be paid $20 if they use the system for at least one week out of the 8. If 
they are selected for an interview and they consent and participate in the interview they will be paid 
an additional $25. Two sites will be operating their own ASM systems. Reliant Health Care Group has 
built a system into MyChart and will ask people if they are willing to have Reliant share his/her name 
and contact information with DARTNet for possible interviews. Up to 15 people to agree to be 
contacted will be paid $20 and if an individual is selected for an interview, consents and participates 
s/he will be paid an additional $25.  Atrium/Wake Forest Health will use a version of the DARTNet 
REDCap system loaded into their REDCap.  We will code a HIPAA A form on the DARTNet iTREAT 
Project Management REDCap system for this system to refer interested individuals to. Similarly to all 
other systems the first 15 people that agree to participate will be paid $20 and if they are selected 
for, consent to and participate in an interview they will be paid an additional $25.
Figure 2. Participant and Data Flow iTREAT 
EHR Query for 
Potentially 
Eligible 
People
EHR Tracking 
for PCP Visits
Phone Call 
Prior to 
Visit
Consent, 
Opt out, 
Call back 
after visit
Call back 
after visit 
consent, 
opt out
Consent
Inform 
Practice 
and PCP, 
Obtain Rx if 
needed
Enroll in 
PEERS, 
baseline 
data
30 – 40 Day 
call back to 
answer 
questions
Reminders, 
phone calls 
outcome data 
collection
Outcome data 
collection on 
line, phone, 
paper
Outcome
adjudicated
Patients 
contacted if no 
evidence of 
exacerbation in 
EHR
Sites 
contacted for 
positive 
triggers
Timely 
completion 
= raffle 
entry
Complete study 
– continue on 
intervention(s) if 
desired
Opt out of 
study
Full set of 
study data
CBC 
biomarkers 
some 
participants
 For the full study EHR data indicate that 100 – 120 practices can be expected to have over 
35,000 potentially eligible individuals. With an 8% asthma prevalence rate, an average of 2,500 
adolescent or 7,000 adult individuals per site (per EHR data), 85% of people with asthma on an ICS or 
ICS/LABA, approximately 45% of individuals with asthma have an exacerbation per year and at any 
given time approximately 50% are in poor control. Combining these estimates over the 34-month 
recruitment timeline, we conservatively estimate 60%+ of individuals will become eligible over the 
recruitment timeframe, providing a minimum of 120 eligible adolescents and over 330 adults per 
clinical site. With a 20% - 25% consent rate, Recruitment Implementation sites will need 10 to 12 
physical sites to meet study recruitment. 
The consent rate for our PREPARE study was over 90% for eligible individuals. All Research 
Implementation organizations have 3 to over 15 times this number of potential clinical sites. Since 
 
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the final sites are not known exact EHR data is not available, though the information above derives 
from the participating clinical organizations.
Participant flow is shown in Figure 2.  Recruitment is expected to follow slightly different 
paths depending on local decisions by each Research Implementation team. In the PREPARE study, 
the most effective recruitment method consisted of EHR searches to find potentially eligible people 
coupled with EHR tracking that notified the research team when a potentially eligible individual had 
scheduled a visit. For sites using this approach the research team will then call the individual several 
days ahead of the appointment to remind the patient of the appointment and ask if the patient 
would be interested in hearing about a research study for which s/he may be eligible. Phone 
recruitment script is provided in Appendix 5. If patients expressed interest and eligibility is 
confirmed, the study would be described over the phone. At that point some individuals may elect 
to consent while others may elect to speak with their clinician first. Of course, some will opt out at 
this point. For those consenting over the phone, study staff will obtain consent, collect baseline data, 
and randomize the patient. If the randomization requires a new prescription is needed, the study 
clinician is notified. If the person elects to talk with their clinician first, a note about the call will be 
sent to the clinician including a reminder about the study within the EHR. After the visit a call back 
occurs to complete the same process. Our PREPARE study shows that over 90% of individuals will 
consent if their clinician indicates the study is safe and reasonable for the individual. At some sites a 
research staff member may meet the individual at the practice after assessing interest and eligibility 
over the phone. Some sites may use cold calls to potentially eligible individuals as well as 
appointment-based approaches, though the appointment-based approaches typically achieve higher 
consent rates among eligible individuals they are labor intensive and may not be possible for 
organizations with recruiting sites that cover a large geographic area. Consent can occur over the 
phone. 
9) STUDY TIMELINES
Full  Feasibility pilot – Up to 125 participants across 5 research hubs, each participant will be asked 
to remain in the study for 3 months. Recruitment will be over 4 months.
Asthma Symptom Monitoring pilot – up to 65 participants across 5 research hubs, each participant 
will be asked to complete weekly symptom reports for up to 8 weeks maximum. 4 months 
recruitment time period
Full study:  3200 participants recruited across 10 research hubs. Each participant will be asked to 
complete a questionnaire every 2 months for 16 months. Selected participants will be 
offered to continue in a Challenge study for an additional 12 months. Recruitment time 
period will be up to 32 months. 
10)PROCEDURES INVOLVED
Feasibility study – at this point no procedures are included in the feasibility pilot studies. 
Full Study -The only study procedure will be phlebotomy of selected individuals. All participants who 
do not have a total eosinophil account available in their clinical data in the past 5 years will be asked 
to have a CBC performed. Eight hundred of the individuals on AZ (1600 total) will be asked to have 
blood specimens collected and stored for testing for Mycoplasma pneumoniae RNA through highly 
sensitive PCR and testing for chlamydia pneumoniae IgE antibodies. Six hundred of the 800 will 
actually be tested. (See below.) 
11)SPECIMEN BANKING
 
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Whole blood and serum will be obtained from a subset of participants who are chosen and agree to 
undergo phlebotomy for study purposes. Agreeing to phlebotomy is optional and declining will not 
affect study status. All samples will be labelled with a study code so that lab analysis personnel will 
be unable to identify individuals or their treatment assignment. The sample code key allowing 
identification of individuals will be stored securely as described elsewhere for other iTREAT-PC study 
data. Specimens will be curated and stored in the laboratory of Dr. Chengming Wang, Director, 
Molecular Diagnostics Laboratory, Department of Pathobiology, College of Veterinary Medicine, 
Auburn University. Dr. Wang’s laboratory will aliquot, store and distribute specimens for this study 
analysis to his laboratory and to two other designated laboratories described elsewhere in this 
protocol. Remaining samples will be stored indefinitely in Dr. Chengming’s laboratory for future 
possible biomarker studies, at the discretion of the iTREAT-PC Executive Committee that has sole 
discretion to approve future studies on the samples.
12)DATA MANAGEMENT
14.1) Data Analysis 
We are intentionally avoiding the factorial design framework for the purpose of analysis. 
This is because we are uncertain about whether the combined treatments will have an additive 
effect. If the combined effect is less than additive, then the standard main effects analysis based on 
the factorial design is not optimal. The primary analysis will consist of three hypothesis tests 
comparing each of the three treatment arms against the control. We will employ the maximum 
likelihood framework based on the Negative Binomial distribution (with offset to account for 
differential follow-up time due to dropout or treatment failure) to perform these tests.  In addition 
to treatment assignment, the model will also include fixed-effect covariates sex, race, smoking 
history, asthma treatment step at enrollment, TEC and facility with mobile technology, as well as 
multi-level random-effects of organization and practice within organization. As we consider SMART 
and PARTICS approaches to be equivalent these will be combined for the all primary analyses, 
therefore individuals that switch between these approaches will not impact the primary outcome 
analyses.
In the presence of non-compliance, the ITT analysis may underestimate the efficacy of treatment at 
the patient level. Since non-compliance may be driven by confounders such as disease severity, the 
traditional per-protocol analysis of treatment efficacy may introduce confounding bias. We will apply 
causal-inference based methods to adjust for confounders. Particularly, we will perform adjusted 
per-protocol analysis using inverse probability weighting technique, where the probability of 
adherence will be estimated. We will also explore the instrumental variable approach, which does 
not rely on confounder adjustment, but only allows a crossover type of non-adherence. Instrumental 
variable approach can be used to estimate the complier average causal effect for randomized trials 
when certain assumptions are satisfied.
Heterogeneity of Treatment Effect: Additional analyses to examine heterogeneity of treatment 
effect will employ the same modeling framework, except that interaction effects between the 
treatment effect and pre-specified covariates will be included. These include SMART vs PARTICS, 
1500mg vs 750mg AZ dosage, eHealth Literacy, compliance with treatment assignment, TEC, 
smoking, and lower respiratory tract infection[n (LRTI) onset of asthma.  By examining these 
interactions, we will be able to determine which of these characteristics might contribute to 
heterogeneity of therapeutic interventions.  We are particularly interested in the following 
hypotheses:
1.
AZ will be more effective among those participants that smoke or have a history of LRTI 
onset.
2.
R-ICS therapy will be more effective among those with higher eosinophil counts.
 
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The DCC team discussed approaches to the heterogeneity analyses concerning people that may 
switch between the two ICS as rescue therapy options. At this point they are not prepared to 
commit to an approach. If the number of people who do switch is low it may not be possible to 
include this as an interaction variable. 
Secondary Outcomes:  Analyses for secondary outcomes including the ACT both as a continuous 
and dichotomized at 20, Quality of Life, and number of school/work days missed due to asthma will 
be conducting using the same framework as the primary analysis in terms of testing strategy and 
covariate adjustment.  However, different likelihood distributions will be used as appropriate. The 
Normal distribution will be used for the ACT continuous and Qualify of Life outcomes, while the 
Binomial likelihood will be used for the ACT dichotomized outcome, and the Negative Binomial for 
the number or school/work days missed due to asthma.  For the outcomes that are repeatedly 
measured, we will expand the mixed-effect models to include subject-specific random effects to 
account for within-subject correlations. As with the primary analysis, we will employ the Bonferroni 
adjustment for the three comparisons of treatment against control separately for each outcome. 
Missing data: For the primary outcome, asthma exacerbations over the 16 months of follow-up, 
all available data will be included and an offset will be incorporated to account for differential 
follow-up. The mixed-effects models that will be employed can yield appropriate results in the 
presence of missing at random data, but we will also employ sensitivity analyses to determine the 
potential impact of missing not at random data, including an extreme case tipping point analysis. If 
covariates of interest are missing, multiple imputation methods will be applied to implement the 
mixed-effects models. In our previous PERPARE study overall data missingness was < 4%. 
Exploratory analyses: Utility of Biomarkers for predicting azithromycin treatment outcome: 
Infectious biomarkers, including IgG, IgA, IgE serology and PCR, will be assessed for up to 600 
participants on AZ treatment. We will define three different phenotypes depending on IgA, IgE and 
PCR positivity and test our hypothesis that (1) Cp IgA or IgE seropositivity AND a positive PCR OR Mp 
CARDS IgE seropositivity is predicted to be the most responsive to AZ; (2) seropositivity OR Cp PCR 
positivity is predicted to show less AZ response; and (3) IgG only or no positive biomarker results will 
demonstrate the lowest rate or degree of AZ responsiveness. The level of response will be based on 
ACT scores (both ACT continuous and ACT dichotomized at 20). ACT scores (> 3 point improvement) 
will be used to classify patients into responders versus non-responders. We will first examine the 
number of patients in each observed combination of biomarker results and carry out the statistical 
tests for the combinations with sufficient sample sizes. We will compare ACT scores across different 
groups based on biomarker positivity patterns and use linear or logistic regression models to 
evaluate the predictive values of individual biomarkers and combined biomarkers. Prediction 
accuracy measures, such as R-squared (coefficient of determination), will be calculated for linear 
prediction model; ROC (Receiver Operating Characteristic) analyses will be performed for logistic 
regression model to determine the prediction power and area under the ROC curve (AUC), 
sensitivity/specificity, and positive/negative predictive value will be calculated. Ten-fold cross-
validation method will be used to assess and validate the performance of prediction models. Finally, 
we will evaluate if historical and demographic data, including a self-reported lower respiratory tract 
infection at the time an individual’s asthma developed, self-reported controller use at baseline, race, 
and smoking status, add prediction value to the biomarkers. We may potentially have a large 
number of predictors (including interaction terms) to consider, so we will use penalized regression 
methods (e.g., LASSO) to alleviate the overfitting problem.  
Azithromycin Cessation Challenge: The study will include an AZ Cessation Challenge sub-
study among participants in the AZ monotherapy and AZ + R-ICS arms. The primary outcome will be 
asthma control as measured by the ACT with time to first exacerbation and mini-AQoL as secondary 
outcomes. This sub-study is exploratory but tracks entirely with the recommendations of the recent 
Cochrane AZ review57 and the European Respiratory Society/American Thoracic Society guideline.61 
The goal of this sub-study is not to test the effect of ceasing AZ as opposed to not ceasing, but rather 
to identify patient characteristics associated with long term improvement or relapse after AZ is 
 
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withdrawn.  For the continuous ACT and AQoL outcomes we will use mixed-effects models including 
effects for time (on and off AZ), patient characteristics of interest, and interactions between time 
and patient characteristics. The interaction effects will be of primary interest because those can be 
used to identify predictors of changes in asthma control resulting from AZ withdrawal. For the time 
to first exacerbation outcome we will use Kaplan-Meier and proportional hazards model regression 
analysis to identify risk factors for relapse.  
Outcomes for Step-up sub-study: We expect that up to 4 - 6% of participants (N=23 – 48 per 
control and monotherapy arms) may step-up to the R-ICS or dual pharmacologic arms due to 
treatment failures. The primary and secondary outcomes will be ACT and AQoL respectively. As with 
the AZ cessation challenge, the goal of this portion of the study is not to test whether additional 
therapy is superior to continuation on the same therapy, but rather whether there are patient 
characteristics associated with improved outcomes when additional therapy is given. As with the AZ 
cessation challenge, we will use mixed-effects models with interactions between time and patient 
characteristics to identify characteristics associated with response to additional treatment. 
14.2) Study Endpoints 
Primary outcome: The annualized rate of major asthma exacerbations (a hospitalization 
for asthma or 72+ hours of oral/parenteral steroids). Major asthma exacerbations are a core 
asthma outcome for asthma clinical research99 and a major health risk (including death) that causes 
distress to people with asthma and their families.100 Our patient and parent/caregiver stakeholders 
overwhelmingly endorse asthma exacerbations that require changes in their daily lives (consistent 
with major exacerbations) as the most important event related to their asthma. Clinicians focus on 
ongoing exacerbations as a marker of poor control (over standardized asthma control instruments), 
and thus endorse this outcome as their most important metric. Policy stakeholders indicate that 
from both an overall society cost, individual’s costs and quality of life perspectives they consider 
exacerbations as the main driver of all three concerns. Our definition of “major exacerbation” is 
aligned with US Guideline Expert Review Panel 4 definition and NIH Asthma Outcome workshop.24, 99 
Secondary outcomes: Asthma control is consistently mentioned by clinicians and supported 
by research as the intermediate outcome that best predicts ongoing exacerbations.101, 102 The 
National Asthma Education and Prevention Program's Expert Panel Report 3103 (NAEPP 2007) and 
Report 4,87 of which Drs. Pace, Israel, Yawn, Elward, Wisnivesky and Bryant-Stephens were members 
or reviewers (Panel 3 or 4), emphasizes the importance of asthma control as a goal of therapy 
because of its relevance to patients and providers in the ongoing assessment of asthma. Based on 
the input of our stakeholders we will use the Asthma Control Test (ACT) to measure asthma control.
Exploratory outcomes: Data, including demographic, historical, and biological data, will be 
collected to define sub-groups of individuals with asthma. The following sub-groups will be 
considered exploratory using the same primary and secondary outcomes:  Black race, positive v. 
intermediate v. negative infectious biomarkers, and overlap syndrome (both an asthma and COPD 
diagnosis). The infectious biomarkers are a highly sensitive PCR for Chlamydia pneumoniae and 
specific serologic tests (including IgA, IgG and IgE) for Chlamydia pneumoniae and Mycoplasma 
pneumoniae to guide AZ therapy. 
Outcome Collection 
Participants will complete online surveys that include all outcomes instruments (see Table 
6). Patients will receive survey reminders via automated voice, text, and email messages as well as 
via follow up phone calls. Text and email survey reminder messages are in Appendices 6 and 7, 
respectively.  Surveys are designed to account for a missing previous survey using dynamic questions 
related to the timing of possible exacerbations. The data systems include daily reporting for study 
staff to inform them of participants with missing surveys and tracking actions to collect these data. 
As in PREPARE, we will collect outcomes directly from participants using standardized instruments 
(ACT,92 mini-AQLQ,98, 104 missed days of work/school105) and the Asthma Exacerbation 
Questionnaire96 for exacerbation trigger questions. This questionnaire is sensitive but not specific, 
 
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meaning it will overestimate exacerbations, thus requiring confirmation. But it does not miss 
potential exacerbations. Participants will be asked to complete their surveys every two months using 
various methods. Exacerbations will then be adjudicated through a multi-step process that includes 
the site’s review of EHR or health information exchange data, communication with the patient, and 
occasionally requests for outside medical records. Once the data have been assembled, an initial 
blinded two-clinician review will occur. If there are any concerns or non-agreement at this level, an 
independent adjudication committee will blindly review and make a final determination. The 
standard operating procedures for these activities are well worked out as our team reviewed 
approximately 3000 such events during our PREPARE study. For the full set of analytical groups see 
the Power Analysis/Analysis plans. 
Table 6 - Primary and Secondary Outcomes (All Power Analyses adjusted for multiple outcomes 
using Bonferroni adjustment) 
Primary or 
Secondary
Name of 
Outcome
Specific measure to be used
Time-
points
Estimated 
power (if 
applicable)
Primary
Annualized 
rate of 
major AEXs
Hospitalization for asthma or 72+ hours of oral/parenteral 
steroids
Every 
two 
months
.90 (α .016)
Secondary 
Asthma 
Control 
Asthma Control Test (ACT) score.98, 106-111 Validated for 
patient report, developed to have low patient burden and 
available in multiple languages.92 Has been evaluated in 
multiple populations and can be self-administered,112 
administered by telephone91 or by mail.113 Recommended 
by the NAEPP and the NIH Asthma outcome workshop103, 
114 for research use due to extensive validation data, across 
a range of criterion and construct measures, including 
demonstration of responsiveness to therapy and a minimal 
important difference (MID - the smallest difference in a 
score of interest which patients perceive as beneficial and 
which would support a change in the patient's 
management.115) The ACT MID is 3 for individuals116 and 
cut-off values are  ≤ 19 for “uncontrolled asthma” 92 and 
≤15 “very  poorly controlled” asthma.92, 112 
Every 
two 
months 
(q 2 mo)
ACT 
Dichotomized 
.96
ACT 
continuous 
.99
Secondary
Quality of 
Life
Mini-Asthma Quality of Life Questionnaire (mini-AQLQ). 
An ideal outcome measure for comparative effectiveness 
analysis would capture the risks and benefits for the 
interventions from the patient's point of view. The mini-
AQLQ captures this information.98, 117  The full measure was 
developed entirely from patient experiences. Patients 
were asked to assign a relative value to different health 
states. The original instruments (adult and pediatric109, 118, 
119) have undergone validation across multiple languages 
and constructs for all severities of asthma. Test-retest 
reliability is very high (intraclass correlation of 0.95). The 
instruments are responsive to change117, 120 and have a 
well-established MID of 0.5.110 Both instruments have 
shortened versions that correlate very well with the longer 
versions and will be used for this study. The AQLQ and its 
variants are frequently used in asthma studies including 
large multicenter clinical trials.121-127 
q 2 mo
Mini-AQLQ 
continuous 
.99
Secondary
Days Lost 
from Work 
or School
Validated and utilized as part of the National Health 
Interview Survey.105 
q 2mo
.99
14.3) Data Quality 
 
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The processes of ensuring data quality being with the build of the data collection processes. 
In building our data collection and study management project into REDCap we consistently assess 
how we can assure high initial data capture. For instance, patient facing questionnaires are all 
designed such that every question must be answered with prefer not to answer or similar options 
available when logical. This assures that all completed questionnaires do not have null data that 
cannot be distinguished between unintentional missingness or purposeful missingness. Reports are 
constructed that track partially completed questionnaires as well as questionnaires that are due to 
be completed. Central research staff then reach to participants to complete these questionnaires. 
We also build in logical data skip patterns such that data collected by study coordinators at 
enrollment are not missing. Finally, for patient collected data we run logic checks on responses and 
send out correction notices for illogical responses. 
For the exacerbation and adverse event data reporting we will develop REDCap data 
collection forms for sites and central staff to work together to complete data collection. Forms that 
are not complete are in a report for central staff to track. Once completed the exacerbation forms 
are reviewed by two clinicians on the central team for data missingness and final determination of 
the outcome. This two-person review identifies any missing data that is not discretely captured. 
Finally, if there are discrepancies between the two initial reviewers on the outcome assignment the 
information is reviewed by a second level committee. This committee may ask for additional 
information as well. 
Adverse events that are tracked are initially sent to the site so coordinators can add 
information they are aware of and so the PI or senior staff can determine the scales to be applied to 
the AE event. If there is insufficient information for these judgements, then the form will be 
returned to the central study team to contact the patient and obtain additional information. Medical 
records may be requested for SAEs that may be related to the study medications. Once a full data 
set is compiled the AE form is returned to the site to add the relevant assessments as to causation 
and severity. These forms are then reviewed internally using the same process as described above 
for the exacerbations.
Finally, the DCC will download the full data set on at least a quarterly basis and run their 
own quality and logic checks for the full population without any study arms being identified. These 
reports will be reviewed by the Operations Committee and any data quality concerns will require the 
development of a resolution plan to be implemented and tracked.
 
14.4) Confidentiality  
             Patient level data collected for this study will be housed in DARTNet’s REDCap system, which 
is operated out of a HIPAA compliant AWS data center in Portland, Oregon. Personal identifying 
information will be stored in one database linked to study data via a study ID. Data downloaded by 
the DCC will utilize only the study ID and specific required demographic data such as date of birth, 
race and ethnicity. Data collection forms, such as for exacerbations, will only list the study ID 
requiring users to access patient information from the system. Access to the REDCap system will be 
based on site level permissions. Each research site will only be able to see their own participants 
while the central research team will be able to see all participants.  Sites may develop tracking 
systems for study recruitment. Site specific data handling is described below. 
               Data elements for participants will include name, date of birth, gender, race, ethnicity, 
address, phone number, back up contact name and phone number. Data for the research project are 
in the questionnaires that are attached as separate documents. Research data will be retained for 7 
years. Participant data, if a participant agrees to be contacted for future studies, will be retained for 
5 years. If a participant does not allow future contact that participant’s PHI will be deleted when the 
data is locked for the study. 
              Access to the full data set will be allowed for central research team members and the DCC 
(excluding PHI for the DCC). Local research team members will have access to their own sites data. 
Data will be entered directly into REDCap where it will be stored. Files that are attached to a REDCap 
 
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form are encrypted at the time of transmission. The DCC will download data directly from REDCap or 
from files created out of REDCap using sFTP. Files that are not attached to a REDCap form will be 
posted to a site’s Egnyte folder to be picked up by central research staff. In general, we expect files 
to be attached to REDCap forms. 
Data management for this project will be shared between DARTNet, and the DCC. The 
project will use DARTNet’s HIPAA compliant, secure computing and file sharing resources, Egnyte, 
for sharing files between sites if necessary. Most files will be attached to the correct REDCap form 
that is being completed and stored within the DARTNet REDCap environment in AWS. DARTNet 
operates HIPAA compliant AWS services housed in the Portland, OR, data center. The systems within 
these organizations for this project include file transfer systems, patient-facing data collection 
systems, study management systems, data transformation systems, and data analytical systems. All 
of these systems exist in secure, locked, monitored environments (at the University of Colorado, 
PennState or AWS); all systems are encrypted at rest; and all data transmissions are encrypted at 
AES-1024 or higher level of encryption. Physical servers at the University of Colorado are in a 
climate- and access-controlled environment with 24-hour video monitoring as well as access 
monitoring at the individual level. Nightly, weekly, and monthly back-ups include transaction level 
files and images that are stored both locally and in the cloud. The University of Colorado runs a Palo 
Alto firewall with multiple layers of intrusion detection. Only limited systems are available through 
the firewall. All other systems require VPN, multi-factor authentication to access. The DARTNet 
servers sit in a specific sub-network that is not visible to other users within the University behind a 
second firewall and intrusion detection system, with IP filtering for access. User accounts for both 
organizations require strong passwords and all local machines run centrally monitored and updated 
anti-virus and malware software. 
Pennsylvania State Security: Privacy and data integrity are of critical importance to the 
DPHS. Network access is controlled through multiple layers of protection which, at a minimum, 
consists of unique username and password authentication. Multi-factor authentication is employed 
in most cases. Strict password strength and aging policies are applied to all user accounts from the 
operating system to custom-developed DPHS applications. Access to systems, data, and other 
network IT resources are always controlled using the principle of least privilege, role-based 
authorization. Additionally, the DPHS network and IT systems are protected from security threats by 
enterprise level firewall and intrusion detection systems managed by our cyber security partners at 
Penn State Health and College of Medicine as well as Penn State University Park network levels. 
Different levels of encryption are used to protect data at various stages. Data transmitted across the 
internet is secured via 2048-bit SHA-2 Secure Sockets Layer (SSL) and/or Virtual Private Network 
(VPN)/Internet Protocol Security (IPSec) encryption. Applications developed by DPHS staff encrypt 
identifiers before storing the values to the database. All host servers operate under encryption at 
rest protection implemented through enterprise-level SAN hardware, compliant with IEEE 1619-
2007 and NIST Special Publication 800-38E. All VMware host servers are physically attached to the 
protected SAN infrastructure and all guest servers are provisioned under encryption at rest 
protection. 
            Biospecimen data will be stored initially at Auburn University after testing has been 
completed. Data files will be transferred to DARTNet’s AWS site via sFTP when files are complete. 
See next section for details on data security at Auburn University. 
LOCAL DATA SECURITY
AAFP NRN (Now a part of DARTNet)
AAFP NRN will primarily store data on the iTREAT-PC Egnyte system. Any human subjects data stored 
locally will be stored on secured research servers at the University of Colorado. University of 
Colorado provides secure physical server space for DARTNet through a service contract that includes 
informatics support. Research data housed on research specific servers are not only behind the 
 
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University of Colorado firewall, but visible only to select IP groups within the overall University of 
Colorado network. In addition, these data are stored on directories with limited user access. Data 
servers are managed by the University of Colorado Department of Family Medicine, which includes a 
locked, environmentally controlled, 24-hour monitored server farm with redundant backup systems. 
Analysis will be performed on University of Colorado servers maintained by the campus information 
services, located on core or local workstations maintained by the Department of Family Medicine. 
No data will be stored on local workstations. The research team has been certified and trained by 
the CITI Program.
DARTNet Institute Partners
DARTNet collaborates with over 1200 clinical organizations across the country across our portfolio 
of activities. DARTNet partners with several practice-based research networks that have electronic 
data capabilities. We partner with numerous larger health care systems on specific projects related 
to the use of existing data. We have over 5000 clinical organizations that send us EHR data for our 
Practice Performance Registry through vendor agreements, through self-pull of their EHR data or 
through DARTNet operated data extraction systems. DARTNet currently has recent EHR data sets 
that cover over 40 million people. 
Data Handling Capacity
DARTNet operates its own physical servers and data storage space in a HIPAA compliant server room 
within the University of Colorado Informatics infrastructure. DARTNet also rents HIPAA compliant 
cloud servers and space from AWS. DARTNet owns multiple physical servers and approximately 1 PB 
of storage space in multiple environmental tiers and behind several layers of security within these 
environments. Within the University of Colorado environment DARTNet operates a multi-tiered, 
multi-dimensional business intelligence system, secure file transfer systems (using Egnyte and the 
AWS cloud) as well as software to merge, translate and de-identify existing electronic health data – 
EHR, claims and patient reported data – into standardized data sets for analytical purposes. We 
operate SAS servers in this secure environment for remote access data analytics as well having SAS, R 
and other analytical packages available to all analysts for local usage. The space is monitored 24/7 by 
the University of Colorado police and all access is controlled and monitored. The University operates a 
Palo Alto firewall with additional intrusion detection software while DARTNet operates a second fire 
wall within their sub-network with a second level of intrusion detection. All servers are encrypted at 
rest and particularly sensitive databases use embedded database encryption in addition. No DARTNet 
servers in the University space traverse the firewall. They are all only addressable after establishing a 
VPN connection to the network using two factor authentication. 
DARTNet handles EHR data that arrives in multiple formats, including CSV files pulled by sites, 
vendors or using our own software, CCDs, CCDAs and are adding FHIR at this time. We are very 
familiar with the problems with all of these data extraction methods and can provide extensive use 
case support for the project.  Files are transferred using sFTP with a minimum of 2048 bit key. 
DARTNet physical servers undergo incremental back-ups nightly into our NAS local storage. Weekly 
full images are also stored locally. Monthly images are also stored in the AWS cloud and retained for 
1 year. AWS servers are backed up by AWS on a continuous basis 
DARTNet Assets
All DARTNet computers, primarily laptops, have DARTNet-installed and centrally monitored anti-
virus, anti-malware systems. Updates are pushed regularly. All activity of DARTNet assets is centrally 
monitored. No data is stored on any laptop or other remote device. Laptops are used to run Office 
 
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functions and to connect to either the physical servers or various cloud-based systems used by 
DARTNet, including partner systems on which DARTNet staff carry out data manipulation tasks. 
REDCap 
DARTNet maintains an instance of REDCap in our AWS HIPAA compliant workspace. The system is 
encrypted with a SSL interface. DARTNet staff routinely monitor the REDCap community / messaging 
for new updates (such as the recent security concerns) and if any updates include high risk concerns 
will update the system typically within 2 hours. Routine updates are performed regularly. 
The Department of Public Health Sciences (DPHS) at Penn State University College of Medicine 
DPHS Information Technology Management Team: The DPHS has dedicated system architects, 
administrators, and technical support/helpdesk staff that design, implement, and support the 
computing environment and specialized technical requirements of faculty, investigators, students, 
collaborative researchers, and staff. The primary environment includes an on-site data center 
housing highly-available VMware vSphere virtualization infrastructure host servers. The 
virtualization infrastructure is leveraged to host dedicated, high performance servers providing both 
dynamic computing scalability and system redundancy.  Within this enterprise-level configuration is 
an integrated network of servers running primarily Microsoft Windows Server and Red Hat 
Enterprise Linux computing platforms.
The department’s Windows servers are used primarily for utility and operational services such as 
secured remote access, department-level application services, and VDI/Virtual Desktop 
Infrastructure (Citrix XenApp, XenDesktop). Additional DPHS-dedicated Information Technology 
stacks include financial/operational systems, educational/learning management systems, 
communication, and collaboration services (e.g. Microsoft Exchange email, SharePoint, document 
management, process workflows, etc.). Linux servers are primarily utilized to provide higher 
performance platforms for Bioinformatics, research, and clinical trials hosting as well as a technology 
innovation sandbox and custom statistical, web application, and database development ecosystem. 
A four-tier configuration is implemented to provide discrete proof of concept/pilot/application 
development, quality assurance/acceptance/scalability testing, staging and production hosting 
environments. This architecture provides a proven, stable base for development and testing of 
custom web applications and databases, staging of updates, and deployment of finished software 
into production. Enterprise-level SAN (Storage Area Network) services are based on a highly 
available RAID configuration with additional protection provided through automated hot spare fail-
over disks and self-healing file systems. All critical and production infrastructure are configured with 
subsystem redundancies and proactive hardware, operating system, database and application 
monitoring to support high availability.
 
Additional highlights of the DPHS standard operational computing services include a 10 gigabit 
Ethernet backbone with at least 1 gigabit service to all department servers and clients. Distributed 
file systems are centrally administered, provide over 250 terabytes redundant disk array (RAID) 
storage capacity, and are available to all computing platforms through the use of additional secured 
technologies including Samba, NFS, and SMB/CIFS protocols. 
Modeling best practice ITIL (Information Technology Infrastructure Library) and ITSM (IT Service 
Management) principles, DPHS IT staff regularly utilizes critical IT management tools to proactively 
identify and mitigate performance problems. Some of these tools include Oracle Enterprise 
Manager, OSSEC (system health, log and intrusion detection monitoring), Solarwinds Network 
Performance Monitor, Microsoft System Center Configuration Manager (SCCM), BMC Track-It! and 
ServiceNow (helpdesk/technical request/service delivery management).
 
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The DPHS employs a dedicated, private fiber optic back-up network (separate from the primary 
network) to provide high-speed, high-capacity backup and recovery services. Penn State Health and 
College of Medicine (including DPHS) are protected by enterprise backup solutions that span two 
geographically separate locations. This system maintains development, test, production, and 
research data from various operating systems and physical locations onto redundant spinning disk 
arrays or archival tape. Data is maintained under retention periods as short as seven days to over 10 
years depending on requirement. The solution is capable of standard file level back-ups to complete 
system snap shots (physical and virtual images) to dedicated software specific copies. This enterprise 
solution maintains over 3 PB of data with a current daily ingest of ~40 TB from over 1200 systems. 
Included in the backup technology stack protecting DPHS are vendor software and services provided 
by IBM Tivoli Storage Manager (TSM), Commvault Data Management, and Veeam Back-
up/Replication.  This robust, multi-vendor service model provides multiple layers of redundancy in 
backup and recovery services, helping to ensure complete disaster recovery capabilities and the 
ability to comply with any regulatory or research project/data archival requirement. Along with daily 
monitoring and reporting, backup integrity is regularly tested through disaster recovery exercises. 
Security, privacy, and data integrity are of critical importance to the DPHS. Network access is 
controlled through multiple layers of protection which, at a minimum, consists of unique username 
and password authentication. Multi-factor authentication is employed in most cases. Strict password 
strength and aging policies are applied to all user accounts from the operating system to custom-
developed DPHS applications. Access to systems, data, and other network IT resources are always 
controlled using the principle of least privilege, role-based authorization. Additionally, the DPHS 
network and IT systems are protected from security threats by enterprise level firewall and intrusion 
detection systems managed by our Cyber Security partners at Penn State Health and College of 
Medicine as well as Penn State University Park network levels. Access and audit logs provide a 
chronological record of access and changes to system configurations and data at all levels.
Different levels of encryption are used to protect data at various stages. Data transmitted across the 
internet is secured via 2048 bit SHA-2 Secure Sockets Layer (SSL) and/or Virtual Private Network 
(VPN)/Internet Protocol Security (IPSec) encryption. Applications developed by DPHS staff encrypt 
identifiers before storing the values to the database. All portable computing file systems are fully 
encrypted including laptops, tablets, and MacBooks. Critical workstation and server file systems are 
also encrypted. Additionally, all host servers operate under encryption at rest protection 
implemented through enterprise-level SAN hardware, compliant with IEEE 1619-2007 and NIST 
Special Publication 800-38E. All VMware host servers are physically attached to the protected SAN 
infrastructure and all guest servers are provisioned under encryption at rest protection.  DPHS 
faculty, investigators, and staff also utilize LOK-IT flash (thumb) drives, which provide both 
encryption and a physical locking mechanism that requires entry of a PIN code to gain access. Per 
DPHS policy, standard (non-encrypted) flash drives and other personal storage medium are not 
permitted within the department. Secure email services are available through Cisco Registered 
Envelope Services (CRES). DPHS faculty and staff are able to send TLS (Transport Layer Security) 
encrypted messages via a registered electronic envelope. The registered envelope is a password-
protected, encrypted email that can only be opened by authorized recipients who authenticate 
themselves.
The department employs anti-virus, anti-malware and anti-spam protection on all servers, 
workstations, portable computing platforms, and the email gateway to further protect from risk of 
compromise. All department server and work stations are maintained with security patches and 
software updates released by manufacturers through a regularly scheduled rhythm of monthly 
automated and immediate manual (when needed) maintenance services. Security awareness 
 
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campaigns and threat announcements are also regularly provided to department faculty, 
investigators, students, and staff.  
For each project, a departmental security team ensures that systems are secure, meet regulatory 
requirements such as HIPAA-compliant storage, HIPAA de-identified datasets and obtaining HIPAA 
waivers where required, and adhere to information technology polices developed by Penn State 
University and the Penn State Health IS, Cyber Security, and Risk Management departments which 
periodically audit DPHS processes and procedures. Penn State Health Cybersecurity scans each 
server within the department nightly and provides a vulnerability report to DPHS systems 
administrators, who remediate any findings. In addition, all systems are patched regularly. The DPHS 
databases are proactively monitored and backed up through multiple levels of redundancy using 
Oracle Enterprise Manager, RMAN, and IBM Tivoli Storage Manager. IBM Tivoli Storage Manager is 
used to backup other servers on the network including the web servers. Backups are retained locally, 
archived at the Penn State Health secure data center and collocated at an identical data center at 
University Park. Disaster recovery exercises are performed regularly to insure DPHS staff has the 
ability to recover a database, database server, or web server. All applications are assessed against a 
Cyber Security Governance Framework based on the National Institute for Standards and Technology 
Special Publication 800-18, are HIPAA compliant. 
The DPHS hosts and manages a dedicated Citrix XenApp/XenDesktop research environment to 
provide a number of collaborative research capabilities including customizable Virtual Desktop 
Infrastructure (VDI) services. Almost any operating system or software package can be published and 
made available to launch through a Citrix VDI session.  
RAND
RAND will primarily store data on the iTREAT-PC Egnyte system and store only limited data 
separately at RAND where necessary for analyses. And Human subjects data stored at RAND will be 
stored in locked filing cabinets or on encrypted, password-protected computers at RAND to which 
only investigators and staff directly associated with the study will have access. These data will be 
reported only as summaries, in aggregate. Where it is necessary to report individual data such as 
quotations, names will not be disclosed and the source will be de-identified. The research team has 
been certified as trained by the CITI Program and will have current certifications on file for the 
duration of the project. The principal investigator will conduct regular checks with the team to 
review the status of all study data. Any unauthorized use or disclosure of the interview data would 
immediately be reported to the RAND Human Subject Protection Committee. 
University of North Carolina
Microsoft Teams will be used to store and share a screening log accessible to only IRB approved 
personnel (no accounts outside of UNC).  The owner of this of this file is required to manage users 
and permissions. This file will never be downloaded from the Teams platform.  These files will 
include name, address, subject ID, MRN and other PHI. Microsoft Teams provides a secure platform 
that can be used to collect and share data. Access to all data (both PHI and non-PHI) on Teams will 
require a 2-step verification via Office 365.  Only authenticated users, study personnel and select 
technical personnel, will have access.
Brigham and Women’s Hospital
Data obtained by Mass General Brigham, including recruitment logs and tracking data,
will be collected and stored electronically on secure servers located within the Mass General 
Brigham network. Access to the data will be restricted to authorized personnel only. All study data 
will be kept secure for a minimum of 7 years after study completion. After this period, the data will 
be deleted in accordance with Mass General Brigham policies and federal regulations. Data 
 
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management will be overseen by the principal investigator and research staff, who will ensure the 
accuracy and integrity of the data throughout the study. Data backups will be conducted regularly to 
prevent data loss due to technical failures. Any breaches or potential breaches of data security will 
be reported to the Mass General Brigham data security officer and the institutional review board 
promptly.
Kelsey-Seybold
Data obtained by Kelsey Research Foundation, including recruitment logs and tracking data, will be 
collected and stored electronically on secure servers located within the Kelsey Research Foundation 
network. Access to the data will be restricted to authorized personnel only. All study data will be 
kept secure for a minimum of 7 years after study completion. After this period, the data will be 
deleted in accordance with Kelsey Research Foundation policies and federal regulations. Data 
management will be overseen by the principal investigator and research staff, who will ensure the 
accuracy and integrity of the data throughout the study. Data backups will be conducted regularly to 
prevent data loss due to technical failures. Any breaches or potential breaches of data security will 
be reported to the Kelsey Research Foundation data security officer and the institutional review 
board promptly.
University of Colorado
The University of Colorado will collect data including recruitment logs and tracking data and store it 
electronically on university secure servers. Only authorized members of the research team will have 
access, and we will put protocols for accessing data in place.  We will maintain secure storage of 
collected data for 7 years after study completion. University and Federal policies will determine data 
deletion after that.  The Principal Investigator will oversee all data management, with research staff. 
We will regularly back up data, to avoid data loss. Any breaches or potential data security breaches 
will be immediately reported to the University of Colorado data security office and the IRB.
University of Washington
Data obtained by the University of Washington team, including recruitment logs and tracking data, 
will be collected and stored electronically on secure servers located within the university's network. 
Access to the data will be restricted to authorized personnel only. All study data will be kept secure 
for a minimum of 7 years after study completion. After this period, the data will be deleted in 
accordance with university policies and federal regulations. Data management will be overseen by 
the principal investigator and research staff, who will ensure the accuracy and integrity of the data 
throughout the study. Data backups will be conducted regularly to prevent data loss due to technical 
failures. Any breaches or potential breaches of data security will be reported to the university's data 
security officer and the institutional review board promptly.
Reliant Health System
To maintain the confidentiality of data collected as part of the iTREAT-PC protocol, Reliant will:
•
Utilize Velos (A Clinical Trial Management System) for all iTREAT-PC study activities: for more 
information please see https://www.wcgclinical.com/services/eresearch-ctms/
•
Ensure research personnel are appropriately trained
•
Restrict access to those who have a need to know for performance of their job duties
•
Store paper records (if any) in a secure location accessible to research personnel only
Rutgers 
Study data will be collected at the study visits and entered into a secure Electronic Data Capture 
system, as may be provided by the sponsor.  Data entry will be done by research nurse/research 
assistant or Investigator and access will be limited to research personnel through password 
protection.   
 
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All research related source documents and all raw data will be placed in separate binders for each 
subject and stored and locked in the site PI's office, currently Room 1330 at 89 French Street. Only 
study staff will have access to subject binders.  Data will not routinely be stored on mobile 
computers or flash drives; in the unlikely event that mobile storage is necessary study personnel will 
ensure that all devices on which patient information is stored are encrypted to meet or exceed 
Rutgers security requirements for PHI, including HIPAA compliance and that these are securely 
scrubbed clean of these data to ensure privacy in a timely manner.   
 
Investigators and staff are well trained on protecting privacy and confidentiality of health 
information of study subjects, having received Rutgers required HIPAA Compliance and Collaborative 
Institutional Training Initiative (CITI) training for Biomedical Responsible Conduct of Research and 
Biomedical/Clinical Research Investigators or for Social & Behavioral Research.  Subject information 
with PHI will never be transmitted via email. Private information collected will be limited to that 
necessary to conduct the research.  
Mt. Sinai
Recruitment tracking and research data collection will be performed by a team of clinical research 
coordinators trained on the study’s protocol using REDCap software. Each subject will be assigned a 
unique alphanumeric study identification number. A cross walk linking study participants to their 
study ID will be maintained via a REDCap report in the recruitment tracking database. Data 
downloaded from REDCap will be stored on secure drives supported by the encrypted Mount Sinai 
server network. Research data will be collected and stored using REDCap software in a separate 
REDCap database. Only members of the research team will have access to the REDCap databases. 
Any paper-based study documentation such as consent forms and HIPAA documents will be stored 
in locked cabinets within locked offices of Division of General Internal Medicine. Only members of 
the research team will have access to these files. During the study period, the study team will follow 
all Icahn School of Medicine at Mount Sinai policies regarding data transfer and security.
Atrium Health
Atrium Health uses the computing infrastructure of Wake Forest University School of Medicine 
(WFUSM). At WFUSM, REDCap is hosted through the Clinical and Translational Science Institute 
(CTSI). This system offers easy data manipulation with audit trails and reports for reporting, 
monitoring, and querying patient records. While REDCap can be used to collect virtually any type of 
data in any environment (including compliance with 21 CFR Part 11, FISMA, HIPAA, and GDPR), it is 
specifically geared to support online and offline data capture for research studies and operations. 
User logins are tied to an individual’s medical center ID and authenticated across platforms. 
OnCore is the enterprise-wide Clinical Research Management System. This system is used to address 
all areas of clinical research management, including regulatory, subject, and protocol management; 
data management and study design; billing and financial management; and reporting. OnCore is 
used by the Clinical and Translational Science Institute (CTSI) as the repository and reporting of 
enrollment on all clinical research.
 
Auburn
The data related to this project will be recorded in Excel file and shared among investigators. During 
the whole process of the research, the original data will be recorded on the hand-written notebook 
which will be kept in a secure location. Simultaneously, the data will be recorded on the university 
computer. The computer and PCR machines belong to Auburn University; a password is needed to 
log in and access the data.  The data will be periodically archived in the external hard drive with 
encryption protection. In addition, the data is also backed up to Auburn’s networked storage 
 
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through the Office of Information Technology at Auburn University.  The Auburn OIT provides Box, 
which is protected by two-factor authentication.
14.5) Future Use of Data 
Per research best practices a fully de-identified data set of participant demographics, baseline 
characteristics, outcomes, and biospecimen data will be available for other researchers once the 
main effects paper has been accepted. PCORI data retention guidelines require data to be retained 
for 7 years. PCORI provides a central storage location for these data. Data release guidelines will 
follow PCORI guidelines. These policies are available on the PCORI website. The third-party data 
request policies are copied below.
Third Party Data Requests to a PCORI-Designated Repository
1. Submission of Data Requests
a.
Data request process – Individual investigators or teams of investigators seeking access to 
data from PCORI-funded studies must complete and submit a data request form to a PCORI-
designated repository. The repository will independently review requests for data based on 
qualifications of the data requestors and the scientific merit of the request (see below). If 
the data request is approved, the data requestor’s institution must enter into a Data Use 
Agreement (DUA) with the repository. The DUA specifies the terms and conditions of data 
use, as well as the responsibilities and obligations of data requestors. Individual investigators 
must enter into an assurance of compliance with the terms of the DUA that shall be 
incorporated as an exhibit to the DUA.
b.
Data requestor qualifications – A data requestor that submits a data request will be 
evaluated for its overall qualifications and experience (e.g., across a proposed team of 
specified individuals) to achieve the stated research purpose underlying the data request. 
Neither PCORI nor the Awardee investigators will provide technical assistance directly to 
data requestors. However, either party may provide input to the repository upon request. 
c.
Required documentation for data requests – At a minimum, requests for Awardee data must 
include the following elements: a statement of the proposed research purpose, an assurance 
that the data requested will be used to develop or contribute to generalizable knowledge, a 
justification that the proposed research can be achieved using the requested data, and a 
data security plan.
i.
Data requests for nonscientific uses, such as in support of litigation, general educational 
purposes, quality improvement projects, and for promotional/marketing purposes will not 
be accepted.
ii.
Requestors submitting incomplete or unclear requests for data access will be asked to revise 
their request and/or provide all required information.
2. Review of Data Requests
a.
Review process – Upon receipt, all requests for data will undergo review by an independent 
committee directed by a PCORI-designated repository. The purpose of the review is to 
ensure that the proposal has scientific merit, in that: the research purpose is clearly 
described; the data requested will be used to develop or contribute to generalizable 
knowledge to inform science, medicine, and/or public health; the proposed research can be 
reasonably addressed using the requested data; the data requestor team has the 
appropriate expertise to conduct the proposed research; and the proposed research 
includes questions and outcomes that are relevant to patients.
b.
Review committee – The independent review committee will be convened as needed and 
will be comprised of five voting members: a representative from the PCORI-designated 
repository, a data scientist, a clinical researcher with expertise germane to the data request, 
a PCORI staff member, and a patient representative. Other relevant stakeholders (e.g., 
payers, policy makers) may be invited to participate, as warranted. PCORI Awardees who 
 
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generated the data being requested will be invited to attend the review as nonvoting 
participants. The review panel will be administered by the PCORI-designated repository.
c.
Prohibitions against re-identification and redistribution of data – This Policy and the required 
DUA strictly prohibit re-identification of any individual who is a subject of the data, as well as 
the redistribution of the data to any entities that are not party to the DUA or individuals who 
have not entered into an assurance of compliance as an exhibit to the DUA.
d.
Transparency of data requests – The PCORI-designated repository will post a summary of 
each approved data request that includes the research purpose and identity of requestors to 
its website. Awardees will be notified in the event that a request for their data is approved. 
The posting and notification will occur within five (5) business days of the approval.
e.
Transparency of research findings related to data requests – Requestors are required to 
provide a summary of all findings (including negative findings) related to the secondary use 
of Awardee data to the repository for posting to the repository’s website within 12 months 
of the date of approval of the data request.
f.
Acknowledgment of Awardees and PCORI – Requestors are required to acknowledge the 
Awardee as the primary source of the data and PCORI as the funder in all publications or 
presentations resulting from secondary use of Awardee data.
Awardee Data Sharing Costs
For Awardees depositing the Full Data Package (or required data elements, as applicable) into a 
PCORI-designated repository, PCORI will cover reasonable costs associated with the time and effort 
needed for preparing, depositing, and maintaining the Full Data Package in the repository for a 
period of at least seven (7) years following acceptance by PCORI of the Final Research Report.
13)PROTECTING THE PRIVACY OF SUBJECTS
The majority of participants are expected to be consented using telehealth approaches. 
Thus, consenting adults and assenting adolescents will be in a location of their choosing, presumably 
their own homes. For those individuals consented within a clinical environment, research 
coordinators will be encouraged to contact possible participants prior to a routine clinic visit and 
meet them at the clinical site upon agreement to consider study participation. The research staff 
would then use a private space within the clinical area to complete the consent process. The only 
other possible face to face interaction with research staff or clinical staff for sample collection would 
be for a phlebotomy. This visit would not be distinguishable to any other clinically oriented visit for a 
phlebotomy and thus does not expose the participant to loss of confidentiality related to study 
participation. 
After consent, risks to data confidentiality will be mitigated by removal of all but study IDs 
before secure transfer from the DARTNet data collection site to Penn State and by security protocols 
for the participant-reported outcomes data capture and exacerbation and severe adverse event 
tracking systems. All users of REDCap will be tracked and only provided access in a secure fashion 
following established DARTNet Standard Operating Procedures. These include strong passwords, 
changed every 90 days, two factor authentication and strong recommendations of the use of a local 
VPN for connectivity. Connectivity over public wi-fi is prohibited. DARTNet utilizes REDCap to handle 
multiple research and clinical data collection processes across thousands of individuals 
simultaneously. This project will be totally isolated from all other ongoing research activities. 
Participants will only have access to their personal information, questionnaires appropriate for their 
study arm, and the educational video(s) associated with their arm of the study. Site research staff 
will only have access to the participants enrolled by their site. AAFP NRN/DARTNet staff will have 
access to participant contact data for all participants, as well as reports indicating questionnaire 
completion status for each individual. The REDCap system will automatically lock the monthly 
questionnaire for six weeks following completion by an individual assuring that we do not have 
duplicate data completion. The system will automatically remind individuals to complete 
 
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questionnaires and unlock them at appropriate times. Missed questionnaires will not be locked until 
another questionnaire is completed. The risks of loss of confidentiality are minimal given the secure, 
central handling of data.
14)ENSURING THE SAFETY OF SUBJECTS 
1. Recruitment and Informed Consent
The research team will work with the Operations Committee and patient partners to draft an 
Informed Consent Template that is as brief as possible and meets IRB requirements. Consent forms 
will be uniform throughout the sites except for minor modifications as required by a site's IRB. We 
expect all sites to use the BRANY IRB. We will work on multiple approaches to completion of 
informed consent, including online, a web (video) conference, over the phone or in person. Each site 
will have a specific consent form present on the online system, and consent will be recorded in the 
online system by the participant or research staff no matter which form of communication is used. If 
a local site requires that a paper copy of the consent be retained, sites will be responsible for this 
retention. Participants will be able to download a copy of the consent or will have one mailed to 
them if they wish a hard copy. No participants will be enrolled without documentation of informed 
consent. A waiver of consent for a limited EHR data set will be requested for the analysis. EHR data 
will be collected at the end of the study one time. 
2. Risk of asthma exacerbation
This study is directed toward the reduction of asthma exacerbations. Acute management of 
participants’ asthma is not changed by the study and will be handled by the participant’s clinician or 
health system. The use of R-ICS for acute symptom relief or AZ is intended to further reduce the risk 
of exacerbations; no data have been published to show that the use of R-ICS or macrolides increases 
exacerbation potential. Data collection will include assessment of exacerbations. Due to the 
pragmatic nature of the study, no additional interventions will be provided unless the participant has 
an allergic reaction to the ICS/LABA or AZ used for this study. If such is the case both the participant 
and their care site will be notified to assure they have information on the exact medication to which 
the reaction occurred, and the participant’s use of the medication will be discontinued. The 
participant will be asked to remain in the study. 
3. Adverse Event Monitoring
(a) Asthma-Related Adverse Events: Data collection will include assessment of exacerbations. 
Exacerbation care will be at the discretion of treating clinicians and the participant. 
(b) Non-Asthma Adverse Events: We won’t monitor for minor events as these are well characterized. 
We will monitor how many participants require step-down AZ therapy due to side effects.
(c) Serious Adverse Events: These events meet the following criteria: results in death, is life-
threatening, requires or prolongs hospitalization, results in persistent/significant disability, or results 
in a congenital anomaly/birth defect. These also include any other adverse event that, based upon 
appropriate medical judgment, may jeopardize the participant's health and may require medical or 
surgical intervention to prevent one of the outcomes listed above. These will be monitored and 
reported to the DSMB by study arm through the DCC on a bi-annual basis. The DSMB will have the 
discretion to stop the study or one arm of the study if excess severe adverse events occur in one arm 
of the study. The full description for handling adverse events, both serious and non-serious are 
discussed more fully in the DSMP. 
4. Management of Asthma Exacerbations
Acute management of participants’ asthma is not changed or mandated by the study and will be 
handled by the participant’s clinician in their usual manner. Clinicians and participants using R-ICS 
therapy will be advised, per recent US asthma guidelines, to not increase their ICS controller 
 
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medication in an attempt to treat an exacerbation. 
5. Data and Safety Monitoring Plan/Board
A Data and Safety Monitoring Plan and Board will be appointed by the DCC in the first year and will 
include the type of data to be monitored, the frequency of monitoring and monitoring procedures. 
The monitoring plan will be developed with review and modification/agreement of the patient 
partners and stakeholders with final approval by the DSMB. All participants will receive written 
instructions on the use of their medications. If participants experience an adverse event, they will 
contact their local physician, who will evaluate the participant and determine the nature and 
severity of the event, working with the local site PI a determination of whether the event it is related 
to the study procedures or medications will be made and reviewed and verified by the central 
research staff. The site PI will ensure appropriate documentation, participant management, and 
follow up to resolution. The DCC will prepare bi-annual reports to be reviewed by the DSMB. Annual 
reports will also be prepared by the clinical coordinating center for IRB review as needed.
The DSMB members will be recruited by Drs. Mauger and Kong with assistance from Dr. Pace, if 
requested. The DSMB members will not be affiliated with any of the organizations participating in 
iTREAT-PC, and will include: at least one individual with asthma expertise, one biostatistician, one 
clinical trialist, one member of the public and one ethicist. The DCC will provide administrative 
support to the DSMB. All communications between the DSMB and research staff will be conducted 
through the DCC through Dr. Kong. The DSMB Charter is attached as Appendix 2. 
15)WITHDRAWAL OF SUBJECTS
The only circumstance we can envision where we would withdraw a study participant is if we 
discovered that they knowingly falsified information to be enrolled in the study, in particular, that 
they did not have asthma. We see this circumstance as extremely unlikely as the enrollment criteria 
require a verified clinician’s diagnosis of asthma at least one year prior to enrollment. Should an 
enrollee elect to stop all study medications or not wish to use the Asthma Symptom Monitoring 
system s/he would still be asked to complete all data collection until the end of their expected 
enrollment period and would be paid for submitting data and be eligible for raffle payments. The 
primary outcome is based on an intent to treat analysis and thus we have no intent to remove 
subjects whether they follow study protocols or not. As we are not providing study interventions, in 
the unlikely event we remove someone from the study we would contact them and indicate that we 
no longer need them to continue to provide data. We would shut down their REDCap account. If the 
individual wished to continue on any study medications they have been prescribed they may do so 
as their prescription is not being paid for by the study. Renewals of the prescription(s) would be 
between the individual and his/her asthma clinician. There are no required procedures as part of the 
study. If requested to have either a CBC drawn of if requested to provide a blood draw for infectious 
biomarkers, an individual may decline and it will not impact their ongoing enrollment in the study.
16)RISKS TO SUBJECTS
This study will add interventions to the participant’s current therapy:  PRN ICS/ LABA, (potentially 
PRN ICS/ SABA,) AZ (initially at 500 mg/three times per week or 10 mg/kg three times per week to a 
maximum of 500 mg/dose), or a combination of these. Participants in the R-ICS arms may require a 
change in their controller medication if they are on an ICS/LABA containing salmeterol. In these 
individuals a change to budesonide/formoterol, guided by the individual’s current ICS dosage, will be 
made. All other changes in participant medications will be made by the participant’s personal 
clinician or a research clinician who is clinically active within the participant’s Research 
Implementation site. At baseline, participants will either be on ICS/LABA combination, or on ICS 
 
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monotherapy, and will continue on similar therapy. 
Medication Fulfillment
Participants randomized to the pharmacology intervention arms will receive a prescription to fill at 
their usual pharmacy. Those currently having an asthma exacerbation will be considered to be 
uncontrolled and will be asked to see their physician to re-evaluate treatment before enrolling. They 
will be eligible 30 days after the current exacerbation. All participants will be informed that the 
alternative to participation is to continue their baseline asthma therapies. We will continue to work 
with budesonide/formoterol manufactures to determine if any of them (currently 3 in the US) would 
consider donating product for the study (TEVA donated ICS for the PREPARE study) but given the 
current package insert none of them will currently consider this nor are they offering a MAP 
programs specifically for SMART. We will utilize MAP programs with a focus on "controller" therapy 
if required for the conversion to budesonide/formoterol. AZ is relatively inexpensive and as a generic 
offered by many companies does not have an available MAP program. 
Inhaled Corticosteroids Risks
All participants will be prescribed daily ICS maintenance therapy prior to enrollment. Low adherence 
to controller medication will not impact enrollment.  Overall corticosteroid dosing may be increased 
in the R-ICS intervention groups, especially in the short term. However, efficacy studies of the R-ICS 
approach suggest that total ICS dose will actually decrease due to improved participant control. 
Additionally, since we are targeting a group that has a high risk of exacerbation, for many 
participants the total yearly dose of corticosteroids will be decreased even further due to avoidance 
of oral corticosteroid bursts resulting from the decrease in asthma exacerbations. Participants will 
be informed that when taken at high doses for extended periods, ICS can produce hoarseness, sore 
throat, and thrush, as well as rarely cause osteoporosis, adrenal gland suppression, weight gain, 
bruising of the skin, and diabetes, and to see their physician if they experience bruising, acne, 
hoarseness, or fatigue. ICS use has also been associated with reduced growth velocity in children, 
but mostly at ages under 12.
Azithromycin Therapy
Azithromycin is approved for all ages included in this study. When taken with asthma medications, 
AZ has no greater risk for side effects than amoxicillin. AZ should not be used in people with an 
allergy to a macrolide, or on other medications known to prolong the QT interval (we will provide a 
list to prescribers which will be checked by the research assistants at consent). Azithromycin, like 
most antibiotics, can result in Clostridium difficile associated diarrhea. Individuals developing 
diarrhea will be instructed to stop AZ and, if they develop a fever or severe diarrhea, to be tested for 
C. difficile. If the diarrhea resolves in ≤5 days they will be restarted using a step-down dose. AZ is 
associated with hearing loss in a small percentage of people. This is typically reversible when 
stopping AZ. Participants will be asked to report any hearing loss and will be asked about hearing 
with each bi-monthly survey. AZ is associated with nausea, vomiting, and abdominal pain in 2–5% of 
people taking multiple doses. Other side effects in <1% of people include dizziness, vertigo, 
headache, fatigue, somnolence, and chest pain. Participants who experience mild side effects will 
have the medication stopped for 5 days and then restarted at the next step-down dose. The step-
down doses will be from 500 mg 3x weekly (10 mg/kg) to 500 mg 2x weekly (10 mg/kg) to 250 mg 3x 
weekly (5 mg/kg/dose 3x weekly). AZ is considered safe for use in pregnancy, but we will not enroll 
women who are pregnant or breastfeeding. If a woman becomes pregnant during the study while on 
AZ, we will recommend that she stop therapy but continue in the study. If her maternity care 
clinician believes that continued use of AZ is beneficial then she will be allowed to continue the 
therapy until delivery or 38 weeks gestation, then therapy will be stopped to avoid exposure to her 
infant through breastfeeding. We will recommend that participants in the AZ interventions who start 
taking other antibiotics during the course of the study, stop taking AZ.  Participants can restart AZ 
 
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after 72 hours (3 days) of taking other antibiotics.  
The informed consent language is provided below related to AZ.
Azithromycin. The Informed Consent will state: Azithromycin is an antibiotic approved for use in the 
US and is frequently prescribed to treat respiratory infections. Long-term use of azithromycin has 
recently been included in all major asthma guidelines as a treatment option for people with severe 
asthma. We are using the same weekly dose of azithromycin that is FDA-approved to treat 
respiratory infections, and repeating this dose weekly to see if we can identify which people with 
uncontrolled asthma will benefit and who will not. This knowledge will help doctors to prescribe 
azithromycin for asthma more accurately and will help to avoid antibiotic overuse in the future. 
Azithromycin is generally well tolerated but there are a number of possible side effects. These 
include:
•
Diarrhea (5%)
•
Abdominal pain (3%)
•
Nausea (3%)
Side effects reported with a frequency of less than 1%:
•
Rash, itching, swelling, sun sensitivity)
•
Palpitations, chest pain
•
Flatulence, black stool, yellow skin
•
Yeast infection, vaginal irritation, kidney inflammation
•
Abnormalities of liver enzymes
•
Fatigue
All these side effects improve by either reducing the dose of the drug or stopping it. The dose of 
azithromycin may be cut by 50% for side effects. 
Another potential problem with azithromycin is due to its bacteria-killing properties, which could lead 
to the development of resistance in bacteria that might be in your airways (that means that bacteria 
lose their sensitivity to being killed by azithromycin). There is evidence that this can happen, but so 
far, no adverse consequences have been seen. Importantly, if you should develop a chest infection 
and the bacteria are resistant to azithromycin there are many other types of antibiotics that can be 
used. You should also know that people randomized to long-term azithromycin in several large 
studies actually had significantly fewer episodes of bronchitis and pneumonia compared to the 
people in the same studies who did not receive azithromycin. Although there is no evidence that 
antibiotic resistance will harm you directly our study will look for spread of resistant bacteria into 
your community by monitoring locally available clinic and hospital antibiotic resistance patterns.
Some studies of long-term azithromycin have reported a low frequency (<1%-2.8%) of hearing loss 
that was mostly reversible after stopping azithromycin so please contact our study personnel if you 
start having trouble hearing while taking azithromycin.
Asthma Symptom Monitoring
The risks of use of Asthma Symptom Monitoring, such as with the smartphone application, are 
considered minimal. There is a small risk of loss of data confidentiality during data collection and 
transmission. The various data collection approaches will include encrypted data transmission and 
encryption at rest for the stored data. Once in the clinical EHR, the data is at no greater risk than 
other EHR data for loss of confidentiality. For adolescents there is the requirement for shared 
information with parents/guardians. There is a small risk that individuals having a severe 
exacerbation would delay seeking treatment at an emergency room or urgent care center while 
waiting for a reply from their office. It will be clearly indicated that Asthma Symptom Monitoring is 
not for emergency communication. All ASM applications will specifically instruct people to expect a 
 
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call no sooner than 24 hours and to seek care directly if they need help sooner. As noted above ASM 
will be offered to all study participants as well as to any individual with asthma in all participating 
practices that wish to do use the system as part of routine care.
Pregnancy and Breast Feeding
Pregnancy is not a contraindication to asthma controller therapy, including ICS, azithromycin, or use 
of ASM. Improved asthma control has been shown to be associated with improved pregnancy 
outcomes. It is unknown if AZ is excreted in breastmilk but is assumed that it is. Out of an abundance 
of caution we will only enroll women that are pregnant or breastfeeding after she has consulted 
with her maternity or infant care provider with approval of that provider. We will not require a 
pregnancy test or effective birth control be used to be enrolled for women of child-bearing age but 
will ask that they inform us if they become pregnant. We will recommend that pregnant women on 
AZ (either arm) to stop this treatment until discussing with her maternity care provider. We will 
advise all women to seek maternity care as soon as they are aware of the possibility of pregnancy 
and to inform their maternity care clinician of their study participation. Should the participant and 
her maternity care clinician feel that continued use of AZ is warranted then she may continue on 
therapy until delivery or 38 weeks gestation, whichever comes sooner. Pregnant or breastfeeding 
women in the R-ICS or control arms of the study will be allowed to continue without interruption.
Asthma Questionnaires Risks
There are minimal risks associated with questionnaires. The surveys do not ask sensitive questions or 
about mental health. The main risk from the surveys is loss of confidentiality if someone were to 
hack an email or text message or if the survey database is breached. Someone with illicit access to a 
participant’s email or text messages would not be able to see any of the participant’s answers, but 
by seeing the survey would know the person has asthma. The database servers for REDCap related 
systems are located in secure, HIPAA compliant data centers with multiple layers of intrusion 
detection. The servers are encrypted at rest and all transmissions are encrypted in transit. The 
greatest threat to a data breach were if someone were to intercept an email or text message to a 
participant or uncover a username and password for site personnel. If this was for a participant, then 
the hacker may be able to see the participant’s latest survey data, but generally the messages link to 
a new survey, and old information will not be viewable. If this was a research staff member’s login 
then the hacker could see potentially all participants’ information for that site or if it was one of the 
central staff they could see all participant’s information. Research staff will be required to use strong 
passwords and change them every 90 days. We will institute 2 factor authentication for REDCap for 
all research members but not for participants. All our data systems have strong firewalls and 
multiple layers of intrusion detection.
Procedural Risks
No study specific procedures other than phlebotomy, data collection, and medical record review are 
planned. Participants who do not have an historical CBC with differential will be offered to have one 
performed by the local site or a centrally contracted laboratory. Individuals in the AZ arms will be 
offered the opportunity to undergo mycoplasma and chlamydia serology testing and chlamydia PCR 
testing. These blood tests involve a venipuncture that poses no greater risk than usual clinical care.  
17)POTENTIAL BENEFITS TO SUBJECTS
The potential benefit to participants in the intervention arms is unknown, but may include 
decreased exacerbations, decreased symptoms, and reduced need for asthma medications. 
Implementation of ASM at all primary care practices may improve rates of asthma control. The 
potential for benefit to society and individuals with asthma is very significant as the study 
interventions represent newer approaches to asthma therapy, and the study will inform who may 
respond best to a given approach and if approaches work using alternative delivery approaches for 
R-ICS. Any chance to determine ways to reduce asthma exacerbations and learn how to better treat 
 
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individuals presents a clear benefit to people with asthma. If the study shows that these approaches 
reduce exacerbations or improve other important outcomes differentially, then each approach can 
easily be adopted in the context of current care. 
18)COMMUNITY-BASED PARTICIPATORY RESEARCH
This research is not a classic community-based participatory research project. That said, it has and 
will be heavily guided by Community Advisors, including patients and caregivers, that are invested in 
the project and its results. Thus, we have included our engagement approach here, but again, it is 
not CBPR.
Substantial commitment to and demonstrated experience with effective stakeholder 
engagement is a major strength of iTREAT-PC. A variety of stakeholders have been involved 
throughout the study design and will continue to inform the project in both phases as well as 
implementation, interpretation, and dissemination efforts. Eight stakeholder groups including 1) 
patients/caregivers, 2) patient advocacy groups, 3) clinicians (physicians, nurses, and pharmacists), 
4) professional societies, 5) healthcare policy experts, 6) payers, 7) asthma experts and researchers, 
and 8) site research teams have all been engaged in formulating our questions, identifying the study 
groups, selecting the interventions, choosing outcomes, and suggesting the exploratory aims and 
analyses for this study. Experienced individuals have accepted stakeholder roles for all these groups; 
each iTREAT-PC implementation site will provide clinical and local researcher stakeholders along 
with two patient stakeholders. Due to their in-depth understanding of local contexts concerning 
community and research partnerships, site PIs are best suited to identify appropriate participant 
stakeholders from sites. Site PIs have been consulted during the development process. In addition to 
ongoing engagement of select stakeholders from PREPARE, we have worked with several new 
stakeholders in all categories to provide continuous feedback in the development of this proposal. 
For iTREAT-PC, we have support from the American Lung Association, Asthma and Allergy 
Foundation of America; stakeholders who represent payers, policy makers; and individuals that will 
represent the American Academy of Family Physicians, the American Academy of Allergy, Asthma 
and Immunology and the American College of Asthma, Allergy, and Immunology. The American 
Academy of Pediatrics, the National Medical Association and the National Hispanic Medical 
Association will only appoint representatives after a project is funded due to high request volume. 
Our scientific advisors are experienced asthma researchers. Once these groups have met with the 
central research staff, stakeholders will advise if additional groups or individuals from a specific 
group should be added to support project activities.
Our stakeholders will be integral members of the study team with decision making authority. 
Specific changes will continue to be made to the iTREAT-PC study based on input, meeting 
outcomes, and comments from our stakeholders. The eight stakeholder groups will be divided into 
six work groups (WGs): 1) those directly impacted by asthma or aligned with individuals impacted by 
asthma (WG 1: patients and caregivers); 2) decision-makers related to informing and advocating for 
therapeutic options (WG 2: advocacy, policy, and payers); 3) organizations that notify medical 
professionals about cutting-edge research advancements (WG 3: professional societies); 4) 
individuals who would deliver demonstrated options (WG 4: clinicians; clinical administrators); 5) 
individuals who oversee and guide the research process (WG 5: asthma experts and researchers); 
and 6) individuals implementing research activities within their practices (WG 6: site research 
teams). These groupings were vetted and recommended by the stakeholders themselves. We will 
have separate meetings with the six WGs. A few of our stakeholders hold multiple roles (e.g., 
individual with asthma who is caregiver of a child with asthma, with scientific knowledge). These 
individuals possess unique perspectives and can share experiential knowledge from multiple 
viewpoints. All individuals will have a primary stakeholder role and may be asked to participate in a 
secondary role based on their experience. All WGs will have one or two members on the Ececutive 
Committee (a WG can chose to have one or two). These individuals will present to the Executive 
Committee at each meeting to facilitate communication. During WG meetings information that is 
 
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relevant from one WG will be presented to another group.  WGs will also combine for meetings as 
appropriate or requested by the WGs. Differing recommendations across WGs wil be presented to 
the Executive Com. (and the Scientific Com if the recommendation impacts the science of the study) 
for consideration. Final decisions will take into consideration the Scientific Com if required and 
adjudicated by the Executive Com which has representation from all WGs.
Engagement Approach: 
The primary research question has been affirmed as patient-centered and crucially 
important by key stakeholder partners from all categories: asthma patient stakeholders, asthma 
researchers, policy stakeholders (a former state Medicaid director and a former PBM manager), and 
clinicians (primary care, allergy and pulmonology). Each stakeholder group will have two 
representatives on the Executive Committee (EC). The full stakeholder group will meet at least 
annually; subgroups will meet regularly based on project and stakeholder input/needs. Stakeholders 
will meet frequently during the feasibility phase and first year of the full project (see Table 7). All 
final study directions and major decisions will be reviewed and approved by the EC; thus, all 
stakeholder groups will have decision making authority. At a minimum, all patient facing information 
will be approved by the full patient stakeholder group. All implementation activities will be reviewed 
by the clinician group, and all research decisions will be reviewed by the Scientific group. All 
outcome assessments will be reviewed by all groups with attention from the patient/caregiver, 
advocacy/policy/payer, professional society, and scientific groups. Using this engagement approach, 
our PREPARE stakeholders have consistently indicated they feel valued, involved, and listened to. 
(See “Other Stakeholders” section below for information about expanding or changing stakeholder 
group composition.)
Convening Stakeholders: See Table 7 for stakeholder meeting timing and frequency in both 
phases of the study. Dr. Calhoun and Ms. Brooks-Greisen will coordinate all stakeholder activities, 
with support from Drs. Filippi and Hester. In addition to regular meetings of the EC, Operations 
Committee, and stakeholder sub-groups, the full stakeholder panel and study team will meet once a 
year in person, virtually or in a hybrid format for 1 ½ days. Goals for the annual full group gathering 
will be to work collaboratively on major ideas, share ideas, and encourage co-learning. All meetings 
will be conducted utilizing partnership principles guided by an honest, transparent and trustworthy 
process.
Table 7 - Schedule of in-person meetings and conference calls for various stakeholder groups
Phase 1
Phase 2
Work Groups & Committees
Startup (8 mos)
Vanguard (6mos)
Finalize (4 mos)
Startup
(6 mos)
Enrollment/ 
Follow-up
(45 mos)
Data Analysis/ 
Dissemination
(9 mos)
In-Person Convenings
Full Stakeholder and Study Team
Once in first year
Once at initiation
Annually
Once for wrap up 
Virtual Convenings
1: Patients & Caregivers
Up to bi-monthly
Up to bi-monthly
Monthly
Monthly
2: Advocacy, Policy, & Payers
Quarterly
Quarterly
Quarterly
Monthly
3. Professional Societies
Quarterly
Quarterly
Quarterly
Monthly
4: Clinicians
5: Scientific Advisors
Up to monthly
Up to monthly
Quarterly
Quarterly
6: Site Research Teams
Up to monthly
Up to monthly
Up to monthly
Up to monthly
7: Operations Committee 
Bi-weekly
Bi-weekly
Bi-weekly
Bi-weekly
 
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8: Executive Committee
Monthly
Monthly
Monthly
Monthly
Table 8 - Key Committed Stakeholders
Patients & Caregivers
(primary, secondary role*)
Advocacy, Policy& 
Payers (relevant 
experience)
Professional Societies**
Scientific Advisors
Alex D. Colon Moya 
(patient)
Aracelis Diaz (patient)
Allyson Jasper (caregiver)
Margie Lorenzi (patient)
Suzanne Madison (patient)
Kathy Monteiro Williams 
(patient)
Wilfredo Morales-Cosme 
(patient)
Addie Perez (patient)
Janet Robles (patient)
Marsha Santiago (patient) 
Nikki Schultek (patient, 
caregiver)
Opal Thompson (patient)
Mary White (patient)
Gretchen Hammer 
(past Medicaid 
Director)
Amy Howell-Nguyen, 
MD (OptumCare)
Hemal Shah (Value 
Matters, LLC) 
Jack Westfall, MD 
(Robert Graham 
Policy Center)
Barbara Kaplan 
(American Lung 
Association)
Sanaz Eftekhari 
(Asthma and Allergy 
Foundation of 
America)
Michael Blaiss, MD 
(President, ACAAI)
Kurt Elward, MD (AAFP; 
NAEPPCC , EWG4) (Dr. 
Elward has joined the 
DSMB) 
Giselle Mosnaim, MD 
(President, AAAAI)
AAP, NMA, NHMA will 
only offer stakeholders 
after funding due to 
request overload. 
PREPARE had 
stakeholder from NMA 
and NHMA. 
Tyra Bryant-Stephens, MD 
(pediatrician, EWG-4)
Tom Casale, MD (Allergist)
Juan Carlos Cardet, MD 
(Allergist)
Anne Fuhlbrigge, MD 
(Pulmonology)
Neil Skolnik, MD (Family 
Medicine)
Jacques Turgeon, MD (PharmD)
Juan Wisnivesky, MD (Internal 
Med., NAEPPCC) 
Barbara Yawn, MD (Family 
Medicine, EWG3)
*Secondary role if applicable. Stakeholders may be consulted to provide perspective for secondary role but will primarily 
represent primary roles.
** AAAAI = American Academy of Allergy, Asthma & Immunology; ACAAI = American College of Allergy Asthma and 
Immunology; AAFP = American Academy of Family Physicians; EWG4 = Expert Work Group 4; EWG3 = Expert Work 
Group 3; NAEPPCC = National Asthma Education and Prevention Program Coordinating Committee
Other Stakeholders
In the feasibility phase and throughout the implementation of the entire project, other 
stakeholder groups may be deemed important. Should the need for inclusion of new or different 
stakeholder representation emerge, we will identify, engage, and integrate new stakeholders as 
appropriate. Through the feasibility phase, the patient and other stakeholder partners will have 
direct roles and influence in re-drafting the study materials, videos, and implementation of the 
project. The initial draft protocol will be presented to the EC for approval to begin the Vanguard. 
During the Vanguard implementation and interpretation, protocol adjustments may be made 
keeping the EC informed, and a final protocol will be developed for EC approval. After the Vanguard 
process, conference and webinar-supported calls with our stakeholders will continue to assure 
continued engagement with all stakeholders on schedules that change with the phase of the trial 
(Table 7). At least one member of the operations committee will be assigned to one stakeholder 
partner WG ensuring continuity in communication. 
19)SHARING OF RESULTS WITH SUBJECTS
The iTREAT-PC study team is committed to returning results to the individuals who take part 
in this project. We have experience sharing information with participants, even prior to the end of 
the study, even within the confines of a randomized trial. We have done this in our PREPARE study 
when we needed to communicate with patients about COVID-19. We also shared information about 
how to establish ongoing treatment as people exited the study. 
For iTREAT-PC, Drs. Pace and Mauger, working in particular with Drs. Callen and Filippi, will 
ensure that processes are in place to achieve and maintain timely and accessible information in a 
manner that is understandable and usable. We will develop a lay summary of the findings through a 
collaborative process with all stakeholder groups, particularly the patient and parent/caregiver 
 
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stakeholders. The goal will be to create a comprehensive summary that is relevant and 
understandable to a wide array of readers. We expect that the summary will include graphical 
displays of information as well as textual information. We will use our technical communication 
experts to draft initial versions of the summary, which will then be iteratively revised based on 
stakeholder feedback.
To distribute the final summary, we will post them to the DARTNet, AAFP and partner 
organizations’ websites, and let participants, stakeholders and AAFP members know when and 
where the results are available. To reach individual participants, we will rely on a key aspect of the 
study design:  the regular contact the research team has with enrolled participants due to the need 
to obtain patient-reported outcomes. The patient-reported outcomes will be solicited via phone, 
email, or text through REDCap.  Because we require this ongoing interaction with participants during 
the trial, we can harness the same communication technologies to distribute information about the 
findings of the study, both at the conclusion and throughout the study period. We will ensure that 
this aspect is included in consent forms so that we have full ability to communicate with patients 
regarding aggregate study results after the end of the trial. We will also ensure that this 
communication is in accordance with all applicable laws.
Our first approach to returning the summary of the study results will be an automated 
communication to participants that includes an explanation of the purpose of the communication, 
along with a URL to an online presentation of the study findings summary. Second, for patients who 
do not access the URL or who request a hard copy, we will mail a summary to ensure thorough 
outreach to our participants. Combined, these approaches will provide wide access to research 
findings, both to study participants as well as the broader public.
We also have the capability of creating personalized feedback reports at the end of the study 
that summarize individual information over the 16+ months in the trial. We will work with our 
patient partners and determine if they believe this is an important value add that we should 
implement.
20)PRIOR APPROVALS
Local IRBs will be asked to sign a reliance agreement with BRANY. The consent and assent forms will 
be created with editable sections. Each local IRB will be asked to review the consent and make 
locally REQUIRED edits within these sections. Once these edits have been made the consent/assent 
forms will be returned to BRANY for final approval. 
21)COMPENSATION FOR RESEARCH-RELATED INJURY
We believe the research will be considered minimal risk as all interventions are currently available 
for the treatment of asthma. Each site will review, edit if necessary and approve the research related 
injury clause in the consent form. This clause will indicate that the site will provide care for a 
research related injury, or refer the individual to a location that can provide care. Such care will be 
billed to the individual’s insurance carrier. 
There is no relevant contract language related to compensation for research-related injuries. 
22)ECONOMIC BURDEN TO SUBJECTS
Participants will be responsible for paying for any co-pays required for study prescribed medications, 
should they elect to take the medication. PCORI specifically prohibits the inclusion of these costs as 
part of study costs. Medication selection for the different approaches to ICS rescue therapy may be 
made on the basis of cost to the participant. Virtually all insurance plans include a stand-alone ICS as 
a Tier 1 medication with either no co-pay or very low co-pays. Azithromycin is covered as a Tier 1 
 
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medication by virtually all insurance carriers. For individuals without any insurance coverage 
azithromycin as the full dose of 500mg three times a week is available for a little as $12/month. The 
250mg dose can be found for under $6/month. Inhaled corticosteroids are more expensive with 
Pulmicort one of the lowest cost ICS MDIs. Pulmicort costs approximately $85 per MDI. Given that 
this medication is used PRN it is not possible to provide exact monthly costs. The majority of 
participants (based on our previous study results) can be expected to use 2 to 4 MDI canisters over 
the life of the study. 
23)CONSENT PROCESS AND DOCUMENTATION
Routine Consent
Study coordinators at each research site will perform the consents. These are research 
trained individuals with human subjects training that the central team will work with to be sure they 
understand the consent, the study and their role. We expect many will have master’s degrees and 
virtually all the rest will have bachelor’s degrees. We will train them. Have them watch a mock 
consent by one of our central team and then ask them to perform a teach back where they walk 
through the process and then consent one of the central team that will have sets of questions 
concerning the study to be asked of the site personnel. We have used this approach on numerous 
multi-site studies with a high level of success. 
The consent process will be either in person or done remotely by video conferencing or via 
phone. We expect the eligibility and consent process to take 30 – 40 minutes. Individuals will have 
ample time to ask questions be sure they are fully informed. We will generally provide a copy of the 
consent document prior to the interaction electronically. If someone wishes a hard copy it will be 
mailed to them. After consent is complete the individual will receive a signed electronic or hard copy 
depending on their wishes. 
While many studies expect a clinician to perform the consent, for low-risk studies of this 
nature we find that approach is more coercive than have an individual the patient does not know 
well or at all conduct the consent. We will emphasize to study coordinators that it is essential the 
people are free to decide to participate or not and free to drop out at any time. In a study where 
each site generally has hundreds if not thousands to eligible individuals the need to obtain consent 
from any one individual should be lessened. Given that we are not providing free medication access 
or a large sum of money for participation we believe the study protocol has focused on avoiding 
coercion and we will strive to impart that approach to all consenting individuals. 
The consent form has “check questions” built into it to try and capture misunderstandings of 
key points. Consent check questions are provided in Appendix 8. While these questions are not 
designed to stop the consent process but to provide points where further clarification can be 
provided by the study coordinators. The consent itself is written in simple terms and will be 
extensively reviewed by our patient advisors to be sure it is understandable. Study coordinators will 
be instructed to read the consent aloud if any appears to be having issue interpreting the document. 
We do ask health literacy questions as the first part of our enrollment process to help guide the 
study coordinator’s work with patients, but that is by necessity after the consent process. If an 
individual is at risk for health literacy issues once those questions are asked we will have the study 
coordinator’s check along the way with people about their understanding of their activities related 
to the study. 
The study will involve standard, formal consent processes for both components of the feasibility 
phase. For the full study feasibility component consent/assent will be primarily by telehealth 
approaches including telehealth systems available at the sites, commercial video conferencing 
systems or plain phone conversations. These same approaches will be used for the Asthma Symptom 
Monitoring component of the feasibility phase of the project. Either consent/assent process could 
 
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be conducted at a central research site for the clinical site if the potential participant is willing to 
travel to that site or within the primary care office where the participant receives usual care. If at 
home or office, the participant will have control of and decision-making authority for continuing, 
waiting, or changing to a more private location if desired. If in a central research site then consent 
will occur in a private space that is typically reserved specifically for consent and/or interview like 
activities. If in a clinical site then the consent will take place in a private area, such as an exam room, 
within the clinical space. It is not expected that many consents will be done in clinical settings. 
Consents will be available in REDCap in both English and Spanish. The participant will “sign” the 
consent using their finger or a mouse within the REDCap system. This will be the same approach for 
the assent process. Should consent be obtained over the phone then the consent will be obtained 
after two paper copies of the consent/assent has been sent to the potential participant. Consent and 
assent will then be recorded over the phone and the participant and adolescent if assent is required 
will be asked to physically sign one copy of the consent and assent and mail them back in a provided, 
postage paid envelope. These “hard copies” will be scanned and uploaded to REDCap. The recording 
will also be uploaded to REDCap. 
Non-English Consents
Study staff obtaining consent in Spanish will be bilingual. If a site needs support for the consent 
process in Spanish the site will, through a locally used interpreter process, ask the potential 
participant if a member of the central research staff can join the consent meeting. If the person 
agrees then a bilingual member of the central research staff will join the meeting to serve as an 
interpreter who understands the study and has CITI training. This will be done in conjunction with 
the local research staff that will be the “responsible party” for obtaining consent. 
Should the individual indicate they are not comfortable with a central research staff joining the 
meeting then the meeting can be rescheduled for a time when a local bilingual study staff member is 
available, the participant can agree to a local translator to translation service or the person will not 
be consented. At this time the study does not intend to support other languages than English and 
Spanish.
Assent Processes
The study plans to enroll individuals ages 12 to 17. These individuals will require the consent of one 
parent or guardian as well providing their own assent. The process is expected to occur in sequence 
using the same approaches as described above.
Cognitively Impaired or Otherwise Unable to Consent
Individuals that are not able to provide consent or assent in English or Spanish will not be eligible for 
the study. Primarily this is due to the fact the study outcomes are entirely dependent on 
participants’ ability to answer regularly administered surveys.
Other items
No waiver of consent or waiver of storage of consent is requested. The trial is therapeutic in nature 
and no devices are being used. 
24)DRUGS OR DEVICES
While the project does involve drugs, these drugs will be dispensed by a pharmacy of the 
participant’s choice and only be handled in accordance with typical clinical usage. Neither the central 
research team nor any of the sites will handle, store or dispense any medications. 
 
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References
1.
Centers for Disease Control and Prevention. Asthma in the US. Updated May 3, 2011. 
Accessed October 2, 2021. https://www.cdc.gov/vitalsigns/asthma/index.html
2.
Zahran HS, Bailey CM, Damon SA, Garbe PL, Breysse PN. Vital Signs: Asthma in Children - 
United States, 2001-2016. MMWR Morb Mortal Wkly Rep. Feb 9 2018;67(5):149-155. 
doi:10.15585/mmwr.mm6705e1
3.
Healthy Schools Campaign. Five Health-Related Causes of Chronic Absenteeism. Updated 
August 29, 2016. Accessed October 2, 2021. https://healthyschoolscampaign.org/blog/five-health-
related-causes-of-chronic-absenteeism/
4.
McGregor MC, Krings JG, Nair P, Castro M. Role of Biologics in Asthma. Am J Respir Crit Care 
Med. Feb 15 2019;199(4):433-445. doi:10.1164/rccm.201810-1944CI
5.
Institute for Clinical and Economic Review. Biologic Therapies for Treatment of Asthma 
Associated with Type 2 Inflammation: Effectiveness, Value, and Value-Based Price Benchmarks. Final 
Evidence Report. Updated December 20, 2018. Accessed October 2, 2021. 
https://icer.org/assessment/asthma-2018/
6.
Peters M. Single-inhaler combination therapy for maintenance and relief of asthma: a new 
strategy in disease management. Drugs. 2009;69(2):137-50. doi:10.2165/00003495-200969020-
00001
7.
O'Byrne PM, Bisgaard H, Godard PP, et al. Budesonide/formoterol combination therapy as 
both maintenance and reliever medication in asthma. Am J Respir Crit Care Med. Jan 15 
2005;171(2):129-36. doi:10.1164/rccm.200407-884OC
8.
Rabe KF, Pizzichini E, Stallberg B, et al. Budesonide/formoterol in a single inhaler for 
maintenance and relief in mild-to-moderate asthma: a randomized, double-blind trial. Chest. Feb 
2006;129(2):246-56. doi:10.1378/chest.129.2.246
9.
Scicchitano R, Aalbers R, Ukena D, et al. Efficacy and safety of budesonide/formoterol single 
inhaler therapy versus a higher dose of budesonide in moderate to severe asthma. Curr Med Res 
Opin. Sep 2004;20(9):1403-18. doi:10.1185/030079904X2051
10.
Jenkins CR, Eriksson G, Bateman ED, et al. Efficacy of budesonide/formoterol maintenance 
and reliever therapy compared with higher-dose budesonide as step-up from low-dose inhaled 
corticosteroid treatment. BMC Pulm Med. Apr 20 2017;17(1):65. doi:10.1186/s12890-017-0401-y
11.
Bisgaard H, Le Roux P, Bjamer D, Dymek A, Vermeulen JH, Hultquist C. 
Budesonide/formoterol maintenance plus reliever therapy: a new strategy in pediatric asthma. 
Chest. Dec 2006;130(6):1733-43. doi:10.1378/chest.130.6.1733
12.
Global Initiative for Asthma. Global strategy for asthma management and prevention 2021 
report. Accessed October 2, 2021. https://ginasthma.org/gina-reports/
13.
Global Initiative for Asthma. Difficult-to-treat and severe asthma in adolescent and adult 
patients. Diagnosis and management. Accessed October 2, 2021. https://ginasthma.org/gina-
reports/gina-2020-full-report_-final-_wms
14.
National Asthma Education and Prevention Program Coordinating Committee Expert Panel 
Working Group. 2020 Focused Update to the Asthma Management Guidelines Summary from: A 
Report from the National Asthma Education and Prevention Program Coordinating Committee 
Expert Panel Working Group. Accessed October 1, 2021. https://www.nhlbi.nih.gov/health-
topics/all-publications-and-resources/2020-focused-updates-asthma-management-guidelines
15.
Centers for Disease Control and Prevention. Asthma Attacks in the Past 12 Months by Year. 
Accessed October 2, 2021. https://www.cdc.gov/asthma/data-visualizations/health-
outcomes.htm#anchor_1569609411376
16.
Centers for Disease Control and Prevention. Asthma Attacks among People with Current 
Asthma, 2014–2017. Accessed October 2, 2021. https://www.cdc.gov/asthma/asthma_stats/attacks-
current-asthma.htm
 
IRB APPROVED
08/06/2024


PROTOCOL NUMBER: 23-10-462
VERSION DATE: 07_23_2024
Page 47 of 113
17.
Centers for Disease Control and Prevention. Asthma as the Underlying Cause of Death. 
Updated April 24, 2018. Accessed January 6, 2021. 
https://www.cdc.gov/asthma/asthma_stats/asthma_underlying_death.html
18.
Moorman JE, Akinbami LJ, Bailey CM, et al. National surveillance of asthma: United States, 
2001-2010. Vital Health Stat 3. Nov 2012;(35):1-58. 
19.
Szentpetery SE, Forno E, Canino G, Celedón JC. Asthma in Puerto Ricans: Lessons from a 
high-risk population. J Allergy Clin Immunol. Dec 2016;138(6):1556-1558. 
doi:10.1016/j.jaci.2016.08.047
20.
Bartolomei-Díaz JA, Amill-Rosario A, Claudio L, Hernández W. Asthma mortality in Puerto 
Rico: 1980-2007. J Asthma. Mar 2011;48(2):202-9. doi:10.3109/02770903.2010.528498
21.
Calmes D, Huynen P, Paulus V, et al. Chronic infection with Chlamydia pneumoniae in 
asthma: a type-2 low infection related phenotype. Respiratory Research. 2021/02/26 2021;22(1):72. 
doi:10.1186/s12931-021-01635-w
22.
Ray A, Camiolo M, Fitzpatrick A, Gauthier M, Wenzel SE. Are We Meeting the Promise of 
Endotypes and Precision Medicine in Asthma? Physiological Reviews. 2020/07/01 2020;100(3):983-
1017. doi:10.1152/physrev.00023.2019
23.
Wenzel SE. Severe Adult Asthmas: Integrating Clinical Features, Biology, and Therapeutics to 
Improve Outcomes. Am J Respir Crit Care Med. Apr 1 2021;203(7):809-821. 
doi:10.1164/rccm.202009-3631CI
24.
Expert Panel Working Group of the National Heart Lung and Blood Institute, National 
Asthma Education and Prevention Program Coordinating Committee (NAEPPCC), Cloutier MM, et al. 
2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma 
Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy 
Clin Immunol. Dec 2020;146(6):1217-1270. doi:10.1016/j.jaci.2020.10.003
25.
Israel E, Banerjee TR, Fitzmaurice GM, Kotlov TV, LaHive K, LeBoff MS. Effects of inhaled 
glucocorticoids on bone density in premenopausal women. N Engl J Med. Sep 27 2001;345(13):941-
7. doi:10.1056/NEJMoa002304
26.
Peters SP. Safety of inhaled corticosteroids in the treatment of persistent asthma. J Natl Med 
Assoc. Jun 2006;98(6):851-61. 
27.
Zhang L, Prietsch SO, Mendes AP, et al. Inhaled corticosteroids increase the risk of 
oropharyngeal colonization by Streptococcus pneumoniae in children with asthma. Respirology. Feb 
2013;18(2):272-7. doi:10.1111/j.1440-1843.2012.02280.x
28.
Zhang L, Prietsch SO, Ducharme FM. Inhaled corticosteroids in children with persistent 
asthma: effects on growth. Cochrane Database Syst Rev. Jul 17 2014;(7):CD009471. 
doi:10.1002/14651858.CD009471.pub2
29.
Zollner EW, Lombard CJ, Galal U, Hough FS, Irusen EM, Weinberg E. Hypothalamic-pituitary-
adrenal axis suppression in asthmatic school children. Pediatrics. Dec 2012;130(6):e1512-9. 
doi:10.1542/peds.2012-1147
30.
Htun ZM, Aldawudi I, Katwal PC, Jirjees S, Khan S. Inhaled Corticosteroids as an Associated 
Risk Factor for Asthmatic Pneumonia: A Literature Review. Cureus. Jun 20 2020;12(6):e8717. 
doi:10.7759/cureus.8717
31.
Pandya D, Puttanna A, Balagopal V. Systemic effects of inhaled corticosteroids: an overview. 
Open Respir Med J. 2014;8:59-65. doi:10.2174/1874306401408010059
32.
Papi A, Canonica GW, Maestrelli P, et al. Rescue use of beclomethasone and albuterol in a 
single inhaler for mild asthma. N Engl J Med. May 17 2007;356(20):2040-52. 
doi:10.1056/NEJMoa063861
33.
Papi A, Caramori G, Adcock IM, Barnes PJ. Rescue treatment in asthma. More than as-
needed bronchodilation. Chest. Jun 2009;135(6):1628-1633. doi:10.1378/chest.08-2536
34.
1900-2012: History of steroid use for asthma x. Updated January 9, 2012. Accessed January 
6, 2021. https://hardluckasthma.blogspot.com/2011/05/history-of-antiinflammatories-for-use.html
 
IRB APPROVED
08/06/2024


PROTOCOL NUMBER: 23-10-462
VERSION DATE: 07_23_2024
Page 48 of 113
35.
Israel E, Cardet JC, Carroll JK, et al. Reliever-Triggered Inhaled Glucocorticoid in Black and 
Latinx Adults with Asthma. N Engl J Med. Feb 26 2022;doi:10.1056/NEJMoa2118813
36.
Papi A, Corradi M, Pigeon-Francisco C, et al. Beclometasone-formoterol as maintenance and 
reliever treatment in patients with asthma: a double-blind, randomised controlled trial. Lancet 
Respir Med. Mar 2013;1(1):23-31. doi:10.1016/S2213-2600(13)70012-2
37.
Kew KM, Karner C, Mindus SM, Ferrara G. Combination formoterol and budesonide as 
maintenance and reliever therapy versus combination inhaler maintenance for chronic asthma in 
adults and children. Cochrane Database Syst Rev. Dec 16 2013;(12):CD009019. 
doi:10.1002/14651858.CD009019.pub2
38.
Pauwels RA, Lofdahl CG, Postma DS, et al. Effect of inhaled formoterol and budesonide on 
exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International 
Study Group. N Engl J Med. Nov 13 1997;337(20):1405-11. doi:10.1056/NEJM199711133372001
39.
Calhoun WJ, Ameredes BT, King TS, et al. Comparison of physician-, biomarker-, and 
symptom-based strategies for adjustment of inhaled corticosteroid therapy in adults with asthma: 
the BASALT randomized controlled trial. JAMA. Sep 12 2012;308(10):987-97. 
doi:10.1001/2012.jama.10893
40.
Israel E, Cardet JC, Carroll JK, et al. A randomized, open-label, pragmatic study to assess 
reliever-triggered inhaled corticosteroid in African American/Black and Hispanic/Latinx adults with 
asthma: design and methods of the PREPARE trial. Contemporary Clinical Trials. 2021;101, 
106246doi:10.1016/j.cct.2020.106246
41.
AstraZeneca Pharmaceuticals LP. SYMBICORT Prescribing Information. Accessed January 6, 
2021. https://www.azpicentral.com/symbicort/symbicort.pdf 
42.
Shavit O, Swern A, Dong Q, Newcomb K, Sazonov Kocevar V, Taylor SD. Impact of smoking on 
asthma symptoms, healthcare resource use, and quality of life outcomes in adults with persistent 
asthma. Qual Life Res. Dec 2007;16(10):1555-65. doi:10.1007/s11136-007-9267-4
43.
Wenzel SE, Schwartz LB, Langmack EL, et al. Evidence that severe asthma can be divided 
pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. 
Am J Respir Crit Care Med. Sep 1999;160(3):1001-8. doi:10.1164/ajrccm.160.3.9812110
44.
Stapleton M, Howard-Thompson A, George C, Hoover RM, Self TH. Smoking and asthma. J 
Am Board Fam Med. May-Jun 2011;24(3):313-22. doi:10.3122/jabfm.2011.03.100180
45.
Polosa R, Thomson NC. Smoking and asthma: dangerous liaisons. Eur Respir J. Mar 
2013;41(3):716-26. doi:10.1183/09031936.00073312
46.
Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and 
quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, 
placebo-controlled trial. Lancet. Aug 12 2017;390(10095):659-668. doi:10.1016/S0140-
6736(17)31281-3
47.
Hiles SA, McDonald VM, Guilhermino M, Brusselle GG, Gibson PG. Does maintenance 
azithromycin reduce asthma exacerbations? An individual participant data meta-analysis. Eur Respir 
J. Sep 12 2019:DOI: 10.1183/13993003.01381-2019. doi:10.1183/13993003.01381-2019
48.
Hahn DL, Grasmick M, Hetzel S, Yale S. Azithromycin for bronchial asthma in adults: an 
effectiveness trial. J Am Board Fam Med. Jul-Aug 2012;25(4):442-59. 
doi:10.3122/jabfm.2012.04.110309
25/4/442 [pii]
49.
Wagshul FA, Brown DT, Schultek NM, Hahn DL. Outcomes of Antibiotics in Adults with 
"Difficult to Treat" Asthma or the Overlap Syndrome. J Asthma Allergy. 2021;14:703-712. 
doi:10.2147/JAA.S313480
50.
Steel HC, Theron AJ, Cockeran R, Anderson R, Feldman C. Pathogen- and host-directed anti-
inflammatory activities of macrolide antibiotics. Mediators Inflamm. 2012;2012:584262. 
doi:10.1155/2012/584262
 
IRB APPROVED
08/06/2024


PROTOCOL NUMBER: 23-10-462
VERSION DATE: 07_23_2024
Page 49 of 113
51.
Kraft M, Cassell GH, Henson JE, et al. Detection of Mycoplasma pneumoniae in the airways 
of adults with chronic asthma. Am J Respir Crit Care Med. Sep 1998;158(3):998-1001. 
doi:10.1164/ajrccm.158.3.9711092
52.
Wood PR, Hill VL, Burks ML, et al. Mycoplasma pneumoniae in children with acute and 
refractory asthma. Ann Allergy Asthma Immunol. May 2013;110(5):328-334 e1. 
doi:10.1016/j.anai.2013.01.022
53.
Essilfie AT, Horvat JC, Kim RY, et al. Macrolide therapy suppresses key features of 
experimental steroid-sensitive and steroid-insensitive asthma. Thorax. May 2015;70(5):458-67. 
doi:10.1136/thoraxjnl-2014-206067
54.
Hansbro PM, Starkey MR, Mattes J, Horvat JC. Pulmonary immunity during respiratory 
infections in early life and the development of severe asthma. Ann Am Thorac Soc. Dec 2014;11 
Suppl 5:S297-302. doi:10.1513/AnnalsATS.201402-086AW
55.
Hahn DL. A Cure for Asthma? What Your Doctor Isn't Telling You, and Why. Peoples 
Pharmacy Press; 2013.
56.
Hahn DL. Chlamydia pneumoniae and chronic asthma: Updated systematic review and meta-
analysis of population attributable risk. PLoS One. 2021;16(4):e0250034. 
doi:10.1371/journal.pone.0250034
57.
Undela K, Goldsmith L, Kew KM, Ferrara G. Macrolides versus placebo for chronic asthma. 
Cochrane Database Syst Rev. Nov 22 2021;11:CD002997. doi:10.1002/14651858.CD002997.pub5
58.
Hahn DL, Plane MB, Mahdi OS, Byrne GI. Secondary outcomes of a pilot randomized trial of 
azithromycin treatment for asthma. PLoS Clin Trials. 2006;1(2):e11 DOI: 
10.1371/journal.pctr0010011. 
59.
Brusselle GG, Vanderstichele C, Jordens P, et al. Azithromycin for prevention of 
exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-
controlled trial. Thorax. Apr 2013;68(4):322-9. doi:10.1136/thoraxjnl-2012-202698
60.
GINA. Difficult-to-Treat and Severe Asthma in Adolescent and Adult Patients: Diagnosis and 
Management. 2019;https://ginasthma.org/severeasthma/ accessed August 1, 2021
61.
Holguin F, Cardet JC, Chung KF, et al. Management of severe asthma: a European Respiratory 
Society/American Thoracic Society guideline. Eur Respir J. Jan 
2020;55(1)doi:10.1183/13993003.00588-2019
62.
Smith D, Du Rand IA, Addy C, et al. British Thoracic Society guideline for the use of long-term 
macrolides in adults with respiratory disease. BMJ Open Respir Res. Apr 
2020;7(1)doi:10.1136/bmjresp-2019-000489
63.
Webley WC, Hahn DL. Infection-mediated asthma: Etiology, mechanisms and treatment 
options, with focus on Chlamydia pneumoniae and macrolides. Respiratory Research. 2017;18(1)98. 
doi:10.1186/s12931-017-0584-z
64.
Crocker DD, Kinyota S, Dumitru GG, et al. Effectiveness of home-based, multi-trigger, 
multicomponent interventions with an environmental focus for reducing asthma morbidity: a 
community guide systematic review. Am J Prev Med. Aug 2011;41(2 Suppl 1):S5-32. 
doi:10.1016/j.amepre.2011.05.012
65.
Lang DM. New asthma guidelines emphasize control, regular monitoring. Cleveland Clinic 
journal of medicine. 2008;75(9):641-653. 
66.
van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological response 
and all-cause mortality among patients with chronic hepatitis c and advanced hepatic fibrosis. JAMA. 
2012;308(24):2584-2593. doi:10.1001/jama.2012.144878
67.
Shingo S, Zhang J, Reiss T. Correlation of airway obstruction and patient-reported endpoints 
in clinical studies. European Respiratory Journal. 2001;17(2):220-224. 
68.
Teeter JG, Bleecker ER. Relationship between airway obstruction and respiratory symptoms 
in adult asthmatics. CHEST Journal. 1998;113(2):272-277. 
69.
Braido F. Failure in asthma control: reasons and consequences. Scientifica. 2013;2013
 
IRB APPROVED
08/06/2024


PROTOCOL NUMBER: 23-10-462
VERSION DATE: 07_23_2024
Page 50 of 113
70.
Yawn BP, Bertram S, Wollan P. Introduction of Asthma APGAR tools improve asthma 
management in primary care practices. J Asthma Allergy. Aug 31 2008;1:1-10. doi:10.2147/jaa.s3595
71.
Marcano Belisario JS, Huckvale K, Greenfield G, Car J, Gunn LH. Smartphone and tablet self 
management apps for asthma. Cochrane Database Syst Rev. Nov 27 2013;(11):CD010013. 
doi:10.1002/14651858.CD010013.pub2
72.
Rasmussen LM, Phanareth K, Nolte H, Backer V. Internet-based monitoring of asthma: a 
long-term, randomized clinical study of 300 asthmatic subjects. Journal of Allergy and Clinical 
Immunology. 2005;115(6):1137-1142. 
73.
Okelo SO, Butz AM, Sharma R, et al. Interventions to modify health care provider adherence 
to asthma guidelines: a systematic review. Pediatrics. 2013:peds. 2013-0779. 
74.
Wisnivesky JP, Lorenzo J, Lyn-Cook R, et al. Barriers to adherence to asthma management 
guidelines among inner-city primary care providers. Annals of Allergy, Asthma & Immunology. 
2008;101(3):264-270. 
75.
Whitehead L, Seaton P. The Effectiveness of Self-Management Mobile Phone and Tablet 
Apps in Long-term Condition Management: A Systematic Review. J Med Internet Res. May 16 
2016;18(5):e97. doi:10.2196/jmir.4883
76.
Rudin RS, Fanta CH, Predmore Z, et al. Core Components for a Clinically Integrated mHealth 
App for Asthma Symptom Monitoring. Appl Clin Inform. Oct 2017;8(4):1031-1043. doi:10.4338/aci-
2017-06-ra-0096
77.
Rudin RS, Fanta CH, Qureshi N, et al. A Clinically Integrated mHealth App and Practice Model 
for Collecting Patient-Reported Outcomes between Visits for Asthma Patients: Implementation and 
Feasibility. Appl Clin Inform. Oct 2019;10(5):783-793. doi:10.1055/s-0039-1697597
78.
Pew Research Center. Mobile Fact Sheet. Accessed December 17, 20214. 
https://www.pewresearch.org/internet/fact-sheet/mobile/
79.
!!! INVALID CITATION !!! 75;
80.
Lella A. U.S. Smartphone Penetration Surpassed 80 Percent in 2016. 2017. February 3, 2017. 
https://www.comscore.com/Insights/Blog/US-Smartphone-Penetration-Surpassed-80-Percent-in-
2016
81.
Graetz I, Huang J, Brand RJ, Hsu J, Yamin CK, Reed ME. Bridging the digital divide: mobile 
access to personal health records among patients with diabetes. Am J Manag Care. Jan 
2018;24(1):43-48. 
82.
Rudin RS, Perez S, Rodriguez JA, et al. User-centered design of a scalable, electronic health 
record-integrated remote symptom monitoring intervention for patients with asthma and providers 
in primary care. J Am Med Inform Assoc. Oct 12 2021;28(11):2433-2444. doi:10.1093/jamia/ocab157
83.
Fiks AG, DuRivage N, Mayne SL, et al. Adoption of a Portal for the Primary Care Management 
of Pediatric Asthma: A Mixed-Methods Implementation Study. J Med Internet Res. Jun 29 
2016;18(6):e172. doi:10.2196/jmir.5610
84.
Loskutova NY, Callen E, Pinckney RG, Staton EW, Pace WD. Feasibility, Implementation and 
Outcomes of Tablet-Based Two-Step Screening for Adult ADHD in Primary Care Practice. J Atten 
Disord. Apr 24 2019:1087054719841133. doi:10.1177/1087054719841133
85.
DeAlleaume L, Parnes B, Zittleman L, et al. Success in the Achieving CARdiovascular 
Excellence in Colorado (A CARE) Home Blood Pressure Monitoring Program: A Report from the 
Shared Networks of Colorado Ambulatory Practices and Partners (SNOCAP). The Journal of the 
American Board of Family Medicine. September 1, 2015 2015;28(5):548-555. 
doi:10.3122/jabfm.2015.05.150024
86.
Bousquet J, Boulet LP, Peters MJ, et al. Budesonide/formoterol for maintenance and relief in 
uncontrolled asthma vs. high-dose salmeterol/fluticasone. Respir Med. Dec 2007;101(12):2437-46. 
doi:10.1016/j.rmed.2007.07.014
87.
National Asthma Education and Prevention Program Coordinating Committee Expert Panel 
Working Group. 2020 Focused Updates to the Asthma Management Guidelines: A Report from the 
National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working 
 
IRB APPROVED
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Page 51 of 113
Group. National Heart, Lung and Blood Institute. Accessed January 8, 2021. 
https://www.nhlbi.nih.gov/health-topics/all-publications-and-resources/2020-focused-updates-
asthma-management-guidelines
88.
Global Initiative for Asthma (GINA). Science Committee. Updated August 2020. Accessed 
January 8, 2021. https://ginasthma.org/science-committee/
89.
Wagshul FA, Brown DT, Schultek NM, Hahn DL. Long-term (>1 year) Outcomes of Antibiotics 
to Treat Asthma. Chest. under review;
90.
Hahn DL. Treatment of Chlamydia pneumoniae infection in adult asthma: A before-after 
trial. Journal of Family Practice. 1995 1995;41(4):345-51. Not in File. 
91.
Schatz M, Zeiger RS, Drane A, et al. Reliability and predictive validity of the Asthma Control 
Test administered by telephone calls using speech recognition technology. J Allergy Clin Immunol. 
Feb 2007;119(2):336-43. doi:10.1016/j.jaci.2006.08.042
92.
Nathan RA, Sorkness CA, Kosinski M, et al. Development of the asthma control test: a survey 
for assessing asthma control. J Allergy Clin Immunol. Jan 2004;113(1):59-65. 
doi:10.1016/j.jaci.2003.09.008
93.
Erskine J, Lanigan A, Emsermann CB, Manning BK, Staton EW, Pace WD. Use of the 
Americans in Motion-Healthy Intervention (AIM-HI) to create a culture of fitness in family practice. J 
Am Board Fam Med. Sep-Oct 2012;25(5):694-700. doi:10.3122/jabfm.2012.05.110071
94.
Yawn BP, Wollan PC, Rank MA, Bertram SL, Juhn Y, Pace W. Use of Asthma APGAR Tools in 
Primary Care Practices: A Cluster-Randomized Controlled Trial. Ann Fam Med. Mar 2018;16(2):100-
110. doi:10.1370/afm.2179
95.
Carroll JK, Pulver G, Dickinson L, et al. Effect of 2 clinical decision support strategies on 
chronic kidney disease outcomes in primary care: A cluster randomized trial. JAMA Network Open. 
2018;1(6):e183377. doi:10.1001/jamanetworkopen.2018.3377
96.
Wechsler ME, Yawn BP, Fuhlbrigge AL, et al. Anticholinergic vs Long-Acting beta-Agonist in 
Combination With Inhaled Corticosteroids in Black Adults With Asthma: The BELT Randomized 
Clinical Trial. JAMA. Oct 27 2015;314(16):1720-30. doi:10.1001/jama.2015.13277
97.
Yawn BP, Dietrich AJ, Wollan P, et al. TRIPPD: A Practice-Based Network Effectiveness Study 
of Postpartum Depression Screening and Management. Ann Fam Med. Jul 2012;10(4):320-9. 
doi:10/4/320 [pii]
10.1370/afm.1418
98.
Juniper EF, Guyatt GH, Cox FM, Ferrie PJ, King DR. Development and validation of the Mini 
Asthma Quality of Life Questionnaire. Eur Respir J. Jul 1999;14(1):32-8. doi:10.1034/j.1399-
3003.1999.14a08.x
99.
Busse WW, Morgan WJ, Taggart V, Togias A. Asthma outcomes workshop: overview. J 
Allergy Clin Immunol. Mar 2012;129(3 Suppl):S1-8. doi:10.1016/j.jaci.2011.12.985
100.
Shen J, Johnston M, Hays RD. Asthma outcome measures. Expert Rev Pharmacoecon 
Outcomes Res. Aug 2011;11(4):447-53. doi:10.1586/erp.11.48
101.
Ko FWS, Hui DSC, Leung T-F, et al. Evaluation of the asthma control test: A reliable 
determinant of disease stability and a predictor of future exacerbations. Respirology. 
2012;17(2):370-378. doi:https://doi.org/10.1111/j.1440-1843.2011.02105.x
102.
Przybyszowski M, Polczyk R, Sliwka A, et al. Asthma Control Test (ACT) result as a predictor 
of asthma exacerbations. European Respiratory Journal. 2017;50(suppl 61):PA1124. 
doi:10.1183/1393003.congress-2017.PA1124
103.
National Asthma Education and Prevention Program Third Expert Panel on the Diagnosis and 
Management of Asthma, National Heart Lung and Blood Institute. Expert Panel Report 3: Guidelines 
for the Diagnosis and Management of Asthma. Clinical Practice Guidelines. Report No.: 07-4051. 
National Heart, Lung, and Blood Institute (US). Accessed January 6, 2021. 
https://www.ncbi.nlm.nih.gov/books/NBK7232/
 
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Page 52 of 113
104.
Chantadul V, Poachanukoon O. Mini version of the pediatric asthma quality of life 
questionnaire (MiniPAQLQ): validity among Thai asthmatic children. J Med Assoc Thai. Mar 2015;98 
Suppl 2:S92-100. 
105.
National Center for Health Statistics, Centers for Disease Control and Prevention. National 
Health Interview Survey (NHIS), 2003, 2008, 2013: question, “During the past 12 months, how many 
days of [daycare or preschool, school, school or work] did child miss because of his/her asthma? 
Updated March, 2016. Accessed October 2, 2021. https://www.cdc.gov/asthma/nhis/default.htm
106.
Juniper EF, Buist AS, Cox FM, Ferrie PJ, King DR. Validation of a standardized version of the 
Asthma Quality of Life Questionnaire. Chest. May 1999;115(5):1265-70. 
doi:10.1378/chest.115.5.1265
107.
Juniper EF, Gruffydd-Jones K, Ward S, Svensson K. Asthma Control Questionnaire in children: 
validation, measurement properties, interpretation. Eur Respir J. Dec 2010;36(6):1410-6. 
doi:10.1183/09031936.00117509
108.
Juniper EF, Guyatt GH, Feeny DH, Ferrie PJ, Griffith LE, Townsend M. Measuring quality of 
life in the parents of children with asthma. Qual Life Res. Feb 1996;5(1):27-34. 
doi:10.1007/BF00435966
109.
Juniper EF, Guyatt GH, Feeny DH, Ferrie PJ, Griffith LE, Townsend M. Measuring quality of 
life in children with asthma. Qual Life Res. Feb 1996;5(1):35-46. doi:10.1007/bf00435967
110.
Juniper EF, Guyatt GH, Willan A, Griffith LE. Determining a minimal important change in a 
disease-specific Quality of Life Questionnaire. J Clin Epidemiol. Jan 1994;47(1):81-7. 
doi:10.1016/0895-4356(94)90036-1
111.
Juniper EF, Svensson K, Mork AC, Stahl E. Measurement properties and interpretation of 
three shortened versions of the asthma control questionnaire. Respir Med. May 2005;99(5):553-8. 
doi:10.1016/j.rmed.2004.10.008
112.
Schatz M, Sorkness CA, Li JT, et al. Asthma Control Test: reliability, validity, and 
responsiveness in patients not previously followed by asthma specialists. J Allergy Clin Immunol. Mar 
2006;117(3):549-56. doi:10.1016/j.jaci.2006.01.011
113.
Schatz M, Mosen DM, Kosinski M, et al. Validity of the Asthma Control Test completed at 
home. Am J Manag Care. Dec 2007;13(12):661-7. 
114.
Cloutier MM, Schatz M, Castro M, et al. Asthma outcomes: composite scores of asthma 
control. J Allergy Clin Immunol. Mar 2012;129(3 Suppl):S24-33. doi:10.1016/j.jaci.2011.12.980
115.
Jaeschke R, Singer J, Guyatt GH. Measurement of health status. Ascertaining the minimal 
clinically important difference. Control Clin Trials. Dec 1989;10(4):407-15. doi:10.1016/0197-
2456(89)90005-6
116.
Schatz M, Kosinski M, Yarlas AS, Hanlon J, Watson ME, Jhingran P. The minimally important 
difference of the Asthma Control Test. J Allergy Clin Immunol. Oct 2009;124(4):719-23 e1. 
doi:10.1016/j.jaci.2009.06.053
117.
Leidy NK, Coughlin C. Psychometric performance of the Asthma Quality of Life Questionnaire 
in a US sample. Qual Life Res. Feb 1998;7(2):127-34. doi:10.1023/a:1008853325724
118.
Raat H, Bueving HJ, de Jongste JC, Grol MH, Juniper EF, van der Wouden JC. Responsiveness, 
longitudinal- and cross-sectional construct validity of the Pediatric Asthma Quality of Life 
Questionnaire (PAQLQ) in Dutch children with asthma. Qual Life Res. Feb 2005;14(1):265-72. 
119.
Wing A, Upton J, Svensson K, Weller P, Fletcher M, Walker S. The standardized and mini 
versions of the PAQLQ are valid, reliable, and responsive measurement tools. J Clin Epidemiol. Jun 
2012;65(6):643-50. doi:10.1016/j.jclinepi.2011.12.009
120.
Juniper EF, Guyatt GH, Ferrie PJ, Griffith LE. Measuring quality of life in asthma. Am Rev 
Respir Dis. Apr 1993;147(4):832-8. doi:10.1164/ajrccm/147.4.832
121.
Juniper EF, Johnston PR, Borkhoff CM, Guyatt GH, Boulet LP, Haukioja A. Quality of life in 
asthma clinical trials: comparison of salmeterol and salbutamol. Am J Respir Crit Care Med. Jan 
1995;151(1):66-70. doi:10.1164/ajrccm.151.1.7812574
 
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122.
Rutten-van Molken MP, Van Doorslaer EK, Jansen MC, Kerstjens HA, Rutten FF. Costs and 
effects of inhaled corticosteroids and bronchodilators in asthma and chronic obstructive pulmonary 
disease. Am J Respir Crit Care Med. Apr 1995;151(4):975-82. doi:10.1164/ajrccm.151.4.7697275
123.
Drazen JM, Israel E, Boushey HA, et al. Comparison of regularly scheduled with as-needed 
use of albuterol in mild asthma. Asthma Clinical Research Network. N Engl J Med. Sep 19 
1996;335(12):841-7. doi:10.1056/nejm199609193351202
124.
Israel E, Cohn J, Dube L, Drazen JM. Effect of treatment with zileuton, a 5-lipoxygenase 
inhibitor, in patients with asthma. A randomized controlled trial. Zileuton Clinical Trial Group. JAMA. 
Mar 27 1996;275(12):931-6. 
125.
Kemp JP, Cook DA, Incaudo GA, et al. Salmeterol improves quality of life in patients with 
asthma requiring inhaled corticosteroids. Salmeterol Quality of Life Study Group. J Allergy Clin 
Immunol. Feb 1998;101(2 Pt 1):188-95. doi:10.1016/s0091-6749(98)70383-5
126.
Turner MO, Taylor D, Bennett R, Fitzgerald JM. A randomized trial comparing peak 
expiratory flow and symptom self-management plans for patients with asthma attending a primary 
care clinic. Am J Respir Crit Care Med. Feb 1998;157(2):540-6. doi:10.1164/ajrccm.157.2.9703060
127.
Boulet LP, Boutin H, Cote J, Leblanc P, Laviolette M. Evaluation of an asthma self-
management education program. J Asthma. 1995;32(3):199-206. doi:10.3109/02770909509089508
 
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Appendix 1 – Drugs to be Avoided with Azithromycin
Drugs that may increase risk of prolonged QT and/or torsades de pointe (TdP) that are exclusion 
criteria for iTREAT-PC
Source: CredibleMeds: https://crediblemeds.org/, accessed 12/5/2022
KNOWN RISK= prolong QT and associated with TdP even when taken as recommended
Table 9 - Drugs in the US market with KNOWN RISK to prolong QT & induce torsades de pointes 
(TdP)
ANTIARRYTHMICS (n=9)
Ibutilide
Dronedarone
Sotalol
Quinidine
Procainamide
Flecainide
Disopyramide
Dofetilide
Amiodarone
ANTIBIOTICS (n=6)
Levofloxacin
Moxifloxacin
Clarithromycin
Erythromycin
Ciprofloxacin
ANTIPSYCHOTICS (n=5)
Haloperidol
Droperidol
Chlorpromazine
Thioridazine
Pimozide
ANTI-CANCER (n=4)
Arsenic trioxide
Vandetanib
Oxaliplatin
Mobocertinib
ANESTHETICS (n=3)
Sevoflurane
Cocaine
Propofol
ANTIDEPRESSANTS (n=2)
Escitalopram
Citalopram
ANTIANGINAL (n=2)
Bepridil
Papaverine HCl (Intracoronary)
ANTIFUNGALS (n=2)
Fluconazole
Pentamidine
ANTIMALARIAL (n=2)
Chloroquine
Hydroxychloroquine
PHOSHODIESTERASE 3 INHIBITOR 
(n=2)
Anagrelide
Cilostazol
CHOLINESTERASE INHIBITOR (n=1)
Donezepril
OPIOID AGONIST (n=1)
Methadone
ANTIEMETIC (n=1)
Ondansteron 
TOXIN (n=1)
Cesium Chloride
POSSIBLE RISK= can cause prolonged QT but lack of evidence for risk of TdP when taken as 
recommended
 
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115 drugs in the US market with POSSIBLE RISK to prolong QT & induce torsades de pointes (TdP)
Table 10 - Selected drugs from this list that are most likely to be encountered in a primary care 
population
ANTIDEPRESSANTS
Imipramine
Notriptylene
Venlafaxene
Desipramine
Lithium
ANTIPSYCHOTIC
Clozapine
Promethazine
Aripriprazole
ANTIBIOTICS
Ofloxacin
Lefamulin
ANALGESIC
Tramadol
Hydrocodone ER
OPIOID AGONIST
Buprenorphine
PHOSPHODIESTERASE 5 INHIBITOR
Vardenafil
MUSCLE RELAXANT
Tolterodine
ANTICANCER
Tamoxifen
ANTIVIRAL
Remdesavir
 
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Appendix 2 – DSMB Charter 
Charter
Data and Safety Monitoring Board
iTREAT 
 Version 1.1 6/23/2023
Introduction
This charter is for the Data and Safety Monitoring Board (DSMB) for the Individualizing Treatment 
for Asthma in Primary Care (iTREAT) trial. The DSMB may review this charter at regular intervals to 
determine whether any changes are needed.
iTREAT: Twenty-five million people have asthma in the US with over 45% experiencing one 
or more exacerbations (worsening of symptoms that disrupts their lives) per year.  Asthma 
exacerbations cause many lost days from school or work and account for over 3,500 deaths per year. 
Guidelines support the use of inhaled corticosteroids as part of rescue therapy, most commonly as 
Single Maintenance And Reliever Therapy (SMART). Long-term (>6 months) therapy with 
azithromycin (a macrolide antibiotic) has demonstrated similar reductions in asthma exacerbations 
to SMART therapy. Asthma is recognized as including clinical and biological variations. Which 
variations respond best to SMART versus azithromycin is not clear. Furthermore, the two have not 
been studied when used together. 
The Individualizing Treatment for Asthma in Primary Care study will be a four-arm study with 
3200 people. Treatment will vary randomly at the patient level. Study arms will be SMART therapy 
versus azithromycin therapy versus SMART plus azithromycin versus control. All participants will be 
asked to record their asthma symptoms using home monitoring tools.  The primary outcome will be 
yearly asthma exacerbation rates compared across the three intervention arms to the control arm. 
Secondary outcomes will be asthma control (Asthma Control Test or ACT) and asthma quality of life 
(mini-Asthma Quality of Life Questionnaire.) To study the impact of asthma variations, the analyses 
will include total blood eosinophil counts, infectious biomarkers for Mycoplasma pneumoniae and 
Chlamydia pneumoniae, smoking status, health literacy, onset of asthma associated with a lower 
respiratory tract infection and Black/African American race.  We hypothesize that all treatment arms 
will be better than the control arm. We hypothesize that SMART therapy will work better in non-
smokers or those with high total blood eosinophil counts or in people with lower health literacy. We 
hypothesize that azithromycin will work better in smokers or individuals with an associated lower 
respiratory tract infection at the time their asthma began or with selected positive biomarkers. 
Participants will come from primary care practices from across the United States. 
Participants must have an asthma diagnosis for at least one year, be at least 12 years old and under 
76 years old. They must have had an exacerbation requiring steroid pills or shots or a hospitalization 
in the past 12 months OR have an ACT score <20. After consent, participants will complete surveys 
every other month for 16 months. Possible exacerbations will be validated by clinicians who do not 
know the treatment arm of the participant. People who experience three exacerbations in <12 
months will have treatments increased if not already in the dual treatment arm. People in the 
control arm will move to SMART therapy while people in either single therapy will move to dual 
therapy. These participants would be followed for an additional 12 months. Individuals who finish 
either of the azithromycin arms will be offered 6 additional months of follow-up after stopping the 
azithromycin only. How well participants and people in the practices are able to carry out the study 
will be tracked using an approach called PRISM/RE-AIM. 
 
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The analyses will be based on a model called the Negative Binomial distribution. In addition 
to treatment arms, the analysis will assess the impact of sex, race, smoking history, asthma 
treatment at enrollment, total eosinophil count, and ability to use mobile technology, as well as the 
effect of the organization and practice on the outcomes. The variations of treatment effect will use 
the same approach as the main analysis with a focus on interactions between the treatments the 
covariates. 
Study results can be used by clinicians and patients to identify appropriate treatment for 
patients based on their individual characteristics, and by insurers to determine what types of 
therapy to pay for.  
Stakeholders are integral members of the study team with decision making authority 
Stakeholder groups including 1) patients/caregivers, 2) patient advocacy groups, 3) clinicians 
(physicians, nurses, and pharmacists), 4) professional societies, 5) healthcare policy experts, 6) 
payers, 7) asthma experts and researchers, and 8) site research teams have been engaged in 
formulating the research questions, identifying the study groups, selecting the interventions, 
choosing outcomes, and suggesting the exploratory aims and analyses. 
[https://www.clinicaltrials.gov/ct2/show/NCTxxxx]
Responsibilities of the DSMB
The DSMB is responsible for safeguarding the interests of study participants, assessing the safety, 
efficacy, and quality of study procedures, and monitoring the overall conduct of the study.
The DSMB is an independent advisory group charged with providing recommendations about 
starting, continuing, and stopping a study.  As appropriate, the DSMB is also asked to review and 
make recommendations to the Sponsor about the following:
•
Study protocol and consent forms, including any amendments
•
Whether any new data from other sources affect the equipoise of the studies being 
monitored
•
Adherence to protocol requirements
•
Completeness, quality, and analysis of measurements 
•
Performance of individual centers and cores
•
Management of abnormal findings (incidental findings and adverse events)
•
Selection, recruitment, and retention of participants
•
Benefit/risk ratio of procedures 
•
Participant burden
•
Participant safety
 
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Organization and Interactions
DSMB Members and Study Personnel 
DSMB members and their expertise are listed in Appendix A.  Study Staff and their responsibilities 
are listed in Appendix B.  Consistent with PCORI policy, the DSMB has an assigned Executive 
Secretary (ES) to provide an unbiased interface between the Sponsor and the DSMB, especially 
during executive sessions.  The Data Coordinating Center Principal Investigator (PI) is responsible for 
assuring the accuracy and timely transmission of the final recommendations and DSMB summary.
Communication between Investigators and the DSMB
Communication between Study Staff and DSMB will be through the ES in coordination with the PI. It 
is expected that Investigators will not communicate with DSMB members directly except at 
meetings. 
Scheduling, Timing, and Organization of Meetings
Meetings will occur by video conference.  Meetings will be held approximately twice a year, with 
additional meetings scheduled as needed.  Meetings and any interim calls will be scheduled by the 
ES. 
At the first meeting, the PI will convey expectations for DSMB operations and responsibilities. The 
DSMB will review and discuss this charter, and learn about the iTREAT study. The DSMB will review 
and make recommendations about human subjects’ safety and ethics of the protocol, participant 
consent document, and other study materials, and discuss the safety monitoring guidelines.  
Enrollment in the study cannot begin until the DSMB’s recommendation for approval has been 
accepted by the IRBs. 
The agenda for DSMB meetings will be drafted by the PI.  The ES will finalize the agenda after 
consultation with the PI and DSMB Chair.  ES will make the agenda and meeting materials available 
to the DSMB members at least 10 working days before each meeting.
At the time the agenda is sent out, and again at the beginning of each meeting, the ES will ask all 
DSMB members to state whether they have developed any new conflicts of interest since the last 
annual report.  If a new conflict is reported, the Chair and PI will determine if the conflict limits the 
ability of the DSMB member to participate in the discussion.  
The DSMB will review adverse event data, other safety data, quality and completeness of study data, 
and enrollment data at each meeting to ensure proper trial conduct.  The PI should provide any new 
literature particularly pertinent to the trial, along with their recommendation as to whether it affects 
the trial conduct or design. The DSMB will review the consent periodically and/or as needed and 
consider whether the consent form requires revision in light of any new findings or amendments.  
In addition to regular meetings, it may be necessary to convene the DSMB urgently on an ad hoc 
basis to discuss new data or other information that raises questions about equipoise, safety, or 
anything else in the trial.
It is expected that all DSMB members will attend every meeting.  However, it is recognized that this 
may not always be possible.  A quorum of this DSMB is considered to be a majority of the members. 
 
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DSMB Meeting Format 
For each meeting the PI and unblinded statistician will prepare summary reports and tables to 
facilitate the oversight role of the DSMB.  Reports will be separated into Open Session and Closed 
session sections.  
DSMB meetings will be organized into open, closed, and executive sessions.
•
During open sessions, information will be presented to the DSMB by the investigators with 
time for discussion.  PCORI staff may attend open sessions, unless the DSMB Chair decides 
that the presence of PCORI staff may inhibit free and open discussion or appear to 
compromise the DSMB’s independence.
•
During closed sessions, the DSMB and unblinded statistician will discuss confidential data, 
including any necessary information on efficacy and safety by treatment arm.  The DSMB 
reviews masked data, with option to unmask at any time they choose.  If the closed session 
occurs on a conference call, steps will be taken to ensure that only the appropriate 
participants are on the call, and to invite others to re-join the call only at the conclusion of 
the closed session.
•
The DSMB may elect to hold an executive session in which only the DSMB members are 
present.  The ES may attend the executive session at the invitation of the DSMB Chair.  If the 
ES does not attend the executive session, the DSMB Chair will be responsible for 
summarizing the DSMB’s discussion and recommendations.  The DSMB can request to have 
other staff members attend the executive session to provide additional information as 
needed.
Voting on recommendations will follow Robert’s Rules of Order.
At the conclusion of the closed and executive sessions, the DSMB chair will provide a summary of 
the preliminary recommendations to the investigators to provide an opportunity for investigators to 
ask questions to clarify the recommendations.  The meeting is then adjourned.
The ES will prepare Meeting Minutes and formal Summary Recommendations to be approved by the 
DSMB Chair.
Reports of DSMB Deliberations
•
Reports for IRBs:  If the DSMB does not identify any safety or other protocol-related 
concerns, within 14 days after a DSMB meeting the PI will prepare a Summary Report of 
Board Recommendations indicating that: 
•
a review of outcome data, adverse events, and information relating to each study 
performance (e.g., data timeliness, completeness, and quality) across all centers 
involved in the study took place on a given date; 
•
the observed frequency of adverse events did not exceed what was expected and 
indicated in the informed consent; 
•
the DSMB recommends that the study continues without modification of the 
protocol or informed consent.
 
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The PI will send the Summary Report to the sIRB with copy to study investigators at each 
clinical centers.  It is the responsibility of each investigator to forward this information to the 
local IRB.
If DSMB identifies concerns necessitating protocol and/or informed consent changes, the 
Summary Report will outline the concerns, the DSMB’s discussion of the concerns and the 
basis for any recommendations that the DSMB has made in response to the concerns.  
•
A copy of the Summary Report will also be provided to PCORI.  If the DSMB recommends 
major protocol and/or informed consent changes, they will be reviewed with PCORI prior to 
implementation. 
Statistical Monitoring Guidelines
There is no pre-planned efficacy or futility analysis; study protocol details safety interim analysis.
If requested, this charter and accompanying list of Board members may be sent to an IRB.  In the 
case, this charter will be marked as not for dissemination, and be sent by the Principal Investigator 
to the IRB Chair, with a cover letter.
 
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APPENDIX A:  DSMB Members and Expertise
DSMB member
Expertise
Diane Harper, MD, MPH, MS
Professor
Department of Family Medicine
University of Michigan
diane.m.harper@gmail.com
Chair
Benjamin Wilfond, MD
Professor
Divisions of Bioethics and Palliative Care & Pulmonary and 
Sleep 
University of Washington School of Medicine
Phone : 206 884-8355 
bwilfond@uw.edu
Research Ethics
David DeMets, PhD
Max Halperin Emeritus Professor of Biostatistics
Department of Biostatistics & Medical Informatics
University of Wisconsin School of Medicine & Public Health
Phone: 608/263-2947
demets@biostat.wisc.edu
Statistics and Study 
Design/Implementation
Kurt Elward, MD
kselward@me.com
Clinician 
Steven Natrass
Steven.Nattrass@fda.hhs.gov
Community representative
APPENDIX B:  Study Personnel and Roles
Study Personnel
Role
Wilson Pace, MD, FAAFP   
Chief Medical and Technology Officer
DARTNet Institute
Professor Emeritus, University of Colorado Department of 
Family Medicine
Phone: 720-334-6305 
email: wilson.pace@dartnet.info 
Overall Study PI
David Mauger, PhD  
Professor of Biostatistics
Department of Public Health Sciences
Penn State University College of Medicine
Phone: 717-531-3584 
email: dmauger@psu.edu 
Data Coordinating Center Principal 
Investigator
Lan Kong, PhD   
Professor of Biostatistics
Department of Public Health Sciences
Penn State University College of Medicine
email: lkong@pennstatehealth.psu.edu 
Unblinded Statistician 
Abid Kazi 
Department of Public Health Sciences
Penn State University College of Medicine
email: akazi@pennstatehealth.psu.edu
Executive Secretary
 
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Appendix 3 – Questionnaires
Eligibility
1. Is another person living with you already in this study?
Yes (1) Go to General Exit Survey
No (0) Go to next question
2. Are you 12 to 75 years of age?   
Yes (1) Go to next question
No (0) Go to Age Exit Survey
3. Have you had asthma for 1 year or longer?
Yes (1) Go to next question
No (0) go to Asthma Exit Survey
4. In the past 4 weeks, have you taken steroid pills or shots, like prednisone, or been to the 
Emergency Room or urgent care, or been in the hospital overnight for problems with your asthma?
Yes (1) Go to Exacerbation Exit Survey
No (0) Go to next question
5. In the past 6 months, have you had a lung procedure called bronchial thermoplasty? 
Yes (1) Go to Lung Procedure Exit Survey
No (0) Go to next question
6. Are you currently taking oral steroids like prednisone every day or every other day for your 
asthma or any other medical problem?
Yes (1) Go to Medication Exit Survey
No (0) Go to next question
7. In the past 6 months, have you started taking new shots or infusions for your asthma  (other than 
allergy shots)? 
Yes (1) Go to Medication Review Survey
No (0) Go to next question
8.
Have you been told you have COPD, Chronic bronchitis, emphysema or other chronic lung 
disease?
Yes (1) Go to COPD Review Survey
No (0) Go to next question
9.
Have you been asked to take one or more of the asthma medicines listed below?
 
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Check all that apply (1 – selected; 0 – not selected)
Airduo Respiclick (add generic names after each)
Advair HFA or Advair Diskus
Symbicort   
Breo
Dulera
QVAR  
Aerospan 
Alvesco
ArmonAir 
Flovent diskus or Flovent MDI
Asmanex HFA or Twisthaler
Arnuity Ellipta
Pulmicort Flexhaler
Trelogy
None of the above (Go to Medication Exit Survey, all others proceed to 9)
(Ask to see the canister even if not being taken.) 
10. In the past year, have you taken steroid pills or shots, like prednisone or been in the hospital 
overnight for problems with your asthma?
Yes (1) Go to consent
No (0) Go to next question
11. In the past 4 weeks, how much of the time did your asthma keep you from getting as much done 
at work, school or at home?
All of the time (1)
Most of the time (2)
Some of the time (3)
A little of the time (4)
None of the time (5)
12. During the past 4 weeks, how often have you had shortness of breath?
More than once a day (1)
Once a day (2)
3 to 6 times a week (3)
Once or twice a week (4)
Not at all (5)
13. During the past 4 weeks, how often did your asthma symptoms (wheezing, coughing, shortness 
of breath, chest tightness or pain) wake you up at night or earlier than usual in the morning?
4 or more nights a week (1)
2 to 3 nights a week (2)
Once a week (3)
Once or twice (4)
Not at all (5)
 
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14. During the past 4 weeks, how often have you used your rescue inhaler or nebulizer medication 
(such as albuterol)?  
3 or more times per day (1)
1 or 2 times per day (2)
2 or 3 times per week (3)
Once a week or less (4)
Not at all (5)
15. How would you rate your asthma control during the past 4 weeks? 
Not Controlled at All (1)
Poorly Controlled (2)
Somewhat Controlled (3)
Well Controlled (4)
Completely Controlled (5)
If total for items 12-16 is 20 or greater then not eligible – Proceed to General Exit Survey
If total for items 12-16 is less than 20 then eligible – Proceed to Consent
General Exit Survey
Thank you for your time and interest in this study. We are not able to include you in the study at this 
time. Please answer the questions below so we can understand who we talked to about the study. 
You may choose the “Prefer not to answer” box if you do not want to give us this information.
1. Gender 
  
Female (1)
Male (0) 
Other (2)
Prefer not to answer (98)
2. Ethnicity
Hispanic/Latino (1)
Not Hispanic/Latino (0)
Prefer not to answer (98)
3. Race (check all that apply)
Check all that apply (1 – selected; 0 – not selected, unless other or prefer not to answer)
African American/Black
Caucasian/white
Asian
Hawaiian/Pacific Islander
Native American/Alaska Native
Other (96)
Prefer not to answer (98)
 
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Age Exit Survey
This study is open to people between the ages of 12 and 75. Thank-you for your interest.  Please 
complete the three questions below. You may choose the “Prefer not to answer” box if you do not 
want to give us this information. 
1. Gender 
  
Female (1)
Male (0) 
Other (2)
Prefer not to answer (98)
2. Ethnicity
Hispanic/Latino (1)
Not Hispanic/Latino (0)
Prefer not to answer (98)
3. Race (check all that apply)
Check all that apply (1 – selected; 0 – not selected, unless other or prefer not to answer)
African American/Black
Caucasian/white
Asian
Hawaiian/Pacific Islander
Native American/Alaska Native
Other (96)
Prefer not to answer (98)
COPD Review Survey
1.
Have you been diagnosed with a chronic lung disease other than asthma, COPD, emphysema or 
chronic bronchitis? (such as bronchiectasis, pulmonary fibrosis, cystic fibrosis, interstitial lung 
disease and others)
a.
Yes – to COPD exit
b.
No – to B
2.
Are you currently smoking or have you smoked for more than 5 years in your life time?
a.
No – proceed to consent
b.
Yes – to C
3.
Have you had pulmonary function testing in the past 2 years or since you stopped smoking?
a.
Yes – to D
b.
No – to COPD Exit
4.
Study coordinator do have the latest PFTs?
a.
Yes – go to E
b.
No- Exit needs PFTs review 
5.
Are the PFTs in the last 24 months?
a.
Yes – to G
b.
No – to F 
 
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6.
Are the PFTs from after this person stopped smoking?
a.
Yes – proceed to G
b.
No – COPD Exit 
7.
Is the DLCO normal?
a.
Yes – to consent
b.
No – COPD Exit
Other Chronic Lung Diseases Exit Survey
Thank you for your time and interest in this study. This study is not open to people with some other 
chronic lung diseases. Please answer the questions below so we can understand who we talked to 
about the study. You may choose the “Prefer not to answer” box if you do not want to give us this 
information.
1. Gender 
  
Female (1)
Male (0)
Other (2)
Prefer not to answer (98)
2. Ethnicity
Hispanic/Latino (1)
Not Hispanic/Latino (0)
Prefer not to answer (98)
3. Race (check all that apply)
Check all that apply (1 – selected; 0 – not selected, unless other or prefer not to answer)
African American/Black
Caucasian/white
Asian
Hawaiian/Pacific Islander
Native American/Alaska Native
Other (96)
Prefer not to answer (98)
Need PFT Exit Survey
Thank you for your time and interest in this study. To continue in this study the study coordinator 
will need to find or get a copy of your latest pulmonary function testing. 
1.
Where was your lung function testing done?
a.
Inside this medical organization – to C
b.
In another medical organization – to B
2.
Can you get a copy of your last lung function test?
a.
Yes – proceed to C
b.
No – COPD Exit survey
 
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3.
Please provide a phone number and I will call you back when I find your lung test or when I 
get your lung test from you.  
Will need to keep the phone number locally
Medication Review Survey
This is study is open to people using injections or infusion medicine called biologics for their asthma 
if they have been on the same dose of the medication for 6 months or more and have had an 
exacerbation since being on their current does of medication. 
1.
Have you been on your current shot or infusion for at least 6 months with the same dose:
 
Yes – proceed to 2
No – Med Exit survey
2.
Have you used steroids orally or by shot since you started your current dose of your shot or 
infusion medication?
1.
Yes – proceed to consent
2.
No – proceed to 3
3.
Have you been hospitalized for your asthma for 24 hours or more since you started your current 
does of your shot or infusion medication? 
       Yes – proceed to consent
       No – Med Exit Survey
Medication Exit Survey
This study is open to people using an inhaled steroid asthma medication and not open to people 
taking daily oral steroids or newly started on injections or infusion medicine for their asthma. If you 
stop taking daily or every other day steroids or once you are on your shot or infusion for at least 6 
months you may be eligible at that time. The local study team may recontact you if those things 
happen. Thank-you for your interest. Please complete the three questions below. You may choose 
the “Prefer not to answer” box if you do not want to give us this information.
1. Gender 
  
Female (1)
Male (0) 
Other (2)
Prefer not to answer (98)
2. Ethnicity
Hispanic/Latino (1)
Not Hispanic/Latino (0)
Prefer not to answer (98)
3. Race (check all that apply)
Check all that apply (1 – selected; 0 – not selected, unless other or prefer not to answer)
African American/Black
 
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Caucasian/white
Asian
Hawaiian/Pacific Islander
Native American/Alaska Native
Other (96)
Prefer not to answer (98)
Intake
iTREAT Intake Questionnaire - Coordinator Administered
 
Health Literacy  
Medical information can be complex and many people have expressed problems with medical 
information. To be sure we best meet your needs we would like to understand how much of a 
problem dealing with medical information might be for you.  (Ask parent if a child under 16.)
1.
How often does someone help you read things your doctor gives you? 
⃝ Always (4)   
⃝ Often (3) 
⃝ Sometimes (2)
 ⃝ Never (1)
2.
How easy or hard is it to fill out medical forms by yourself? 
⃝ Extremely hard (5)   ⃝ Very hard (4)  ⃝ Somewhat hard (3)    ⃝ Easy (2)  ⃝ Very easy (1)
3.
How often is it hard to understand written information about your medical problems? 
⃝ Always (4)
   
⃝ Often (3) 
⃝ Sometimes (2)
 
⃝ Never (1)
Demographics
4.
What is your birthdate?  ____/____/_______ (MM/DD/YYYY) – [move to area where account is 
created]
5.
Sex assigned at birth?  
⃝ Female (1)
⃝ Male (0) 
5a. At times we are likely to call you. What pronouns do you use to describe yourself?
⃝ He/His/Him (0)
⃝ She/Her (1)
⃝ They/Them (2)
⃝ Other (3):    
6.
Do you consider yourself Hispanic or Latino? 
⃝ Yes (1)
⃝ No (0) 
7.
Which races do you identify with? (Please check all that apply)
⃝ African American/Black (skip next question)
⃝ Asian
 
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⃝ Native American/Alaska Native
⃝ Hawaiian/Pacific Islander
⃝ Caucasian
⃝ Other
8.
What is the highest level of schooling you have completed? 
⃝ Less than 8th grade (1)
⃝ Less than High School (2)
⃝ High School (3)
⃝ Some college or technical school (4)
⃝ College (5)
⃝ Graduate School (6)
⃝ Prefer not to answer (7)
9.
How tall are you? ______ feet     ____ inches
10. How many pounds do you weigh? _______ pounds
Smoking
11. Have you ever smoked at least 100 cigarettes in your life?  ⃝ Yes (1)
⃝ No (0) (If no, go 
to question 16 for second hand smoke)
12. How old were you when you started smoking regularly?  _____ years old
13. Think about now or when you did smoke, how many cigarettes do you or did you usually smoke?
⃝ Less than 5 per day (1)
⃝ 5-9 per day (2)
⃝ 10 (half a pack) per day (3)
⃝ 20 (a pack) per day (4)
⃝ 30 (one and a half packs) per day (5)
⃝ 40 or more (2 packs or more) per day (6)
14. Have you stopped smoking?
⃝ Yes (1)
⃝ No, I still smoke (0) (skip 
question 16)
15.
When was the most recent time you stopped?  (like 1999 or 2013)  Enter year:  ______.
16. Do others regularly smoke in your home?        
⃝ Yes (1)
⃝ No (0)
 
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17. Do others regularly smoke at your work? 
⃝ Yes (1)
⃝ No (0)
18. Do others regularly smoke in your car? 
⃝ Yes (1)
⃝ No (0)
Asthma Problems
19. In the past 12 months, how many times have you gone to the emergency room or urgent care 
for your asthma? Enter number of times: _______.
20. In the past 12 months, without staying overnight in a hospital, how many times have youtaken 
steroid/cortisone/prednisone pills or a shot for your asthma? 
Enter number of times:________.
21. In the past 12 months, how many times have you stayed in the hospital overnight or longer for 
your asthma?
Enter number of times:________.
Comorbidities
22. Have you ever been told you had any of the following? (Please check all that apply)
⃝ Heart disease
⃝ Cancer other than skin cancer
⃝ Stroke
⃝ Diabetes 
If yes 
           Do you have:
⃝ Type 1 
⃝ Type 2 
⃝ Both
⃝ Chronic kidney injury/disease
⃝ COPD/chronic bronchitis
⃝ HIV/AIDS
⃝ Hypertension
⃝ Depression/Anxiety
⃝ Sleep disorder
⃝ Allergies-allergic rhinitis, chronic sinusitis, atopic dermititis, Aspirin, other
⃝ None of the above
Age of Asthma Diagnosis
23. How old were you when a doctor first told you that you had asthma? 
 
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⃝ Less than 5 years old (1)
⃝ 5 to 12 years old (2)
⃝ 13 to 18 years old (3)
⃝ 19-40 years old (4)
⃝ 41-60 years old (5)
⃝ More than 60 years old (6)
 ⃝ I don’t remember (9)  - if chosen go to 24 if not skip to 25
24. How many years have you had asthma?  
⃝ 1 to 10 years (1)
⃝ 11 to 20 years (2)
⃝ More than 20 years (3)
25. Did your very first symptoms that led to an asthma diagnosis begin during or shortly after a 
respiratory illness such as bronchitis, pneumonia or an influenza-like illness?
⃝ Yes (1)
⃝ No  (0)
⃝ Don’t Remember (9)
Socioeconomic Status
26. Which of the following best describes your work/school situation?
⃝ Working for pay at job, business, or at home (1)
⃝ Looking for work (2)
⃝ Seasonal worker and not working right now (3)
⃝ Taking care of house or family (4)
⃝ Working but not for pay at family-owned business or job (5)
⃝ Not working and not looking for work (6)
⃝ On maternity leave (7)
⃝ Student (8)
⃝ Retired (9)
⃝ Temporarily unable to work due to health (10)
⃝ Disabled (11)
⃝ On lay off (12)
⃝ Prefer not to answer (13)
⃝ Other (14)
 
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27. What is your total yearly family household income last year? 
⃝ Less than $10,000 (1)
⃝ $10,001 to $20,000 (2)
⃝ $20,001 to $30,000 (3)
⃝ $30,001 to $40,000 (4)
⃝ $40,001 to $50,000 (5)
⃝ $50,001 to $75,000 (6)
⃝ $75,001 or more (7)
⃝ Prefer not to answer (98)
28. How many other people (adults and children) live in your household? Enter number:________
Asthma Medicines
We want to know about all of the asthma medicine you use.  Check all that apply in each grouping. 
[Coordinator should use medicine chart with pictures]
29. Are you currently taking any of these rescue or quick reliever medicines? (check all that apply)
⃝ Proventil (albuterol)
⃝ Pro Air HFA/ProAir RespiClick (albuterol)
⃝ Ventolin
⃝ Xopenex
⃝ Atrovent
⃝ Combivent
⃝ None of these
30. What do you call the medicine we just talked about? []. Enter patient’s exact words
31. Do you carry this medicine with you? 
⃝ Always (1)
⃝ Often (2) 
⃝ Sometimes (3)
 ⃝ Rarely (4)
⃝ Never (5)
32. About how many puffs of your rescue medicine do you use in a usual month?
⃝ Less than 10 puffs per month (1)
⃝ 10 to 30 puffs in a month (2)
⃝ More than 30 puffs but not a whole canister (3)
⃝ More than 1 canister per month (200 puffs) but less than 2 canisters (4)
⃝ 2 or more canisters per month (400 or puffs per month) (5)
 
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33. Do you ever use a nebulizer when you have shortness of breath or for quick relief, rescue 
medicines? 
⃝ Yes (1)
⃝ No (0) (if no, skip next questions)
34. In an average week, how many times do you use a nebulizer for these asthma symptoms? Enter 
number:_____________
35. Are you taking any of these inhaled corticosteroids medicines? (check all that apply)
⃝ Aerospan HFA (flunisolide)
⃝ Alvesco (ciclesonide)
⃝ Arnuity Ellipta (fluticasone powder)
⃝ ArmonAir Respiclick (fluticasone metered dose inhaler)
⃝ Flovent HFA or diskus (fluticasone inhaler or powder)
⃝ Asmanex Twisthaler (mometasone)
⃝ Pulmicort Flexhaler (budesonide)
⃝ QVAR (betamethasone)
⃝ None of these
36. Are you taking any of these combination medicines? (check all that apply)
⃝ Airduo Respiclick (fluticasone/salmeterol)
⃝ Advair HFA or Diskus (fluticasone/salmeterol
⃝ Symbicort (budesonide/formoterol)
⃝ Breo (fluticasone/vilanterol)
⃝ Dulera (mometasone/formoterol)
⃝ Trelegy (fluticasone/umeclidinium/vilanterol)
⃝ None of these
37. Are you taking any of these bronchodilator medicines? (check all that apply)
⃝ Perforomist (formoterol)
⃝ Striverdi Respimat (olodeterol)
⃝ Spiriva (Tiotropium) Respimat or Handihaler)
⃝ Anoro (umeclidinium/vilanterol)
⃝ Stiolto Respimat (tiotropium/olodeterol)
⃝ Incruse Ellipta (umeclidinium)
⃝ Tudorza Pressair (aclidinium)
⃝ None of these- if last three answered NONE OF THESE = alert not eligible review
 
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38. What do you call the medicine? Enter patient’s exact words.___________– enter the one chosen 
from above?
39. Are you taking any of these pills? (check all that apply)
⃝ Singular
⃝ Zileuton
40. Are you taking any of these other medicines? (check all that apply)
⃝ Omalizumab or Xolair, a shot or IV infusion at the doctor’s office
⃝ Mepolizumab or Nucala, ashot or infusion at the doctor’s office
⃝ Reslizumab or CinquilTM, an IV infusion at the doctor’s office or infusion center
⃝ Dupilumab or Dupixent (currently approved only for eczema), by injection check these
⃝ Benralizumab
⃝ On biologic but not clear about name
Secure or unsecure email link 
41. When you click on the email link to your survey, you can 1) enter a login and password, or 2) go 
directly to the survey.  If you choose to go directly to the survey, the email is not secure.  If this 
email is read by someone else that person could find out that you have asthma. None of your 
previous answers to any questions would be visible. Do you want to login each time you take the 
survey or go directly to the survey?
⃝ Enter login and password each time (1)
⃝ Go directly to survey (0) 
Baseline
Asthma Control Test – can be coordinator or self-administered
1.
In the past 4 weeks, how much of the time did your asthma keep you from getting as much done 
at work, school, or at home?
⃝ All of the time (1)
⃝ Most of the time (2)
⃝ Some of the time (3)
⃝ A little of the time (4)
⃝ None of the time (5)
2.
 During the past 4 weeks, how often have you had shortness of breath?
⃝ More than once a day (1)
⃝ Once a day (2)
⃝ 3 to 6 times a week (3)
⃝ Once or twice a week (4)
⃝ Not at all (5)
3.
During the past 4 weeks, how often did your asthma symptoms (wheezing, coughing, shortness 
of breath, chest tightness or pain) wake you up at night or earlier than usual in the morning?
 
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⃝ 4 or more nights a week (1)
⃝ 2 to 3 nights a week (2)
⃝ Once a week (3)
⃝ Once or twice (4)
⃝ Not at all (5)
4.
During the past 4 weeks, how often have you used your rescue inhaler or nebulizer medication 
(such as albuterol)?  
⃝ 3 or more times per day (1)
⃝ 1 or 2 times per day (2)
⃝ 2 or 3 times per week (3)
⃝ Once a week or less (4)
⃝ Not at all (5)
5.
How would you rate your asthma control during the past 4 weeks? 
⃝ Not Controlled at All (1)
⃝ Poorly Controlled (2)
⃝ Somewhat Controlled (3)
⃝ Well Controlled (4)
⃝ Completely Controlled (5)
PHQ-2 
6.
Over the past 2 weeks, how often have you been bothered by: little interest or pleasure in doing 
things?
⃝ Not at all (1)
⃝ Several days (2)
⃝ More than half the days (3) 
⃝ Nearly every day (4)
7.
Over the past 2 weeks, how often have you been bothered by: feeling down, depressed, or 
hopeless?
⃝ Not at all (1)
⃝ Several days (2)
⃝ More than half the days (3)
⃝ Nearly every day (4)
If any answers score 3 or 4 go to 8 otherwise skip to 14
PHQ-8
8.
Over the past 2 weeks, how often have you been bothered by: trouble falling or staying asleep 
or sleeping too much?
⃝ Not at all (1)
⃝ Several days (2)
⃝ More than half the days (3)
⃝ Nearly every day (4)
 
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9.
Over the past 2 weeks, how often have you been bothered by: feeling tired or having little 
energy?
⃝ Not at all (1)
⃝ Several days (2)
⃝ More than half the days (3)
⃝ Nearly every day (4)
10.  Over the past 2 weeks, how often have you been bothered by: poor appetite or overeating?
⃝ Not at all (1)
⃝ Several days (2)
⃝ More than half the days (3)
⃝ Nearly every day (4)
11. Over the past 2 weeks, how often have you been bothered by: feeling bad about yourself-or 
that you are a failure or have let yourself or your family down?
⃝ Not at all (1)
⃝ Several days (2)
⃝ More than half the days (3)
⃝ Nearly every day (4)
12. Over the past 2 weeks, how often have you been bothered by: trouble concentrating on things, 
such as reading the newspaper or watching television?
⃝ Not at all (1)
⃝ Several days (2)
⃝ More than half the days (3)
⃝ Nearly every day (4)
13. Over the past 2 weeks, how often have you been bothered by: moving or speaking so slowly 
that other people could have noticed.  Or the opposite-being so fidgety or restless that you have 
been moving around a lot more than usual?
⃝ Not at all (1)
⃝ Several days (2)
⃝ More than half the days (3)
⃝ Nearly every day (4)
 
___________
Mini-Asthma Quality of Life Questionnaire (Adult)
Please complete all questions by circling the number that best describes how you have been during 
the last 2 weeks as a result of your asthma.
In general, how much of the time during the last 2 weeks did you:
14. Feel SHORT OF BREATH as a result of your asthma?
 
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All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
15. Feel bothered by or have to avoid DUST in the environment?
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
16. Feel FRUSTRATED as a result of your asthma?
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
17. Feel bothered by COUGHING?
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
18. Feel AFRAID OF NOT HAVING YOUR ASTHMA MEDICATION AVAILABLE?
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
19. Experience a feeling of CHEST TIGHTNESS or CHEST HEAVINESS?
All of the time (1) 
 
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Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
20. Feel bothered by or have to avoid CIGARETTE SMOKE in the environment? 
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
21. Have DIFFICULTY GETTING A GOODNIGHT'S SLEEP as a result of your asthma?
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
22. Feel CONCERNED ABOUT HAVING ASTHMA?
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
23. Experience a WHEEZE in your chest?
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
24. Feel bothered by or have to avoid going outside because of WEATHER OR AIR POLLUTION?
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
 
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Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
How limited have you been during the last 2 weeks doing these activities as a result of your asthma?
25. STRENUOUS ACTIVITIES (such as hurrying, exercising, running upstairs, sports) 
Totally Limited (1)
Extremely Limited (2)
Very Limited (3)
Moderate Limitation (4)
Some Limitation (5) 
A Little Limitation (6) 
Not at all Limited (7)
26. MODERATE ACTIVITIES (such as walking, housework, gardening, shopping, climbing stairs) 
Totally Limited (1)
Extremely Limited (2)
Very Limited (3)
Moderate Limitation (4)
Some Limitation (5) 
A Little Limitation (6) 
Not at all Limited (7)
27. SOCIAL ACTIVITIES (such as talking, playing with pets/children, visiting friends/relatives) 
Totally Limited (1)
Extremely Limited (2)
Very Limited (3)
Moderate Limitation (4)
Some Limitation (5) 
A Little Limitation (6) 
Not at all Limited (7)
28. WORK-RELATED ACTIVITIES (tasks you have to do at work)*
Totally Limited (1)
Extremely Limited (2)
Very Limited (3)
Moderate Limitation (4)
Some Limitation (5) 
A Little Limitation (6) 
Not at all Limited (7)
*If you are not employed or self-employed, these should be tasks you have to do most days.
29. In the last 3 months, how many days did you miss work or school due to your asthma? Numeric 
– max value 90
 
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30. In the last 3 months did you have days you were unable to carry out your usual activities due to 
your asthma?
Yes (1) Go to 32
No (0) Skip to 33
31. How many days you were unable to carry out your usual activities due to your asthma? Numeric 
– max value 90
MARS-5
This question is about your daily maintenance medicine, the inhaler that you call "(insert response 
from Intake, question[insert number]).”
32. I forget to take my (insert response from Intake, question [insert number]).
⃝ Always (1)
⃝ Often (2)
⃝ Sometimes (3)
⃝ Rarely (4)
⃝ Never (5)
33. I change the dosage of my (insert response from Intake, question [insert number]).
⃝ Always (1)
⃝ Often (2)
⃝ Sometimes (3)
⃝ Rarely (4)
⃝ Never (5)
34. I stop taking my (insert response from Intake, question [insert number]) for a while.
⃝ Always (1)
⃝ Often (2)
⃝ Sometimes (3)
⃝ Rarely (4)
⃝ Never (5)
35. I decide to skip my (insert response from Intake, question [insert number]).
⃝ Always (1)
⃝ Often (2)
⃝ Sometimes (3)
⃝ Rarely (4)
⃝ Never (5)
36. I use my (insert response from Intake, question [inset number]) less than is prescribed
⃝ Always (1)
⃝ Often (2)
⃝ Sometimes (3)
 
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⃝ Rarely (4)
⃝ Never (5)
Monthly
Asthma Exacerbation Questionnaire
Note: a “yes”/1 to any of questions 1-4 should trigger a notification for a follow-up call to confirm 
exacerbation.
1.
Since the last time you answered a survey on [pre-populated date __/__/_____], have you taken 
steroids pills or shots, like prednisone to treat an asthma attack?
⃝ Yes (1) 
⃝ No (0)
2.
Since the last time you answered a survey on [pre-populated date __/__/_____], have you 
visited the urgent care or the emergency room for your asthma?
⃝ Yes (1) 
⃝ No (0)
3.
Since the last time you answered a survey on [pre-populated date __/__/_____], have you 
stayed a day or longer in the hospital for your asthma?
⃝ Yes (1) 
⃝ No (0)
Infection and Antibiotic Questions
4.
Since the last survey, did you have an infection that required you to go to the doctor?
 ⃝ Yes (1)
 ⃝ No (0)
(IF YES)
Check all that apply to you:
⃝ You were prescribed antibiotics
⃝ The infection cleared up after the first course of antibiotics
⃝ A doctor told you the infection was antibiotic resistant
⃝ You had to use more than one antibiotic because the first one didn’t work
⃝ Others? _____________
Where was the infection? – check all that apply 
⃝ Viral infection respiratory (upper or lower) 
                             ⃝ Skin
⃝ Sinus
⃝ Lung
 
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⃝ Urinary tract
⃝ Joint
⃝ Other: ______________
Please indicate what your “other” infection was:    text here
Days Lost from Work or School
5.
Since the last time you answered a survey on [pre-populated date __/__/_____], did you miss 
work or school due to your asthma?
 ⃝ Yes (1) – Go to 8
 ⃝ No (0) – Skip to 9 
 ⃝ Don’t go to work or school (2) – Skip to 9
6.
How many days did you miss work or school due to your asthma? Numeric – max value 90 Enter 
number of times:_________.
7.
Since the last time you answered a survey on [pre-populated date __/__/_____], did you have 
days you were unable to carry out your usual activities due to your asthma?
⃝ Yes (1) Go to 10
⃝ No (0) Skip to 11
8.
How many days you were unable to carry out your usual activities due to your asthma? Numeric 
– max value 90 does this need to change given the qom approach? Enter number of 
times:_________.
Asthma Control Test
9.
In the past 4 weeks, how much of the time did your asthma keep you from getting as much done 
at work, school, or at home?
⃝ All of the time (1)
⃝ Most of the time (2)
⃝ Some of the time (3)
⃝ A little of the time (4)
⃝ None of the time (5)
10. During the past 4 weeks, how often have you had shortness of breath?
⃝ More than once a day (1)
⃝ Once a day (2)
⃝ 3 to 6 times a week (3)
⃝ Once or twice a week (4)
⃝ Not at all (5)
11. During the past 4 weeks, how often did your asthma symptoms (wheezing, coughing, shortness 
of breath, chest tightness or pain) wake you up at night or earlier than usual in the morning?
⃝ 4 or more nights a week (1)
 
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⃝ 2 to 3 nights a week (2)
⃝ Once a week (3)
⃝ Once or twice (4)
⃝ Not at all (5)
12. During the past 4 weeks, how often have you used your rescue inhaler or nebulizer medication 
(such as albuterol)?  
⃝ 3 or more times per day (1)
⃝ 1 or 2 times per day (2)
⃝ 2 or 3 times per week (3)
⃝ Once a week or less (4)
⃝ Not at all (5)
13. How would you rate your asthma control during the past 4 weeks? 
⃝ Not Controlled at All (1)
⃝ Poorly Controlled (2)
⃝ Somewhat Controlled (3)
⃝ Well Controlled (4)
⃝ Completely Controlled (5)
Mini-Asthma Quality of Life Questionnaire - Adult
Please complete all questions by circling the number that best describes how you have been during 
the last 2 weeks as a result of your asthma. (Note this will be adjusted when the REDCap option 
choices are clear)
In general, how much of the time during the last 2 weeks did you:
14. Feel SHORT OF BREATH as a result of your asthma?
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
15. Feel bothered by or have to avoid DUST in the environment?
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
16. Feel FRUSTRATED as a result of your asthma?
 
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All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
17. Feel bothered by COUGHING?
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
18. Feel AFRAID OF NOT HAVING YOUR ASTHMA MEDICATION AVAILABLE?
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
19. Experience a feeling of CHEST TIGHTNESS or CHEST HEAVINESS?
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
20. Feel bothered by or have to avoid CIGARETTE SMOKE in the environment?  
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
21. Have DIFFICULTY GETTING A GOODNIGHT'S SLEEP as a result of your asthma?
 
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All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
22. Feel CONCERNED ABOUT HAVING ASTHMA?
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
23. Experience a WHEEZE in your chest?
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
24. Feel bothered by or have to avoid going outside because of WEATHER OR AIR POLLUTION?
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
How limited have you been during the last 2 weeks doing these activities as a result of your asthma?
25. STRENUOUS ACTIVITIES (such as hurrying, exercising, running upstairs, sports) 
Totally Limited (1)
Extremely Limited (2)
Very Limited (3)
Moderate Limitation (4)
Some Limitation (5) 
A Little Limitation (6) 
Not at all Limited (7)
26. MODERATE ACTIVITIES (such as walking, housework, gardening, shopping, climbing stairs) 
 
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Totally Limited (1)
Extremely Limited (2)
Very Limited (3)
Moderate Limitation (4)
Some Limitation (5) 
A Little Limitation (6) 
Not at all Limited (7)
27. SOCIAL ACTIVITIES (such as talking, playing with pets/children, visiting friends/relatives) 
Totally Limited (1)
Extremely Limited (2)
Very Limited (3)
Moderate Limitation (4)
Some Limitation (5) 
A Little Limitation (6) 
Not at all Limited (7)
28. WORK-RELATED ACTIVITIES (tasks you have to do at work)
Totally Limited (1)
Extremely Limited (2)
Very Limited (3)
Moderate Limitation (4)
Some Limitation (5) 
A Little Limitation (6) 
Not at all Limited (7)
*If you are not employed or self-employed, these should be tasks you have to do most days.
Medication Adherence
[ICS Adherence - These questions are for the two groups using ICS as rescue]
29. When you used your rescue inhaler / puffer/ nebulizer did you use the inhaler that also 
contained ICS or the extra inhaler that was an ICS:
⃝ Most or all of the time (1)
⃝ More than half the time (2)
⃝ About half (3)
⃝ Less than half (4)
⃝ Not very often or not at all (5)
Change in Rescue Medication
30. Did you change your rescue medication since you last answered this questionnaire on <<insert 
date>>?
Yes – call participant (1)
No – done (0)
Not sure – call participant (2)
 
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[This question is for the two groups on AZ – note one group will get both of these groups of 
questions]
30. Since the last time you answered a survey on [pre-populated date __/__/_____] have you taken 
your azithromycin:
⃝ Took it three times a week all or most of the time (1)
⃝ Missed up to one dose, or sometimes even two doses in a week but usually took that 
dose before my next dose (2)
⃝ Totally missed one and sometimes even two doses a week (3)
⃝ Took less than half of the doses I was asked to take (4)
⃝ Didn’t take my azithromycin at all (5)
Change in Contact Information
31. Do you or will you have in the next two months a new home address?
⃝ Yes (1) 
⃝ No (0) 
32. Do you or will you have (in the next two months) a new phone number?
⃝ Yes (1) 
⃝ No (0) 
Exit
Study ID:
Last survey date: 
Today’s date:_________________
Asthma Exacerbation Questionnaire
Note: a “yes”/1 to any of questions 1-4 should trigger a notification for a follow-up call to confirm 
exacerbation.
1.
Since the last time you answered a survey on [pre-populated date __/__/_____], have you taken 
steroids pills or shots, like prednisone to treat an asthma attack?
⃝ Yes (1) 
⃝ No (0)
2.
Since the last time you answered a survey on [pre-populated date __/__/_____], have you 
visited the urgent care or the emergency room for your asthma?
⃝ Yes (1) 
⃝ No (0)
3.
Since the last time you answered a survey on [pre-populated date __/__/_____], have you 
stayed a day or longer in the hospital for your asthma?
⃝ Yes (1) 
⃝ No (0)
 
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Infection and Antibiotic Questions
4.
Since the last survey, did you have an infection that required you to go to the doctor?
 ⃝ Yes (1)
 ⃝ No (0)
(IF YES)
Check all that apply to you:
⃝ You were prescribed antibiotics
⃝ The infection cleared up after the first course of antibiotics
⃝ A doctor told you the infection was antibiotic resistant
⃝ You had to use more than one antibiotic because the first one didn’t work
⃝ Others? _____________
Where was the infection? – check all that apply 
⃝ Viral infection respiratory (upper or lower) 
                             ⃝ Skin
⃝ Sinus
⃝ Lung
⃝ Urinary tract
⃝ Joint
⃝ Other: ______________
Please indicate what your “other” infection was:    text here
Days Lost from Work or School
5.
Since the last time you answered a survey on [pre-populated date __/__/_____], did you miss 
work or school due to your asthma?
 ⃝ Yes (1) – Go to 8
 ⃝ No (0) – Skip to 9 
 ⃝ Don’t go to work or school (2) – Skip to 9
6.
How many days did you miss work or school due to your asthma? Numeric – max value 90 Enter 
number of times:_________.
7.
Since the last time you answered a survey on [pre-populated date __/__/_____], did you have 
days you were unable to carry out your usual activities due to your asthma?
⃝ Yes (1) Go to 10
⃝ No (0) Skip to 11
 
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8.
How many days you were unable to carry out your usual activities due to your asthma? Numeric 
– max value 90 does this need to change given the qom approach? Enter number of 
times:_________.
Asthma Control Test
9.
In the past 4 weeks, how much of the time did your asthma keep you from getting as much done 
at work, school, or at home?
⃝ All of the time (1)
⃝ Most of the time (2)
⃝ Some of the time (3)
⃝ A little of the time (4)
⃝ None of the time (5)
10. During the past 4 weeks, how often have you had shortness of breath?
⃝ More than once a day (1)
⃝ Once a day (2)
⃝ 3 to 6 times a week (3)
⃝ Once or twice a week (4)
⃝ Not at all (5)
11. During the past 4 weeks, how often did your asthma symptoms (wheezing, coughing, shortness 
of breath, chest tightness or pain) wake you up at night or earlier than usual in the morning?
⃝ 4 or more nights a week (1)
⃝ 2 to 3 nights a week (2)
⃝ Once a week (3)
⃝ Once or twice (4)
⃝ Not at all (5)
12. During the past 4 weeks, how often have you used your rescue inhaler or nebulizer medication 
(such as albuterol)?  
⃝ 3 or more times per day (1)
⃝ 1 or 2 times per day (2)
⃝ 2 or 3 times per week (3)
⃝ Once a week or less (4)
⃝ Not at all (5)
13. How would you rate your asthma control during the past 4 weeks? 
⃝ Not Controlled at All (1)
⃝ Poorly Controlled (2)
⃝ Somewhat Controlled (3)
⃝ Well Controlled (4)
⃝ Completely Controlled (5)
Mini-Asthma Quality of Life Questionnaire - Adult
 
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Please complete all questions by circling the number that best describes how you have been during 
the last 2 weeks as a result of your asthma. (Note this will be adjusted when the REDCap option 
choices are clear)
In general, how much of the time during the last 2 weeks did you:
14. Feel SHORT OF BREATH as a result of your asthma?
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
15. Feel bothered by or have to avoid DUST in the environment?
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
16. Feel FRUSTRATED as a result of your asthma?
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
17. Feel bothered by COUGHING?
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
18. Feel AFRAID OF NOT HAVING YOUR ASTHMA MEDICATION AVAILABLE?
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
 
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Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
19. Experience a feeling of CHEST TIGHTNESS or CHEST HEAVINESS?
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
20. Feel bothered by or have to avoid CIGARETTE SMOKE in the environment?  
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
21. Have DIFFICULTY GETTING A GOODNIGHT'S SLEEP as a result of your asthma?
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
22. Feel CONCERNED ABOUT HAVING ASTHMA?
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
23. Experience a WHEEZE in your chest?
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
 
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A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
24. Feel bothered by or have to avoid going outside because of WEATHER OR AIR POLLUTION?
All of the time (1) 
Most of the Time (2)
A Good Bit of the Time (3) 
Some of the Time (4)
A Little of the Time (5) 
Hardly Any of the Time (6) 
None of the Time (7)
How limited have you been during the last 2 weeks doing these activities as a result of your asthma?
25. STRENUOUS ACTIVITIES (such as hurrying, exercising, running upstairs, sports) 
Totally Limited (1)
Extremely Limited (2)
Very Limited (3)
Moderate Limitation (4)
Some Limitation (5) 
A Little Limitation (6) 
Not at all Limited (7)
26. MODERATE ACTIVITIES (such as walking, housework, gardening, shopping, climbing stairs) 
Totally Limited (1)
Extremely Limited (2)
Very Limited (3)
Moderate Limitation (4)
Some Limitation (5) 
A Little Limitation (6) 
Not at all Limited (7)
27. SOCIAL ACTIVITIES (such as talking, playing with pets/children, visiting friends/relatives) 
Totally Limited (1)
Extremely Limited (2)
Very Limited (3)
Moderate Limitation (4)
Some Limitation (5) 
A Little Limitation (6) 
Not at all Limited (7)
28. WORK-RELATED ACTIVITIES (tasks you have to do at work)
Totally Limited (1)
Extremely Limited (2)
Very Limited (3)
 
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Moderate Limitation (4)
Some Limitation (5) 
A Little Limitation (6) 
Not at all Limited (7)
*If you are not employed or self-employed, these should be tasks you have to do most days.
Medication Adherence
[[ICS Adherence - These questions are for the two groups using ICS as rescue
29. Have you changed your rescue inhaler that included a steroid since << enter date of last 
survey>>?
Yes
No
Don’t remember 
30. When you used your rescue inhaler / puffer/ nebulizer did you use the inhaler that also 
contained ICS or the extra inhaler that was an ICS:
⃝ Most or  all of the time (1)
⃝ More than half the time (2)
⃝ About half (3)
⃝ Less than half (4)
⃝ Not very often or not at all (5)
[[This question is for the two groups on AZ – note one group will get both of these groups of 
questions
29. Since the last time you answered a survey on [pre-populated date __/__/_____] have you taken 
your azithromycin:
⃝ Took it three times a week all or most of the time (1)
⃝ Missed up to one dose, or sometimes even two doses in a week but usually took that 
dose before my next dose (2)
⃝ Totally missed one and sometimes even two doses a week (3)
⃝ Took less than half of the doses I was asked to take (4)
⃝ Didn’t take my azithromycin at all (5)
For the ICS/AZ arms -
29. Have you had problems using your new medication?
Yes
No
If Yes
Tell us about your problems:
Text box
30. Do you want to continue on your new medication?
 
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Yes
No
Will talk with my doctor
If yes 
Thank you for being a part of this study. We will try and contract you doctor so you can keep using 
you new medication.
For the others
Thank you for being a part of this study. We hope you find good treatments for your asthma.
For the ASM only arm:
29. Were you able to use the asthma reporting system?
Yes
No
Didn’t try
If yes- 
30. Did you have problems with the system?
       Yes
No
If yes
Please tell us about your problems:
Text box
If No or after the question above
31. If you could keep using the reporting system would you want to use it?
        
Yes
No
If it was improved 
Thank you for being a part of this study.  We hope you find good treatments for your asthma.
 
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Qualitative Semi-structured Interview Guides
Domains
Interview Questions
Notes
REACH – Absolute number, proportion & representativeness of individuals who participate – Who? 
How many possible participants? Possible reasons for not participating (practice & patient)? External 
factors?
Practice level/Care Team 
Intervention
Patient/caregiver level
Now that you have implemented the study for a few months we want to 
understand the type of patient that has been most likely to participate in the 
study. How did you decide who to select from your patient panel?
Probes: 
•
Given the past couple of weeks implementing the study, who do you 
think will most experience a health benefit from the study and why? 
•
How were patients approached for study participation (in-person 
during planned visit, on the phone, via email, etc.)? 
•
What encouraged or motivated patients to participate? What types 
of strategies influenced or affected patient recruitment? 
•
What do you think will be the main motivation/value for participating 
in this study?
•
What other supports would be necessary to best integrate the study 
into the workflow systems?
We would like to better understand the facilitators and barriers to 
participating in the study.
Probes:
•
Can you tell me a bit about your experience with asthma?
•
Now that you have heard about the study do you think it would be 
helpful to you? Why?
•
What are some reasons or barriers you would not continue to 
participate in the study?
Is there anything that would make it easier for you to continue to 
participate in the study?
EFFECTIVENESS – Impact on important outcomes including potential negative
effects, quality of life, and economic outcomes. Heterogeneity of effects and reasons for success
N/A
ADOPTION –   The absolute number, proportion, and representativeness of a) settings; and b) intervention 
agents (people who deliver the program) who are willing to initiate a program. Reasons for adoption or non-
adoption. Setting level factors that may affect adoption
Practice Level/Care Team 
Intervention
How was it to integrate the study into your workflow processes?
Probes: Barriers? Cost, time, resources, cultural, biases?
Facilitators? People, resources, structures
•
What immediate concerns (from a patient and practice perspective) 
do you have participating in this study?
•
 
•
 
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Patient – Full Feasibility 
As part of the iTREAT study I would like to talk with you for about 20 minutes. This 
conversation will be recorded so we can review your comments at a later time. There are no 
right or wrong answers to the questions. We are interested in your thoughts about your 
experience in the study and your experiences with asthma. Do you agree to the interview 
and my recording of the interview? Yes – thank you – you will be paid $25 for your time.  No 
– We understand you do not wish to participate in the interview; however, we thank you for 
your continued participation in the full study.
1.
Can you tell me a bit about your experience with asthma?
a.
How did your asthma begin? 
b.
How much does it interfere with your life?
For teenagers: 
•
Are there activities you engage in that you wish you could but now you 
cannot?
Are there activities that you engage in that you know you shouldn’t but 
sometimes you do? 
c.
Do feel like the medications you were on before starting the study were generally 
working for you?
2.
What helped you decide to join the study?
a.
Did your doctor talk with you about the study?
b.
Have you been involved in other studies
c.
What are you hoping to get out of being in the study
3.
Have you had issues or problems with new medications you were asked to 
take for the study?
(For Inhaled Corticosteroids (ICS) SMART or PARTICS (Patient Activated Reliever Trigger 
Inhaled Corticosteroids) group)
a.
Was it hard to decide on which of the new inhaler treatments to use?
b.
Are you concerned with increasing the usage of ICS substantially? If yes, why and have you 
been able to do so as asked?
c.
Did you have any problems at the pharmacy or with your insurance in getting the new 
inhaler treatment?
 
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d.
Have you had problems trying to follow the new inhaler treatments?
For teenagers: 
So you sometimes not follow what you doctor has asked? When are these times(For 
azithromycin groups)
e.
Do you or did you have concerns with using the azithromycin for a long time? Have 
you been able to take it as asked?
f.
Have you had any problems at your pharmacy or with your insurance in getting the 
medication?
4.
Is there anything else you’d like to share about participating in the study that 
we may have missed?
 
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Patient – Asthma Symptom Monitoring (ASM) only 
1.
Can you tell me a bit about your experience with asthma?
a.
How did your Asthma begin?
b.
How much does it interfere with your life?
c.
How well do you think your current medications are working for you?
2.
What helped you decide to try out the ASM monitoring system?
a.
Did you doctor talk with you about the system?
b.
What are you hoping to get out of using the system?
3.
How has the ASM reporting system worked for you so far?
a.
Do you think using this system would help you work with your doctor to keep you 
asthma better controlled?
b.
Have you had problems with the system or notice any areas for improvement?
Did you ask for someone from your practice to call you through the system? If so- did 
they?If you were allowed to continue to use the system would you want to?
4.   Is there anything else you’d like to share about using the monitoring system that 
we may have missed?
 
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Prescribing Clinicians
1.
What has your experience been like in trying to get people their prescriptions?
Has it been difficult to get ahold of people after they are consented?
Do you feel like you are able to answer any questions patients may have?
Have you converted people to Single Maintenance And Reliever Therapy (SMART)? If so, how 
has that gone?
Have people had concerns about azithromycin? Do you feel comfortable answering these 
concerns?
2.
How has deciding upon the Inhaled Corticosteroids (ICS) options SMART or PARTICS 
(Patient Activated Reliever Trigger Inhaled Corticosteroids) gone?
Do you feel like you have the information you need to help people with this decision?
Has it been difficult to figure out which drug to use based on insurance coverage?
Do you generally try and use one of the two options if possible?
3.
Have you had issues from pharmacies or insurance companies for any of the treatments?
Were you able to resolve the issues or did you have to change therapy?
Is there anything you think we can do differently at the full study level  to help with these 
issues?
Would a central study pharmacist help you with any pharmacy or insurance issues?
4.
Anything else you’d like to share about participating in the study that we may 
have missed?
 
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Appendix 4 – Asthma Symptom Monitoring App
Text before baseline
Notification text: Complete asthma baseline questionnaire from your doctor.
Questionnaire and Other App Text
During the past week, how often did you 
have an asthma attack?
a.
Not at all (0 point)
b.
Once or twice (5)
c.
3 to 6 times (10)
d.
Once a day (15)
e.
More than once a day (20)
During the past week, how often have you 
been awakened at night because of your 
asthma symptoms?   Indent82671-9
a.
Never (0 point) 
b.
Hardly ever (5)
c.
Several times (10)
d.
Many times but not every night 
(15)
e.
Every night (20)
During the past week, how much did your 
asthma interfere with your normal activities?
Indent82669-3
a.
Not at all (0)
b.
A little (5)
c.
A moderate amount (10)
 
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d.
A lot(15)
During the past week, how often have you 
used a rescue inhaler that gives quick relief 
from asthma symptoms?  
 Indent82672-7
a.
Never (0)
b.
Once (5)
c.
2 or more times but not daily (10)
d.
Daily (15)
e.
Several times a day, most days 
(20)
During the past week, how often did you 
have shortness of breath?   Indent82670-
1
a.
Not at all (0)
b.
Once or twice (5)
c.
3 to 6 times (10)
d.
Once a day (15)
e.
More than once a day(20)
 
Note, that the questionnaire for the baseline is the same except it asks “In a good 
week…” instead of “During the past week…”
Text used directly by app: 
enums: {
    NoSymptoms: 'No Symptoms',
    BetterThanBaseline: 'Better Than Baseline',
    SameAsBaseline: 'Same As Baseline',
    SlightlyWorseThanBaseline: 'Slightly Worse Than Baseline',
    SomewhatWorseThanBaseline: 'Somewhat Worse Than Baseline',
    WorseThanBaseline: 'Worse Than Baseline',
    BetterThanLastWeek: 'Better Than Last Week',
    SameAsLastWeek: 'Same As Last Week',
    SlightlyWorseThanLastWeek: 'Slightly Worse Than Last Week',
    SomewhatWorseThanLastWeek: 'Somewhat Worse Than Last Week',
    WorseThanLastWeek: 'Worse Than Last Week',
    Severe: 'Severe',
}
resultsScreen: {
 
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    title: 'Questionnaire Results',
    yourSymptoms: 'Your asthma symptoms are:',
    details: 'Details',
    wouldYouLike: 'Would you like to request a call from a nurse to discuss your 
asthma?',
    callMe: 'Call me',
    noThanks: 'No, thanks',
    smallChange: 'This small change in your asthma control may not be a major 
concern.',
    reminder:
      "As a reminder, this app doesn't know everything about your asthma. If you 
have any further concerns, you can contact your healthcare provider or visit the 
emergency room.",
    thingsYouCanDo: 'Things you can do next:',
    viewData: 'View my asthma data',
    addData: 'Add/edit weekly note, triggers, or peak flows'
  },
callRequestScreen: {
    beforeWeRequest: 'Before we request the call, please check all that apply 
below.',
    choseNotRequest: 'You chose not to request a call',
    thisWillHelpUs: '(This will help us better assist you.)',
    itsYourResponsibility:
      'Important: Your provider will not be asked to review your questionnaire. ' +
      'It is your responsibility to get help if you need it.',
    toHelpUs: 'To help us keep track of your asthma, check all that apply below.',
    checkAllThatApply: 'Check ALL that apply',
    beenToEd: 'I went to an emergency room or urgent care this week',
    missedDoses: 'I missed some doses of my asthma medications this week',
    confusedAboutMeds: 'I am confused about the difference between my rescue 
inhaler and my controller inhaler',
    alreadyRequestedCall: 'I already contacted my provider and am waiting for a 
call back',
    none: 'None',
    next: 'Next'
  },
  confirmNumberScreen: {
    pleaseEnter: 'Please enter the phone number',
    isThisTheBest: 'Is this the best number to reach you in the next 24 hours?',
    callMe: 'Yes, call me',
    changeNumber: 'Change number'
  },
expectCallScreen: {
    expectCall: 'Expect a call within 24 hours.',
 
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    ifYouNeedHelp:
      'If you need help sooner, contact your healthcare provider directly, call 
911, or visit your local emergency room.',
    thingsYouCanDo: 'Things you can do while you wait for the nurse to call you:',
    thingsYouCanDoDecline: 'Things you can do next:',
    viewData: 'View my asthma data',
    addWeeklyData: 'Add/edit weekly note, triggers, or peak flows'
  },
symptomCheck: {
    question: 'In the past week, did you have any of the following?',
    symptom1: '– Asthma attacks',
    symptom2: '– Awakened at night',
    symptom3: '– Asthma interfered with normal activities',
    symptom4: '– Used your rescue inhaler',
    symptom5: '– Shortness of breath',
    yes: 'YES\n\nI had one or more of these',
    no: "NO\n\nI didn't have any of these",
    areYouReady: 'Are you sure?',
    notReady: 'No, go back',
    submit: 'Yes, proceed'
Notification logic
Definitions
•
Callback 
o
OFFER_CALLBACK
o
NO_OFFER_CALLBACK
•
Symptom_summary: color
o
NO_SYMPTOMS: blue
o
BETTER_THAN_BASELINE: blue
o
SAME_AS_BASELINE: blue
o
SLIGHTLY_WORSE_THAN_BASELINE: orange
o
SOMEWHAT_WORSE_THAN_BASELINE: yellow
o
WORSE_THAN_BASELINE: red
o
o
BETTER_THAN_LAST_WEEK: blue
o
SAME_AS_LAST_WEEK: blue
o
SLIGHTLY_WORSE_THAN_LAST_WEEK: orange
o
SOMEWHAT_WORSE_THAN_LAST_WEEK: yellow
o
WORSE_THAN_LAST_WEEK: red
 
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o
SEVERE: red 
•
Scores
o
TWS = this week score
o
PWS = previous week score
o
BL = baseline score
•
Directionality
o
Higher means more symptoms (0 = no symptoms, 95= extreme symptoms). Multiply the 
score for each item by 5.  
•
# comments start with “#”
Branching Logic
If TWS is most severe on 1 or more items
{
Callback(OFFER_CALLBACK)
Symptom_summary (SEVERE)
}
else if TWS is perfect (no symptoms)
{
Callback(NO_OFFER_CALLBACK)
Symptom_summary (NO_SYMPTOMS)
}
else if PWS == NULL
{
case TWS
{
Higher than BL by 30 or more: 
Callback(OFFER_CALLBACK); 
Symptom_summary(WORSE_THAN_BASELINE)
Higher than BL by 15, 20, or 25: 
Callback(OFFER_CALLBACK); 
Symptom_summary(SOMEWHAT_WORSE_THAN_BASELINE)
Higher than BL by 5 or 10: 
Callback(NO_OFFER_CALLBACK); 
Symptom_summary(SLIGHTLY_WORSE_THAN_BASELINE)
Same as BL: 
Callback(NO_OFFER_CALLBACK); 
 
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Symptom_summary(SAME_AS_BASELINE)
Lower than BL: 
Callback(NO_OFFER_CALLBACK); 
Symptom_summary(BETTER_THAN_BASELINE)
}
}
else if PWS == BL
{
case TWS
{
Higher than PWS by 30 or more: 
Callback(OFFER_CALLBACK)
Symptom_summary(WORSE_THAN_LAST_WEEK)
Higher than PWS by 15, 20 or 25: 
Callback(OFFER_CALLBACK);
Symptom_summary(SOMEWHAT_WORSE_THAN_LAST_WEEK)
Higher than PWS by 5 or 10: 
Callback(NO_OFFER_CALLBACK); 
Symptom_summary(SLIGHTLY_WORSE_THAN_LAST_WEEK)
Same as PWS: 
Callback(NO_OFFER_CALLBACK); 
Symptom_summary(SAME_AS_LAST_WEEK)
Lower than PWS: 
Callback(NO_OFFER_CALLBACK); 
Symptom_summary(BETTER_THAN_LAST_WEEK)
}
}
else    # PWS != BL && PWS !=NULL 
{
if  (TWS-BL >=30) || (TWS-PWS >=30)
{
Callback(OFFER_CALLBACK);
 
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If BL < PWS  #display page for whichever difference is biggest
Symptom_summary(WORSE_THAN_BASELINE) 
Else 
Symptom_summary(WORSE_THAN_LAST_WEEK) 
}
else if (TWS-BL == [15, 20, or 25]) || (TWS-PWS == [15, 20, or 25])
Callback(OFFER_CALLBACK);
If BL < PWS  #display page for whichever difference is biggest
Symptom_summary(SOMEWHAT_WORSE_THAN_BASELINE) 
Else 
Symptom_summary(SOMEWHAT_WORSE_THAN_LAST_WEEK) 
else if (TWS-BL == [5 or 10]) || (TWS-PWS ==[5 or 10])
Callback(NO_OFFER_CALLBACK);
If BL < PWS  #display page for whichever difference is biggest
Symptom_summary(SLIGHTLY_WORSE_THAN_BASELINE) 
Else 
Symptom_summary(SLIGHTLY_WORSE_THAN_LAST_WEEK) 
else if (TWS == BL) || (TWS == PWS) 
Callback(NO_OFFER_CALLBACK);
If BL = TWS  #display page for whichever is correct
Symptom_summary(SAME_AS_BASELINE) 
Else 
Symptom_summary(SAME_AS_LAST_WEEK) 
else if (TWS<BL) || (TWS<PWS) #will always be better than both if it gets here
Callback(NO_OFFER_CALLBACK);
If BL < PWS  #display page for whichever difference is smallest
Symptom_summary(BETTER_THAN_BASELINE) 
Else 
Symptom_summary(BETTER_THAN_LAST_WEEK) 
}
}
 
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Appendix 5 – iTREAT Phone Recruitment Script
This is [insert name]________ from [name of practice]__________. Can I 
speak to ____________?
[When the person answers, tell the patient]: This is __________ calling from 
Dr. ______’s office.  Dr. _______ invites you to be part of a national study that 
tests different ways to deal with asthma symptoms in order to reduce asthma 
attacks, emergency room or hospital visits, and missed work or school. 
We’re calling patients like you who may be eligible to participate in this 
voluntary study.  Would you like to hear more?”  [If person responds “yes”, 
then continue.  If person responds “no”, please thank them for their time and 
end call].
Our records indicate that you have had an asthma attack in the past year or 
that your asthma may not be fully controlled. Over the 3 months of this study 
you will have one study contact to enroll.  This can be done virtually or you can 
come into the research office and will take about one hour.  We will review the 
consent form, and if you agree to participate be randomly assigned (like the 
flip of a coin) to one of four study groups. Every participant will be given access 
to online asthma symptom tracking tools called Asthma Symptom Monitoring 
(ASM) that has been shown to help manage asthma symptoms.  The four 
groups are:
o Group One: only use ASM and continue with your normal asthma 
care.
o Group Two: use ASM and an antibiotic pill added to your current 
asthma medicines. This pill has been demonstrated to help many 
people with asthma. 
o Group Three: use ASM with the addition of inhaled corticosteroids 
with your rescue medicine – also known as Rescue Inhaled 
 
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CorticoSteroids (R-ICS). Another approach which has been shown 
to help many people with asthma.
o Group Four: use ASM and both an antibiotic pill and R-ICS.
If you are in a group that adds new medicines or inhalers, you and/or your 
insurance will be responsible for paying for them.  No medications are 
provided by the study.
Each month during the study you will answer questions about your asthma, 
asthma medication use and how your asthma is affecting you.  These can be 
answered online with a smart phone, with a research staff person over the 
phone, or a computer. The surveys take about 10 minutes each month. You 
will be compensated for your participation.
Whatever you decide about being in the study will have no effect on your 
medical care here.  The doctor and practice will provide all care as usual if you 
decide not to participate in this study.
What questions do you have?
[Answer all questions- if you don’t know the answer, please contact study 
staff so that we can answer!]
If patient is willing to participate, schedule next appointment. 
 
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Appendix 6 – Text Survey Reminder Messages
Day 26
•
Take your iTREAT survey at xxxx://xxxxxxx.xx/xxxx. Payment will be 
added about 2 business days after completion. Do it within 6 days to 
enter raffle.
Day 28
•
Take your iTREAT survey at xxxx://xxxxxxx.xx/xxxx. Payment will be 
added about 2 business days after completion. Do it within 4 days to 
enter raffle.
Day 30
•
Take your iTREAT survey at xxxx://xxxxxxx.xx/xxxx. Payment will be 
added about 2 business days after completion. Only 2 days left to enter 
raffle.
 
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Appendix 7 – Email Survey Reminder Message
Subject: iTREAT Monthly Survey Reminder
Hello [name], 
Please complete your iTREAT monthly survey. Just a reminder, your payment 
will be added about 2 business days after you finish your survey. 
Please click the link below to access the survey. 
[INSERT SHORT URL]
If the link above does not work, try copying the link below into your web 
browser:
[INSERT LONG URL]
This link is unique to you and should not be forwarded to others.
Thank you,
The iTREAT Team
 
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Appendix 8 – Consent Check Questions
1.
You will be asked to complete surveys…[INSERT AT THE END OF SECTION, “NUMBER OF 
SUBJECTS AND LENGTH OF STUDY PARTICIPATION”]
⃝ Once more
⃝ Every 6 months
⃝ Each month
2.
How many more study visits will you have after today? [INSERT AT THE END OF SECTION, 
“SUBJECT RESPONSIBILITIES”
⃝ 0
⃝ 1
⃝ 2
⃝ 3
3.
Will you still be able to get medical care for asthma from your usual clinicians whether or not 
you decide to be part of this study? [INSERT IMMEDIATELY BEFORE SECTION, “RISKS FOR STUDY 
ACTIVITIES”
⃝ Yes
⃝ No
 
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Appendix 9 – Follow-up Message to Participants that Didn’t Receive 
the End of Study Question(s) at 3 Months.
Dear iTREAT participant,
Thank you for recently completing your Month 3 survey. Please take a moment 
to complete 1 to 3 questions that were not included in the last survey.    You 
may access the questions by clicking this link.  For questions or comments, you 
may respond directly to this email or call 1-800-460-9052. 
Thank you,
iTREAT Study Team
 
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Appendix 10 – End of Study Email Notification to Participants 
Thank you for participating in the iTREAT feasibility study. Your participation 
will help us develop a better study and hopefully find better ways to treat 
asthma. We hope your asthma has improved. 
If you are taking study medications, discuss with your doctor whether to 
continue your study medication. Thanks again, please contact us at 
itreat@dartnet.info or 1-800-460-9052 if you have any further questions.
The iTREAT Study Team
 
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