Clinical trial NCT02995733
Conditions: Asthma
Keywords: asthma African Americans Hispanics
Sponsor: Brigham and Women's Hospital
Start date: 2017-11-27; Completion date: 2021-04-30
Enrollment: 1220 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Asthma imposes a significant burden in the US in terms of morbidity, costs to society, individual suffering, loss of productivity and mortality. African Americans (AA) and Hispanic/Latinos (H/L) bear a disproportionate share of that morbidity. Despite national guidelines for asthma treatment, the gap between these groups and whites has been stable or widening. The need for pragmatic research to address the continuing burden is widely recognized. Patients use asthma reliever inhalers to provide immediate relief of symptoms. Controller inhalers (inhaled corticosteroids (ICS)) are intended to be used regularly to prevent symptoms and attacks. Guidelines suggest that they be used daily, on a fixed basis, in all but the mildest asthma. However, adherence by patients and implementation of evidence-based guideline recommendations by clinicians has been poor. Gap analysis suggests that it is difficult to improve adherence to the current recommendations without complex and resource-intensive interventions. Studies have examined symptom-activated use of ICS triggered by use of a reliever medication. The Investigators call this approach PARTICS - Patient Activated Reliever-Triggered Inhaled CorticoSteroid. Explanatory, non-real world studies suggest that PARTICS can produce up to 50% reductions in asthma attacks compared with usual care, while reducing ICS use by half or more. These studies have been performed in pre-selected populations, which represent less than 5% of asthma patients. The previous studies have been done with repeated education and adherence checks in both the intervention and control arms.

The investigators have consulted with AA and H/L patients, health care providers, leaders of professional societies, advocacy groups, health policy leaders, pharmacists, and pharmaceutical manufacturers. All groups have indicated that asthma decision making would be changed if we demonstrated that implementing PARTICS improves important asthma outcomes such as reducing exacerbations. The Investigators have designed a study with the stakeholders to determine whether PARTICS can improve outcomes that are important to patients when superimposed on a background provider-educated standard of care through the Asthma IQ system. The Investigators propose a study entitled PREPARE: Patient Empowered Strategy to Reduce Asthma Morbidity in Highly Impacted Populations. The Investigators aim to determine whether PARTICS can reduce asthma morbidity in AA and H/L.

Detailed description:
Asthma imposes a significant burden on the US population in terms of morbidity, costs to society, individual suffering, loss of productivity and mortality. African Americans (AA) and Hispanic/Latinos (H/L) bear a disproportionate share of that morbidity. Despite introduction of national guidelines for asthma treatment, the gap between these groups and whites has been stable or widening. The need for pragmatic research to address the continuing burden is widely recognized. Patients use asthma reliever inhalers to provide immediate relief of symptoms. Controller inhalers (inhaled corticosteroids (ICS)) are intended to be used regularly to prevent symptoms and attacks. Guidelines suggest that they be used daily, on a fixed basis, in all but the mildest asthma. However, adherence by patients and implementation of evidence-based guideline recommendations by clinicians has been poor. Gap analysis suggests that it is difficult to improve adherence to the current recommendations without complex and resource-intensive interventions.

Studies have examined symptom-activated use of ICS triggered by use of a reliever medication. We call this approach PARTICS - Patient Activated Reliever-Triggered Inhaled CorticoSteroid. Explanatory, non-real world studies suggest that PARTICS can produce up to 50% reductions in asthma attacks compared with usual care, while reducing ICS use by half or more. However, these studies have been performed in pre- selected populations, which represent less than 5% of patients with asthma. They have been done with repeated education and adherence checks in both the intervention and control arms.

The investigators have consulted with AA and H/L patients, health care providers, leaders of professional societies, advocacy groups, health policy leaders, pharmacists, and pharmaceutical manufacturers. All groups have indicated that asthma decision making would be changed if it was demonstrated that implementing PARTICS improves important asthma outcomes such as reducing rates of exacerbations. Together with our partners and stakeholders, the investigators have designed a study to determine whether PARTICS can improve outcomes that are important to patients when superimposed on a background provider-educated standard care through the Asthma IQ system. The investigators therefore propose a study entitled PREPARE: Patient Empowered Strategy to Reduce Asthma Morbidity in Highly Impacted Populations. The aim is to determine whether a PARTICS strategy can reduce asthma morbidity in AA and H/L. The primary outcome will be asthma exacerbations which have been shown to be important to patient and healthcare stakeholders. The secondary outcomes will include additional outcomes important to patients (i.e. days lost from work or school, asthma control, \& asthma quality of life). The investigators have broad input and involvement from multiple stakeholder groups in study design, implementation, and commitments for dissemination. AA and H/L patients and their advocates have been involved and will continue to play a central role in all phases of the study.

Arms: arm 1: addition of PARTICS strategy - Patient Activated Reliever-Triggered Inhaled CorticoSteroid (PARTICS) using QVAR . Patient will use inhaled corticosteroid at time of rescue inhaler use arm 2: Provider-enhanced usual care arm; no change in asthma management
Interventions: intervention 1: PARTICS using QVAR
Intervention descriptions: intervention 1: Patient takes inhaled corticosteroid at the time of rescue inhaler use

Protocol documents:
Prot_SAP_002.pdf: 
1 
 
Detailed Protocol 
 
Protocol Title: ‘Patient Empowered Strategy to Reduce Asthma Morbidity in Highly Impacted 
Populations (PREPARE) 
 
Principal Investigator: Elliot Israel, MD 
 
Version Date: 09/13/2021 
 
 
Detailed Protocol Table of Contents 
 
 
Protocol Summary .................................................................................................................. 5 
I.  Introduction ......................................................................................................................... 6 
A. Research Questions, Hypotheses, and Study Aims ..................................................... 6 
1. Vanguard ....................................................................................................................... 6 
2. Full study ....................................................................................................................... 6 
B. Background..................................................................................................................... 7 
a. Impact of asthma in the general population ................................................................... 7 
2. Asthma in African Americans and Hispanics and Latinos ............................................... 8 
3. Personal burden of asthma—our patient collaborators’ perspective .............................. 9 
4. Gaps in evidence: problems with current asthma treatment guidelines .......................... 9 
5. Barriers to adherence to controller asthma therapy ........................................................ 9 
6. Alternative approaches to managing asthma: ...............................................................10 
(a) the ‘Patient-Activated Reliever-Triggered Inhaled CorticoSteroid (PARTICS ...............10 
(b) Effectiveness and Efficaciousness of comparator group in situations outside PFA ......10 
7. Evidence supporting the PARTICS strategy..................................................................10 
C. Significance ...................................................................................................................12 
1. Support by Patient Partners and Stakeholders .............................................................12 
2. Dissemination and Sustainability ..................................................................................12 
(a) Reciprocal Relationships: ............................................................................................13 
(b) Co-learning: ................................................................................................................13 
(c) Partnership: .................................................................................................................13 
(d) Trust, Transparency, ...................................................................................................14 
3. Potential to improve healthcare and outcomes .............................................................14 
4. Patient-Centeredness ...................................................................................................14 
(a) Appropriate Engagement of Patients and Stakeholders ..............................................15 
(b) Assuring Representativeness of the Population and the Data .....................................15 
(c) Using Patient Reported Outcomes ..............................................................................15 
(d) Supporting Dissemination ...........................................................................................15 
5. Summary ......................................................................................................................15 
(a) Vanguard: ...................................................................................................................15 
(b) Full Study ....................................................................................................................16 
II. Study Design, Population, and Participant Recruitment .................................................16 
A. Study Overview and Organization ................................................................................16 
1. Vanguard ......................................................................................................................16 
2. Full study ......................................................................................................................18 


2 
 
B. Full study differences: ..................................................................................................18 
Sample size, age, gender, race, ethnicity, clinical status ..................................................19 
1. Vanguard ......................................................................................................................19 
2. Full Study .....................................................................................................................19 
3. Participant subgroups (Full study only) .........................................................................19 
C.  Participant Recruitment, Screening, Enrollment, and Follow-up ..............................21 
1. Eligibility Criteria ...........................................................................................................21 
2. Recruitment and Screening ..........................................................................................23 
(a) Patient Enrollment System (PEERS)-..........................................................................23 
3. Randomization Scheme ................................................................................................23 
4. Allocation Concealment ................................................................................................24 
5.  Blinding/medications ....................................................................................................24 
6. Sample size: .................................................................................................................24 
7. Follow-up Intensity ........................................................................................................24 
8. Adherence to the intervention .......................................................................................25 
9. Enrollment and Restriction of participants .....................................................................26 
10. Source and volume of patients ...................................................................................26 
11. Justification of expected participation rate...................................................................27 
12. Maximizing adherence to the enrollment plan .............................................................27 
13. Literacy and Minority Issues .......................................................................................28 
14. Strategy for Balancing Internal Validity and Generalizability ........................................28 
(a) Degree of flexibility and complexity of intervention.......................................................28 
(b) Recruiting and Enrolling a Representative Population and Avoiding Selection Bias ....29 
15.   Other Full study changes ..........................................................................................29 
D.  Study Procedures .........................................................................................................29 
1. Informed Consent .........................................................................................................29 
2. Study Questionnaires ...................................................................................................30 
(a) PREPARE questionnaires ...........................................................................................30 
Asthma Control Test (ACT) ..............................................................................................31 
Asthma APGAR................................................................................................................31 
Asthma Symptom Utility Index (ASUI) ..............................................................................31 
Days Lost from Work or School ........................................................................................31 
Demographics ..................................................................................................................32 
Eligibility ...........................................................................................................................32 
Co-morbidities ..................................................................................................................32 
Asthma medications .........................................................................................................32 
Smoking status .................................................................................................................32 
Exacerbations in past 12 months ......................................................................................32 
Health Literacy-Brief Form ................................................................................................32 
The Beliefs about Medication Questionnaire (BMQ –Asthma Specific) .............................32 
Patient Health Questionnaire (PHQ)-2 ..............................................................................32 
Dose counter data for rescue ICS and SABA ...................................................................32 
Vanguard specific questions: ............................................................................................32 
(b) Questionnaires administered, by study phase and visit ...............................................33 
1. Vanguard [Complete] ....................................................................................................33 
2. Full Study .....................................................................................................................35 
3. Unbiased and systematic data collection: .....................................................................35 
4. Medications and reimbursement ...................................................................................36 
5. Fractional exhaled nitric oxide (FeNO) test: ..................................................................36 
6. Blood draw (Eosinophils): .............................................................................................36 
E. Participant and Patient Retention .................................................................................37 


3 
 
1. Database Design and Administration ............................................................................38 
2. Data Monitoring and Site Auditing ................................................................................39 
3. Methodology for Collecting Patient Consent and Questionnaire Data ...........................40 
4. Database Lock .............................................................................................................40 
F. Engagement Plan ...........................................................................................................40 
1. Stakeholder Groups ......................................................................................................40 
2. Organizational Participation of the Stakeholders ...........................................................41 
G. Project Milestones and Timeline ..................................................................................41 
III. Study Outcomes and Statistical Analysis .......................................................................42 
A. Patient-centeredness of PREPARE outcomes .............................................................42 
B. Primary Outcome .........................................................................................................42 
C. Secondary Outcomes ..................................................................................................43 
1. Asthma Control: Asthma Control Test (ACT) score .......................................................43 
2. Preference Based Quality of Life: Asthma Symptom Utility Index (ASUI) ......................44 
3. Days Lost from Work or School or Usual activities ........................................................44 
4. FeNO ...........................................................................................................................44 
5. Blood draw/Eosinophils ................................................................................................45 
D. Exploratory Outcomes ..................................................................................................45 
E. Biostatistical Analysis, Statistical Design, and Sample Size ...........................................46 
1. Overview ......................................................................................................................47 
2. Background Data and Baseline Characteristics: ...........................................................47 
3. Treatment Compliance .................................................................................................48 
4. Statistical Analysis for Primary Outcome ......................................................................48 
5. Secondary Outcome Analyses ......................................................................................49 
6. Subgroup Analysis ........................................................................................................49 
7. Exploratory Analyses ....................................................................................................50 
8. Sample Size and Power Considerations .......................................................................51 
9. Interim Analysis ............................................................................................................51 
10. Addressing missing data .............................................................................................52 
IV. Research team ..................................................................................................................53 
A. Overview ........................................................................................................................53 
B. Clinical Coordinating Center at Brigham and Women's Hospital ...............................53 
C. Practice Based Research Networks: American Academy of Family Physicians 
(AAFP) National Research Network (NRN): ..................................................................53 
D. Johns’ Hopkins Adherence Center ...............................................................................54 
E. Data Coordinating Center and Statistical Analysis at Duke (Duke Clinical Research 
Institute (DCRI)) .............................................................................................................54 
F. Clinical Sites ...................................................................................................................54 
G. Back-up sites .................................................................................................................57 
H. Site Management and Monitoring .................................................................................57 
I. Research Staff--Site Interactions ...................................................................................58 
V. Drug supplies .....................................................................................................................59 
VI. Patient Partners/Stakeholder Feedback ..........................................................................59 
A. African-American Patient Partners ...............................................................................59 
B. Hispanic/Latino Patient Partners ..................................................................................59 
C. Patient Advocacy .........................................................................................................60 
D. Healthcare Providers....................................................................................................60 
E. Professional Societies ..................................................................................................60 
F. Health Policy Experts ...................................................................................................60 


4 
 
G. Expert Scientific Advisors ............................................................................................60 
VII. Protection from Risk, Adverse Events, Asthma Exacerbations, and Safety Monitoring
 ...........................................................................................................................................60 
A. Human Subjects Involvement and Characteristics .....................................................60 
1. Human Subject Enrollment ...........................................................................................60 
2. Sources of Materials .....................................................................................................61 
B. Risks to Human Subjects ..............................................................................................62 
1. Change in medications .................................................................................................62 
2. Inhaled Corticosteroids Risks .......................................................................................62 
3. Asthma Questionnaires Risks .......................................................................................63 
4. Procedural Risks ..........................................................................................................63 
5. Blood Draw Risks: ........................................................................................................63 
C. Adequacy of Protection Against Risks ........................................................................63 
1. Recruitment and Informed Consent ..............................................................................64 
2. Risk of asthma exacerbation ........................................................................................64 
3. Risk of excess inhaled corticosteroid use .....................................................................65 
4.  Adverse Event Monitoring ............................................................................................65 
(a) Asthma-Related Adverse Events: ................................................................................65 
(b) Non-Asthma Adverse Events ......................................................................................65 
(c) Serious Adverse Events: .............................................................................................65 
5. Management of Asthma Exacerbations ........................................................................65 
6. Data and Safety Monitoring Plan ..................................................................................66 
7. Risk to Data Confidentiality ...........................................................................................66 
8. Inclusion of Women and Minorities ...............................................................................66 
9. Inclusion of Children/Adolescents .................................................................................67 
D. Potential Benefits and Importance of the Knowledge to be Gained ...........................67 
1. Benefits to Human Subjects and Others .......................................................................67 
2. Knowledge to be Gained ..............................................................................................68 
VIII. Data Sharing and Trial Information ................................................................................68 
A. ClinicalTrials.gov ...........................................................................................................68 
B. Data Sharing Plan ..........................................................................................................68 
IX. Nebulizer Qualitative Sub study ......................................................................................69 
X.  COVID-19 Sub study .........................................................................................................70 
List of Abbreviations ..............................................................................................................70 
XI. References ........................................................................................................................71 
XII. FIGURES ...........................................................................................................................85 
Figure 1. PREPARE Overall Study Structure ....................................................................85 
Figure 2. PREPARE Participant Flow Diagram .................................................................86 
Figure 3. Project Milestones and Timeline .......................................................................87 
XIII. Tables ..............................................................................................................................88 
Table 1: Estimated Final Racial/Ethnic and Gender Enrollment Table ...........................88 
XIV. APPENDIX .......................................................................................................................89 
A. Vanguard Interview Questions: Qualitative Interview - 12 weeks [complete] ............89 


5 
 
Protocol Summary 
 
Asthma imposes a significant burden on the US population in terms of morbidity, costs to 
society, individual suffering, loss of productivity and mortality. African Americans (AA) and 
Hispanic/Latinos (H/L) bear a disproportionate share of that morbidity. Despite introduction of 
national guidelines for asthma treatment, the gap between these groups and whites has been 
stable or widening. The need for pragmatic research to address the continuing burden is widely 
recognized. Patients use asthma reliever inhalers to provide immediate relief of symptoms. 
Controller inhalers (inhaled corticosteroids (ICS)) are intended to be used regularly to prevent 
symptoms and attacks. Guidelines suggest that they be used daily, on a fixed basis, in all but 
the mildest asthma. However, adherence by patients and implementation of evidence-based 
guideline recommendations by clinicians has been poor. Gap analysis suggests that it is difficult 
to improve adherence to the current recommendations without complex and resource- intensive 
interventions. 
 
Studies have examined symptom-activated use of ICS triggered by use of a reliever medication. 
We call this approach PARTICS – Patient Activated Reliever-Triggered Inhaled CorticoSteroid. 
Explanatory, non-real world studies suggest that PARTICS can produce up to 50% reductions in 
asthma attacks compared with usual care, while reducing ICS use by half or more. However, 
these studies have been performed in pre- selected populations, which represent less than 5% 
of patients with asthma. They have been done with repeated education and adherence checks 
in both the intervention and control arms. 
 
We have consulted with AA and H/L patients, health care providers, leaders of professional 
societies, advocacy groups, health policy leaders, pharmacists, and pharmaceutical 
manufacturers. All groups have indicated that asthma decision making would be changed if we 
demonstrated that implementing PARTICS improves important asthma outcomes such as 
reducing rates of exacerbations. Together with our partners and stakeholders, we have 
designed a study to determine whether PARTICS can improve outcomes that are important to 
patients when superimposed on a background provider-educated standard care through the 
Asthma IQ system. We therefore propose a study entitled PREPARE: Patient Empowered 
Strategy to Reduce Asthma Morbidity in Highly Impacted Populations. We aim to determine 
whether a PARTICS strategy can reduce asthma morbidity in AA and H/L. Our primary outcome 
will be asthma exacerbations which have been shown to be important to patient and healthcare 
stakeholders. Our secondary outcomes will include additional outcomes important to patients 
(i.e. days lost from work or school, asthma control, & asthma quality of life). We have broad 
input and involvement from multiple stakeholder groups in study design, implementation, and 
commitments for dissemination. AA and H/L patients and their advocates have been involved 
and will continue to play a central role in all phases of the study. 
 


6 
 
I.  Introduction 
 
A. Research Questions, Hypotheses, and Study Aims 
 
1. Vanguard 
 
Research Questions: 
 
a) 
Are our study operations and processes functional? 
 
These operations and processes include: 
● enrollment process for sites 
● enrollment process for study participants 
● communication with patients 
● communication with physicians 
o is each of our methods of communication effective? 
▪ 
Written 
▪ 
Teleprompt response system 
▪ 
Web system 
● Mobile 
● Desktop 
● drug delivery system 
● does the Propeller system help us understand whether patient adherence 
based on patient-reported outcomes is accurate? 
 
b) What are the barriers to study implementation? 
c) Do patients understand what we mean to communicate to them? 
 
 
Specific Aims: 
 
a) 
To determine whether our study operations and processes are functional. 
 
• 
These operations and processes include the enrollment process for sites and for study 
participants, our communication with patients and with physicians (which include written 
communication, teleprompt response system, web system via mobile and desktop), our 
drug delivery system, and the Propeller system. 
 
b) 
To determine what are our barriers to study implementation. 
 
c) 
To determine whether patients understand what we mean to communicate to them. 
 
 
2. Full study 
 
Full study differences from the Vanguard: The Vanguard is testing the study design and 
process with no Hypothesis testing. The full study outcomes are listed below as well as the 
hypothesis. 
 
Research Question: 


7 
 
 
 
Primary: 
In patient populations that bear a disproportionate burden of asthma morbidity (African 
American and Hispanic/Latino adults) can a patient-empowered PARTICS (Patient- Activated 
Reliever-Triggered Inhaled CorticoSteroid) strategy improve outcomes of importance to 
patients, providers, and the health care system? 
 
Secondary: 
1) Does the effectiveness of PARTICS differ by race/ethnic group (AA vs. H/L). 
 
2) Does the effectiveness differ by smoking status? 
 
Exploratory: How do patient characteristics and patient reported barriers influence PARTICS’ 
effectiveness? 
 
 
Hypothesis: 
In these populations, a patient-empowered strategy of use of ICS triggered by patient use of 
short-acting beta-agonist (SABA) reliever for quick symptom relief (“rescue use”) will reduce 
asthma exacerbations and improve other outcomes important to patients and the health care 
system. 
 
 
Study Aims: 
Working with patient & health system stakeholders, we will conduct a pragmatic real-life study 
in a population of African American and Hispanic/Latino adults disproportionately impacted by 
asthma. 
 
Specific Aim 1: To assess whether a Patient Activated, Reliever-Triggered Inhaled 
CorticoSteroid (PARTICS) strategy can reduce asthma morbidity in this population. 
-Our primary outcome will be asthma exacerbations which have been shown to be 
important to patients and healthcare stakeholders. 
-Our secondary outcomes will include additional outcomes important to patients such as 
days lost from work or school, asthma control, and asthma related quality of life. 
 
Specific Aim 2: To examine whether the effectiveness of a Patient Activated, Reliever-
Triggered ICS (PARTICS) strategy differs between African American or Hispanic/Latino 
adults or by smoking status. 
 
Exploratory Aim: To examine, whether particular patient clinical characteristics (e.g. prior 
exacerbations) or specific barriers to adherence (e.g. beliefs, depression) impact the 
effectiveness of a PARTICS approach in these populations. 
 
 
B. Background 
 
a. Impact of asthma in the general population 
 
Almost 1 in 12 Americans currently have asthma--18.7 million adults (CDC 2014). It 


8 
 
accounts for 1.75 million emergency room visits in the US each year, more than 
14.2 million outpatient visits, and 439,000 hospitalizations, with average stay length at 
3.6 days (CDC 2014). From 2002-2007, annual direct costs of asthma in the US was 
$50.1 billion; indirect costs such as lost productivity contributed an additional $5.9 billion 
(Barnett 2011). Given rising asthma rates, this is likely an underestimate of current costs. 
Asthma attacks, or exacerbations, result in extensive morbidity. In 2011, an estimated 9.1 
million Americans had an asthma attack (CDC 2012). These attacks result in significant 
individual suffering and loss of productivity. Thirty-three percent of adults who had asthma 
attacks missed work as a result. On average, adults miss five days of work per year because of 
asthma attacks (CDC 2011). Among adults, asthma is the fourth leading cause of work 
absenteeism and "presenteeism," accounting for more than 10 million missed days of work and 
an additional 5 million days of "less productive" workdays each year (MMWR 2002). 
Asthma exacerbations drive more than 50% of asthma-related acute health care costs (Reddel 
2009, Lane 2006) and are associated with progressive loss of lung function (O'Byrne 2009), 
leading to long-term morbidity and disability. Avoiding exacerbations is a high priority for 
patients. Asthma can also be deadly. In 2011, 3,345 Americans died of asthma; 94% were 
adults (Hoyert 2012). 
These death rates are twice that of thyroid cancer and 35% that of melanoma. 
 
2. Asthma in African Americans and Hispanics and Latinos 
 
Asthma has a broad impact on African American (AA) and Hispanic and Latino (H/L) 
populations stemming from disparities in disease-specific and healthcare-specific factors. 
These groups bear a disproportionate share of asthma morbidity and mortality (Gold 2005). 
Asthma is more prevalent in these populations (35% and 100% higher in AA and H/L, 
respectively than in Caucasians) (Akinbami 2011, Moorman 2011, Rose 2006, Smith 2005). 
There are also disparities in morbidity independent of prevalence. Both AAs and H/Ls have 
double the rates of asthma related ED (emergency department) visits and hospitalizations as 
Caucasians (Crocker 2009, Ginde 2008, Law 2011, Ash 2006, Boudreaux 2003, Gupta 2006), 
and 50% higher rates of re-hospitalization (Ash 2006). African Americans experience two to 
three times the death rate due to asthma as Caucasians. Among Puerto Rican H/Ls, rates of 
asthma exacerbations are 30% higher (Moorman 2013) and asthma-related death rates are 
75% to 200% higher (Homa 2000). Our team recently completed a study comparing two long- 
acting bronchodilator asthma medications in >1,000 African Americans across the country 
(BELT study submitted for publication). One-third of the subjects had an exacerbation requiring 
corticosteroids in a year. 
 
 
Health care and use of asthma medications differs in AA and H/L populations compared with 
whites as well. AAs are less likely than non-Hispanic whites to receive asthma care that follows 
guidelines (e.g., use of inhaled corticosteroids), and to be educated on self- management 
strategies (Krishnan 2001). H/Ls with current asthma have a 60% higher likelihood of having a 
health service deficit (a composite variable defined as health insurance status, having a 
healthcare provider and a routine physical exam, and deferring medical care due to cost) 
(Lutfiyya 2011). They also are found to have decreased access to asthma specialists (Clement 
2008) and to insufficiently use anti- inflammatory medications (Hunninghake 2006). Both AAs 
and H/Ls are less likely than whites to receive adequate and timely follow up after ED treatment 
for asthma (64% and 41% less likely, respectively) (Shields 2004). Of greatest concern, 
although the morbidity seems to be decreasing among whites, it is not changing among 
minorities. Asthma ED visits decreased by 25% in whites (p=0.02) from 1993 to 2005 but did 


9 
 
not change in AA (p=0.8) (Ginde 2008) and the gap in hospitalizations appears to be widening 
(Getahun 2005). 
 
3. Personal burden of asthma—our patient collaborators’ perspective 
 
The personal burden of asthma cannot be overlooked. Here are just three comments 
from stakeholder patients with asthma that we obtained from focus groups with AA and H/L 
patients with asthma in the spring of 2014: "I felt like we had to live in a cocoon to manage 
asthma." "My mom had a scared look in her eye when I was in the ED. I couldn't breathe, but it 
made me feel even worse to see my mom with that scared look." "My employer said to me 'You 
have a choice to make: either be at work or be at home.' The realistic fact is I am at home and I 
am broke, but my children's well-being means the world to me." 
 
4. Gaps in evidence: problems with current asthma treatment guidelines 
 
As reviewed above, asthma morbidity continues to remain high and mortality persists. 
Current National Asthma Education and Prevention Program (NAEPP) guidelines 
recommend regular use of an inhaled corticosteroid in all but the mildest cases (NAEPP 
2007). Increased use of inhaled corticosteroids has been associated with decreased asthma 
mortality independent of asthma severity (Suissa 2000). 
Unfortunately, clinicians have failed to implement these guidelines. Further, patient do not use 
daily inhaled corticosteroids when prescribed. They fill an average of only three months of 
prescriptions (rather than 12 months) over the course of a year (Apter 2011, Williams 2010, 
Stempel 2005, Delea 2008). Many efforts have been aimed at improving patient and provider 
guideline directed care with little success. 
A Cochrane review examined efforts to increase use of guidelines in chronic diseases, 
including asthma. It evaluated studies that measured both implementation of guidelines and 
outcomes (Haynes 2008). It concluded that “almost all of the interventions that were 
effective for long-term care were complex, including combinations of more convenient care, 
information, reminders, self-monitoring, reinforcement, counseling, family therapy, 
psychological therapy, crisis intervention, manual telephone follow-up, and supportive care. 
Even the most effective interventions did not lead to large improvements in adherence 
and treatment outcomes.” Given the difficulty of managing asthma, the Institute of Medicine 
(2009) believes that new approaches are necessary. It lists evaluations of alternative 
strategies for managing asthma in its top 100 comparative effectiveness research priorities. 
Thus, systematic reviews suggest that we have not been able to improve 
implementation of guidelines and patient self-management without using complex interventions. 
This problem is acute in asthma, especially in AA patients and subsets of H/L patients (see 
above section I.B.2), who bear a disproportionate share of asthma morbidity. A cross- 
sectional retrospective analysis from the National Ambulatory Medical Care Survey from 1998 
to 2004 showed that implementation of NAEPP guidelines was inadequate, especially for 
minority patients (Navaratnam 2008). Further, as mentioned above, despite improvements in 
overall asthma care, the disparities persist and may be widening (Ginde 2008, Gatahun 2005). 
 
 
5. Barriers to adherence to controller asthma therapy 
 
This approach leverages the way patients use their medicines for symptoms and 
bypasses many barriers to adherence such as forgetfulness, motivation, and fear of steroids 
discussed by our patients. 


10 
 
and the extent to which this intervention overcomes known potential barriers to asthma self- 
management, such as beliefs about medication, cost, forgetting medication, health literacy and 
depression. 
 
6. Alternative approaches to managing asthma: 
 
(a) the ‘Patient-Activated Reliever-Triggered Inhaled CorticoSteroid (PARTICS)’ strategy As 
reviewed in section I.C.3, ‘Potential to Improve Outcomes’, we have identified 
a low-complexity alternative strategy for reducing exacerbations that appears to have a high 
likelihood of being effective. It is a strategy that empowers patients. It bypasses much of the 
issue of adherence to regular ICS since it does not depend on the regular use of ICS. Rather 
than relying on complex interventions to increase adherence, it leverages current patient 
patterns of medication use--whenever a patient uses an asthma reliever medication, he or she 
will also use an inhaled corticosteroid (ICS). We call this a Patient-Activated Reliever-Triggered 
Inhaled CorticoSteroid (PARTICS) strategy. 
 
(b) Effectiveness and Efficaciousness of comparator group in situations outside PFA  
To reduce heterogeneity of the underlying treatment that is provided in both the intervention and 
the control, all sites will be applying what we refer to as “provider- educated care” which will be 
standardized by implementation of the instructional component of the Asthma IQ system 
Primary Care Version (www.asthmaiq.org). The comparison will be between adding the 
PARTICS intervention to provider educated care vs. continuing provider educated care alone. 
We will use the on-line provider instructional component of the Asthma IQ to provide the 
standard of “provider- educated care”. The Asthma IQ program was jointly developed by the 
American Academy of Allergy Asthma and Immunology (AAAAI) and the American Academy of 
Family Physicians. The complete program has two components; 1) an on-line instructional 
component for providers and 2) a web-based clinical decision support tool utilizing metrics from 
visits with feedback to providers regarding next treatment steps. 
The on-line instructional component of the Asthma IQ requires ~20 minutes to complete. The 
instructional component of the Asthma IQ has been shown to produce outcomes no different 
than the entire program. Further, it was shown to improve asthma outcomes as compared with 
baseline. Thus, based on the recommendations of our provider stakeholders, patient 
stakeholders, the Principal Investigator of the Asthma IQ study (Dr. Thomas Casale, who will 
serve as an expert advisor for Asthma IQ implementation) and expert stakeholders, we have 
adopted the instructional component of the Asthma IQ as our underlying standard of care. Only 
providers who have completed the instructional Asthma IQ will be able to enter and randomize 
their patients. The AAAAI has graciously agreed to make the modifications to the existing 
Asthma IQ site to accommodate “certification” of providers in our study (www.asthmaiq.org). 
While the Asthma IQ will not absolutely standardize all care, it will reduce variation across the 
enrollment sites. As noted in section III.E.9, ‘exploratory analyses’, we will examine in an 
exploratory manner, the effect of provider adherence on our comparison. While the Asthma IQ 
provider-educated care will likely improve outcomes as compared to non- standardized 
treatment at our sites, we do not believe that it will substantially interfere with our ability to 
demonstrate the superiority of PARTICS. PARTICS has been shown to be superior even to 
enforced NAEPP care. 
 
7. Evidence supporting the PARTICS strategy 
Systematic reviews of efficacy studies suggest that a PARTICS approach can reduce 
exacerbations by 25 to 50% (Cates 2013, Kew 2013) and more likely 40-50% in adults 
(O’Byrne 2006, Rabe 2006, Buhl 2012, Papi 2013, Calhoun 2012). One major gap in 


11 
 
knowledge is whether such results are achievable in a real-world setting with high-risk 
populations. Previous studies were explanatory studies with restricted patient entry. It is 
estimated that only 5% of asthmatics can enter such trials (Herland 2005, Travers 2007). The 
trials contained few if any AA or H/L. Further, some of these studies involved long- acting beta-
agonist withdrawal during the run in, and thus may have made the study populations more 
likely to respond to PARTICS (Cates 2013). Another knowledge gap is whether this reliever-
triggered approach can be implemented in health care systems that treat substantial numbers 
of minority patients. Review articles and a recent editorial have called for this strategy to be 
tested in different asthma populations and varied real-world settings (Beasley 2014, Papi 
2009). We have strong data from efficacy studies to suggest that a PARTICS approach will be 
successful. As mentioned in section I.B.5 above, ‘barriers to adherence to controller asthma 
therapy’, a major implementation barrier to asthma pharmacotherapy involves issues of patient 
acceptance and patient activation. Current national guidelines recommend daily ICS therapy for 
asthma control. However, patients fill less than a quarter of their ICS prescriptions and asthma 
morbidity remains high (Apter 2011, Williams 2010). Dr. 
Israel (senior author) and his colleagues first demonstrated that symptom-based (but not 
reliever-triggered) use of inhaled corticosteroids yields levels of asthma control no worse than 
those produced by regular use of inhaled corticosteroids (Boushey 2005). This led us and 
others to develop and study the PARTICS approach, which involves using an ICS triggered by 
the use of a reliever medication. ICS + SABA and ICS/Long-acting beta-2 agonists (LABA) 
PARTICS-type approaches have been shown to substantially improve asthma outcomes. A 
PARTICS strategy reduced exacerbations by >70% compared with beta- agonists alone and 
produced outcomes equal to that of enforced continuous ICS therapy in a clinical efficacy trial 
(Papi 2007). Further, tightly controlled trials have compared: 1) PARTICS (in this case using 
symptomatic use of a LABA as the trigger) plus regular LABA/ICS therapy; 2) regular 
LABA/ICS; and 3) higher dose ICS therapy. PARTICS plus ICS/LABA was shown to reduce 
exacerbations by more than 50% when compared to ICS/LABA or higher dose ICS (O’Byrne 
2005). These results have been reproduced multiple times (Rabe 2006, Buhl 2012, Papi 2013). 
A systematic review of efficacy studies comparing PARTICS-type strategies with LABA plus 
ICS to regular LABA-ICS estimated a 17%-47% reduction in exacerbations (Kew 2013, Cates 
2013). This reduction occurred in the setting of reducing overall ICS use by almost half in the 
PARTICS groups. In addition to reducing exacerbations, these PARTICS strategies decreased 
asthma symptoms and nocturnal awakenings, and improved lung function, relative to fixed-
dose ICS treatment regimens. Most importantly, Dr. Israel initiated and participated in a study in 
patients with moderate asthma in which we compared the PARTICS approach to enforced 
NAEPP care (q 6 week visits with NAEPP-adjusted care by study staff). In that study, the 
PARTICS approach produced asthma control as good as or better than NAEPP care (Calhoun 
2012). The PARTICS patients used only half the amount of ICS as those receiving every-six-
week enforced physician-adjusted care. The magnitude of reduction of treatment failures was 
equivalent to that seen in other studies (41%) although it did not reach statistical significance in 
this 100 patient/arm 9-month study that was underpowered for this difference (20 exacerbations 
compared with an anticipated >350 in PREPARE). It is critical to understand that the improved 
outcomes with PARTICS occurred despite the fact that the NAEPP guidelines were 
enforced with a reported 90% adherence rate with ICS. As mentioned above, real world 
adherence rates are about 25%. Of note, the PARTICS approach significantly reduced days 
lost from school or work by more than half, again while using half the amount of ICS. In 
addition to the likelihood that PARTICS will improve outcomes including the use of oral 
corticosteroids, which is so dreaded by asthma patients, it has an additional benefit of generally 
resulting in less use of inhaled corticosteroid. Our patient partners, especially our H/L partners, 
have indicated that excess ICS use is a concern to them in addition to their fear of oral 


12 
 
corticosteroids. Decreasing ICS use does have the potential for reducing the small, but very 
real morbidity associated with ICS use, including osteoporosis (Israel 2001), and cataracts 
(Cumming 1997). Studies suggest that PARTICS can reduce ICS use by 50%-80% (Boushey 
2005, Papi 2007, Calhoun 2012, Cates 2013, Kew 2013). 
Although PARTICS-type strategies have been shown to significantly reduce 
exacerbations in carefully controlled efficacy studies by nearly 50%, “a key point to more 
generalized acceptance will be the need to conduct these trials in a real life environment,” 
writes Dr. Busse in a letter supporting this proposal (see Letter of Support, Organizational 
Support). Further, a pragmatic trial of the PARTICS approach among AAs and H/Ls has been 
strongly endorsed by our patient and professional stakeholders (see Section E. Engagement & 
Appendix). 
 
C. Significance 
 
1. Support by Patient Partners and Stakeholders 
 
Our patient partners have explicitly, and unanimously, agreed that if a PARTICS 
approach reduces exacerbations they would be interested in using this therapy and advocating 
for it. They have done so because the outcomes we propose to alter are important to them and 
the intervention is simple and might actually result in a decreased use of ICS as well as oral 
corticosteroids. Our other stakeholders have also been enthusiastic, including leaders of 
professional societies and advocacy groups. The president of one of the major allergy 
organizations said he “would invest in the company that makes” a PARTICS- type inhaler. 
Teva, a major drug company, has agreed to provide free inhaled corticosteroids because they 
believe that this approach will benefit patients. Teva has also agreed to act as our central 
pharmacy and set up electronic prescriptions for electronic health records. The Centers for 
Medicare & Medicaid Services has agreed to work as a stakeholder as well. 
Thus, we have extensive, enthusiastic support from patients and stakeholders. 
 
2. Dissemination and Sustainability 
 
As discussed in II.C.15.a, ‘Complexity of Intervention’, our patient partners and other 
stakeholders are attracted to this study due to the simplicity of the PARTICS intervention and 
the likelihood that it will succeed. The approach is intuitive and relies on the patient-preferred 
pattern of use of reliever medication. This will help make the intervention sustainable. We have 
concrete buy-in from partners and stakeholders who are key to supporting the sustainability 
and implementation of our intervention based on our findings. Several companies have begun 
to discuss development of a single device SABA/ICS should our study be positive. By involving 
Teva, who has agreed to manage the drug delivery, we will de facto be able to demonstrate 
that the delivery is feasible, sustainable, and scalable across the United States. We are also 
designing our intervention to be easily scalable and sustainable on the patient side by solely 
using short (5 minute or less) YouTube-type videos that will be available on the internet for 
instructions and explanation of the intervention, which will be shown in the office when the 
patient is enrolled. It would subsequently be easy to use these in any practice adopting this 
approach. Post-study, physicians wishing to learn the NAEPP guidelines could access it for 20 
minutes on the publicly available Asthma IQ site and receive CME credits and possibly 
maintenance of certification credits, further supporting sustainability on the provider-side. Our 
patient partners have agreed to help us present data in in their e-communities, and to their 
peers. Advocacy groups and professional society stakeholders have agreed to disseminate the 
results to their members and thus potentially create grass-roots demand. Our policy 


13 
 
stakeholders have received commitments to review these findings in their decision making 
bodies when the results have become available to classify the medications in the approach as 
the most reimbursable. The NAEPP has just determined that evaluation of the PARTICS 
approach will be among its top priorities for the next revision (Kiley 2015). We have indications 
from the prior chair of the last NAEPP that the study results would weigh heavily in 
consideration of the evidence based recommendations regarding PARTICS approaches. 
 
We have included specific proposals from each of our stakeholders in the Dissemination 
Section. We will have each stakeholder group have a representative on a Dissemination 
Committee led by Dr. Yawn who has extensive experience in implementation in primary care 
and family medicine practices. Some examples of how our stakeholders have already indicated 
their role in dissemination include:  
1. Participating in our presentation at public forums and peer led blogs and social media;  
2. Advocacy Groups – supporting grass roots campaigns for adoption of PARTICS; 
3. Specialty Societies providing forums for provider and patient presentations using new 
formats including webinars, and online programs;  
4. Insurers identifying pathways to get coverage for PARTICS medications, should the study 
be positive. See the Letters of Support, Organizational Support, for details. To consolidate 
and coordinate the plans for dissemination, we will devote part of our two-day meeting at 
the end of the study to review and plan dissemination.  
 
Our structure reinforces the PCORI engagement principles: 
 
(a) Reciprocal Relationships: 
 
Reciprocal relationships are reflected in the use of stakeholders’ insights and suggestions in 
the crafting of the study and this application as well as in ongoing study governance. The 
Executive Committee (EC) combines representatives from all stakeholder groups, not just the 
academic researchers to review and approve all major study decisions. The Operations 
Committee (OC) has assigned individuals to all stakeholder groups assuring participation and 
seeking feedback. Our initial attention to the recommendations of the stakeholders, as well as 
the initial face to face meeting, will further facilitate bidirectional communication and foster trust. 
 
(b) Co-learning: 
 
Co-learning has already occurred in the planning phases of this study. Each of the stakeholder 
groups has provided new insight and understanding incorporated into the development of 
PREPARE. The Vanguard cohort will provide another intense period of co- learning from the 
patients enrolled in this testing period as well as the stakeholders who will help assemble and 
interpret the feedback. The academic research team includes experts in interaction with each of 
our stakeholder groups with special emphasis on interaction and co- learning with the AA and 
H/L groups: Maureen Fagan, DNP; Jacqueline Rodriquez-Louis, MPH, MEd (AA asthma 
educator from the Caribbean); and co-investigator Juan Carlos Cardet, MD (allergist and native 
of Puerto Rico). 
 
(c) Partnership: 
 
All PREPARE stakeholders are equally valued partners. This is reflected in the structure of the 
EC, which includes representatives from patient and other stakeholder groups who will be a 
majority of the members of the EC. To ensure there are no barriers to communication, and thus 


14 
 
to partnership, interpreters and facilitators will be week available at all meetings. We have 
calibrated all stakeholder involvement to be respectful of the stakeholders’ time. Finally, all 
members of all stakeholder groups will receive equal compensation ($75/hr). 
 
(d) Trust, Transparency, Honesty: 
 
All stakeholders will participate in making major decisions and will have access to all study 
information beginning with representation of all groups on the EC. To date we have 
summarized and shared the comments from all stakeholders and highlighted back to the 
groups how this information has improved the study design including, for example, selection of 
outcomes, inclusion of the Vanguard cohort, and expansion of our Aims to include an important 
exploratory aim to better understand patient characteristics that may affect the success of the 
PARTICS strategy. Our stakeholders have continued to be willing to interact with the academic 
researchers and have been open in criticism as well as support for study design specifics. We 
believe this clearly demonstrates the great potential for ongoing trust and honesty in view of the 
transparency. 
We have used the elements of the PRISM (Practical, Robust Implementation and Sustainability 
Model) as described by Feldstein et al (Feldstein, 2008) to evaluate and structure our 
dissemination and implementation model and to evaluate and promote sustainability. The 
model emphasizes 6 elements within an effective PRISM model (Intervention (Organizational 
and Patient Perspective), External Environment, Implementation and Sustainability Structure, 
and Recipients (Organizational and Patient)). 
 
3. Potential to improve healthcare and outcomes 
 
Our proposal is important to patients and to healthcare systems because it: 1) is based 
on strong preliminary data suggesting that the proposed approach will lead to sizeable 
improvements in outcomes important to patients even when compared to enforced 
implementation of the NAEPP guidelines; 2) addresses an important gap— the 
disproportionate asthma morbidity among affected minority populations (see I.B.2); 
3) is strongly supported by patient and other relevant stakeholders; 4) is likely to be easy to 
disseminate; 5) will likely be sustainable because; a) it is intuitive for patients (treatment- 
preference concordance); b) it will be conducted with a real-life distribution system (Teva and 
electronic scripts in the EHR); and c) it is implemented with an easy, internet-accessible patient 
instruction system of short YouTube-like videos. We first review our preliminary data regarding 
PARTICS-type approaches, then review these other criteria of significance. 
 
The proposal has strong endorsement from all of our patient and other stakeholders. 
Our patient partners have all indicated support of this approach to reduce asthma morbidity in a 
way that they feel would be helpful to them. This has been seconded by our advocacy 
stakeholders and our professional society stakeholders. Our health policy and insurance 
stakeholders have similarly indicated enthusiasm. As further evidence of buy-in, Teva has 
agreed to collaborate with us to implement the study, and agreed to donate drug, retail cost 
almost $1 million. 
 
4. Patient-Centeredness 
 


15 
 
(a) Appropriate Engagement of Patients and Stakeholders 
 
We have already identified and engaged patients and stakeholders in study design and choice 
of outcomes (patients in our BELT study indicated they would like to experience fewer 
exacerbations). As discussed in those sections, patients and stakeholders will be active, 
important participants in choosing final study outcomes, study implementation, analysis, and 
dissemination. Patients and other stakeholders will serve on the trial’s governing Executive 
Committee. Each member of the Operations Committee will serve as a liaison to each 
stakeholder group, ensuring bidirectional communication throughout the study timeline. We 
have engaged patient participation facilitators to assure continued engagement throughout the 
study. All stakeholders are valued for their contribution and are equally compensated. 
 
(b) Assuring Representativeness of the Population and the Data 
 
Our plans for assuring representativeness are described extensively in II.C.15.c, in addition to 
representative recruitment, we are reducing barriers to enrollment and participation by 
providing the option of enrolling patients at home visits and with opportunities for patients with 
low literacy via verbal consent and the option to do the monthly surveys via phone interview by 
trained staff.   
 
(c) Using Patient Reported Outcomes 
 
We use patient reported outcomes almost exclusively. Asthma task forces have 
identified them as critical outcomes. Our outcome, asthma exacerbations, is now used as THE 
major outcome for studies of new therapies in asthma. These outcomes are of interest to 
patients and focus on events or states of health that adversely affect patients’ quality of life and 
ability to participate in usual activities, and result in loss of income or require financial 
expenditures. Our primary outcome, the rate of asthma exacerbations per year, is defined as 
the number of exacerbations, emergency room visits, or hospitalizations requiring oral or 
parenteral corticosteroids, per patient per year. It will be captured by subject self-report via a 
monthly asthma exacerbations questionnaire with follow up to the medical record or patient 
interview. All the study outcomes, their patient centeredness, and validation and properties are 
detailed in section III. 
 
(d) Supporting Dissemination 
 
PREPARE provides a strategy to help reduce excess asthma morbidity in AA and H/L 
populations. Our stakeholders are excited by this possibility. They have already indicated ways 
they will help to disseminate and implement this strategy by engaging with constituencies, 
insurance companies, distribution networks, and regulatory bodies to increase uptake and 
sustainability. Further, they will participate in a Dissemination Committee led by Dr. Yawn to 
help assure dissemination success. 
 
5. Summary 
 
(a) Vanguard: 
 
The Vanguard cohort of a subset of study participants will allow us to observe how well 
the protocol and materials work. This is a large, multi-centered, pragmatic trial, which implies 


16 
 
that the degree of investigator oversight is limited compared to traditional efficacy trials. The 
vanguard process attempts to compensate for limited oversight by testing appropriateness of 
our methods. The methods and issues we will test with the vanguard process include 
participant recruitment; the quality of our instructional videos and whether participants learn 
from them what we want them to learn; the accuracy of our eligibility questions to capture our 
population of interest; suitability of our consent form and registration process; capacity of our 
baseline intake and monthly surveys to capture variations in asthma control and exacerbations; 
randomization process; to assess the patients’ understanding and acceptance of the PARTICS 
strategy; and finally allow us to better understand how our group of researchers will interact 
with our patient stakeholders and others through our Operations Committee and our Executive 
Committee. We will use data from the vanguard process to modify our methods and approach 
to conducting the full PREPARE study. 
 
Full study difference: The Vanguard is testing process whereas the Full Study is testing the 
research question regarding PARTICS, explained below: 
 
(b) Full Study 
 
The optimal strategy for ICS use for the management of persistent asthma remains 
unknown. Daily ICS use seems excessive to some patients when their asthma symptoms are 
controlled, and insufficient when they experience asthma exacerbations. In this PREPARE trial 
we will determine whether the PARTICS strategy--of using additional ICS concomitantly with 
rescue inhaler use--can reduce asthma exacerbations while allowing patients to adjust their 
ICS dose based on their perception of the intensity of their symptoms. We will do this in the 
setting of a pragmatic, patient-centered clinical trial which allows for greater generalizability and 
easier implementation of our results. While asthma is burdensome in terms of morbidity, 
mortality and costs, it is disproportionately so for the African American (AA) and Hispanic/Latino 
(H/L) communities. Conversely, these racial/ethnic groups constitute the minority of participants 
recruited in clinical trials. 
PREPARE will address the need for pragmatic research to address the continuing 
burden of asthma in AA and H/L patients. In consultation with AA and H/L patients, health care 
providers, leaders of professional societies, advocacy groups, health policy leaders, 
pharmacists, and pharmaceutical manufacturers, results from PREPARE may demonstrated 
that implementing PARTICS may improve important asthma outcomes in these highly- 
impacted populations. 
 
 II. Study Design, Population, and Participant Recruitment 
 
A. Study Overview and Organization 
 
1. Vanguard 
 
This is a randomized, open-label trial in AAs and H/Ls 18 years and older* with asthma 
in which a standard of usual care, as requested by PCORI, is introduced (guided by the Asthma 
IQ educational program+ which we will call “provider educated care”), and then patients are 
randomized to addition of a PARTICS strategy vs. continuing this standard of provider-
educated enhanced usual care. Underlying care will be standardized via provider certification in 
the educational component of the online Asthma IQ program. Self-identified+ AA and H/L 
patients at risk for exacerbations (e.g. on controller ICS with poor control, previous history of an 
exacerbation in previous 12 months or using ICS/LABA) will be identified from the clinical sites’ 


17 
 
electronic health records and invited through their local provider’s office* to come for an 
enrollment visit. 
 
The “Vanguard” cohort of 36 patients (16 AA and 20 H/L) from four sites represent our 
study sites’ geographic, health system and practice size diversity; and patients that represent 
our anticipated enrollment of race, sex and age groups. Thirty two of the 36 (16 AA and 16 H/L) 
Vanguard patients will be English speaking patients enrolled 3:1 intervention (PARTICS) to 
non-intervention (enhanced usual care/Asthma IQ) so that we may observe how well the 
protocol and materials work. To test how the materials translated into Spanish work for the 
Spanish speaking patients, we will enroll 4 additional patients (total Vanguard patients 36) at 
one of the Vanguard sites that has a large Spanish speaking population (Mount Sinai). All 4 
Spanish speaking patients will be in placed in the intervention group to be able to sufficiently 
test the intervention materials. The intervention materials include everything included in the 
Usual Care group with additional materials. Each participant will be in the vanguard process for 
three months. After registration, vanguard participants will complete questionnaires at baseline 
(during registration) then two monthly questionnaires as the full study. In addition, the Vanguard 
cohort will be called at 1 week, 6 weeks and at 12 weeks to answer questions about the 
enrollment process, filling out the monthly questionnaires and the videos. The intervention 
group will be asked about the receiving the medication supplied by the study. The interviews 
will be audio recorded. This will enable transcription of the open-ended questions for the 
qualitative analysis. Those agreeing to attend the enrollment visit will have the study explained 
and complete informed consent facilitated by onsite study personnel or through video 
conferencing with central study staff. At the enrollment visit, entry criteria will be confirmed, 
consent obtained (potentially through a centralized 2-way video consent, baseline 
questionnaires completed, and the patient randomized (using a central randomization 
algorithm) to PARTICS with continuation of their provider-educated care or continued with their 
provider-educated care alone. Patients randomized to either study arm will watch a culturally 
appropriate video on proper inhaler technique followed by observation of 
the patient’s inhaler technique. All enrollees will also receive instructions on completion of 
monthly questionnaires and general questions will be answered via the video communications 
or by local staff as necessary. Each enrollee will select one of the patient-partner designed 
inhaler pouches and clip* to hold their quick relief inhaler(s). Those randomized to PARTICS 
will also view a patient partner-approved culturally appropriate video* that explains how and 
why to use the PARTICS dual quick relief medications (ICS+SABA). Patient questions 
regarding PARTICS will be answered in real time via video communication. At the close of the 
visit, PARTICS patients will receive or be mailed an ICS inhaler with a counter and a Velcro 
band* (used to attach the rescue ICS inhaler to the patient’s current SABA (ICS study drug 
donated by Teva.  For PARTICS ICS refills, patients will call the 800 number printed on the 
Velcro band when their counter reaches 40. Teva will send a new ICS inhaler directly to the 
address designated by the patient. 
 
All patients (both PARTICS and control groups) will be asked to complete monthly 
questionnaires using validated instruments to assess exacerbations, symptoms, medical visits 
primarily driven by asthma (visits, ED visits, and hospitalization) and medication use. At 
enrollment patients will choose how they wish to receive reminders as well as primarily 
complete the questionnaire (online, smart phone, mailed—exactly same questions and multiple 
choice answers for each method). Patients will be allowed to changes methods whenever 
requested. Several of the instruments have been validated to be comparable across these 
response methods (Schatz 2007a, Schatz 2007b, and Schatz 2007c). 
 


18 
 
Before sites begin enrolling patients the study team will host centralized training for the 
site PI and key practice personnel, and all clinic team members will be instructed about the overall 
study protocol and the PARTICS approach. 
 
 
2. Full study 
 
B. Full study differences: 
 
The Full study will enroll up to 1210 patients and will be conducted in up to 20 diverse health 
care settings across the country, the patients will be enrolled 1:1 intervention (PARTICS) to 
non-intervention. There will be one follow up call within the first month of enrollment to ask 
questions about the patients experience filling out the survey. There will be NO follow up calls to 
the patients at week 1, 6 and 12 to answer questions about the enrollment process, filling out 
questionnaires and the informational and instructional videos or questions to the intervention 
group about the medication supplied by the study. The patients will have one in person visit to 
enroll in the study then will receive monthly questionnaires for 12 to 15 months depending on 
when they are enrolled. Patients may also be given the option to enroll during a home visit.  
Home enrollment visits will include the same methods as on-site enrollment visits.  
 
 
Those agreeing to enroll will have the study explained and complete informed consent facilitated 
by study personnel. At the enrollment visit, entry criteria will be confirmed, consent obtained, 
baseline questionnaires completed, and the patient randomized (using a central randomization 
algorithm) to PARTICS with continuation of their provider-educated care or continued with their 
provider-educated care alone. Patients randomized to either study arm will watch a culturally 
appropriate video on proper inhaler technique followed by observation of the patient’s inhaler 
technique. All enrollees will also receive instructions on completion of monthly questionnaires 
and general questions will be answered staff as necessary. Each enrollee will select one of the 
patient-partner designed inhaler pouches and clip* to hold their quick relief inhaler(s). 
 
 
During the study visit, we will ask participants to exhale into a machine that determines nitric 
oxide gas levels in their breath. This procedure was not conducted in the Vanguard phase, and 
will only be conducted during the full study.  In addition, patients will be asked if they agree to 
have 3 mL’s of blood drawn for a complete blood count (CBC) with differential. The CBC results 
will include eosinophil counts that are associated with patients’ response to inhaled 
corticosteroids. Depending on the site, the patients will either have their blood drawn during 
their enrollment or be sent to a contracted laboratory in the area.  Samples will be processed 
either at the facility where the enrollment takes place, or by a contracted diagnostics company 
such as LabCorp.   
 
Those randomized to PARTICS will also view a patient partner-approved culturally appropriate 
video* that explains how and why to use the PARTICS dual quick relief medications 
(ICS+SABA). At the close of the visit, PARTICS patients will receive or be mailed an ICS inhaler 
with a counter and a Velcro band* (used to attach the rescue ICS inhaler to the patient’s current 
SABA (ICS study drug donated by Teva. In addition, patients randomized to PARTICS who 
answer “yes” to using a nebulizer on the intake questionnaire will receive a second ICS and an 
extra pouch to hold the ICS along with a Velcro strap to attach the additional pouch with the ICS 
to the nebulizer.  For PARTICS ICS refills, patients will call the 1-800 number printed on the 


19 
 
Velcro band when their counter reaches 20. Teva will send a new ICS inhaler directly to the 
address designated by the patient. All patients (both PARTICS and control groups) will receive a 
refrigerator magnet with adherence instructions. 
 
All patients (both PARTICS and control groups) will be asked to complete monthly 
questionnaires using validated instruments to assess exacerbations, symptoms, medical visits 
primarily driven by asthma (visits, ED visits, and hospitalization) and medication use. At 
enrollment, patients will choose how they wish to primarily complete the questionnaire (online, 
smart phone, mailed—exactly same questions and multiple-choice answers for each method). 
Monthly reminders to complete each monthly survey will be sent to patients through all methods 
of communication that the patient provides (text, email, phone call). Patients will be allowed to 
change methods whenever requested. Several of the instruments have been validated to be 
comparable across these response methods (Schatz 2007a, Schatz 2007b, and Schatz 2007c). 
In addition to monthly survey reminders, patients will also receive quarterly reminder text 
messages about the study and monthly surveys. Patients may opt out of the text messages at 
any time. 
 
Before sites begin enrolling patients, the study team will host centralized training for the site PI 
and key practice personnel, and all clinic team members will be instructed about the overall 
study protocol and the PARTICS approach. 
 
  
 
A. Patient Population 
 
Sample size, age, gender, race, ethnicity, clinical status 
 
1. Vanguard 
 
We will enroll 36 patients (16 AA and 20 H/L) that represent our study sites’ geographic, 
health system and practice size diversity. Each site will be asked to recruit a specific Race or 
Ethnicity for this small pilot based on the predominant Ethnic/Racial group at that site. 18-75 
years old without regard to gender. Race/ethnicity assignment will be based on self-
identification. For patients who self-identify in both categories, they will be randomized as H/L 
since studies on asthma in H/L include those patients as such. Based on our past experience, 
more than 70% will be female. We also expect that almost half will be active smokers or have a 
significant smoking history. Broadly, these patients will have asthma and be at risk for 
exacerbations. They either will have been prescribed ICS/LABA or if taking ICS without LABA 
will still have symptoms or have had an exacerbation in the past year. In our BELT study 
looking at use of long-acting bronchodilators, among >1,000 AA patients that we recruited who 
were either symptomatic on ICS or taking ICS+LABA, more than one- third had an 
exacerbation, of which 80% went to the emergency room. 
 
2. Full Study 
 
Full study difference: We will enroll up to 1210 patients: 605 AAs and 605 H/Ls. 
 
3. Participant subgroups (Full study only) 
 


20 
 
The subgroups of the total study population to be analyzed are AAs, H/Ls, smokers and 
non-smokers. Regarding AAs and H/Ls, the barriers to success of PARTICS may vary in the 
different racial/ethnic groups. In fact, in one PARTICS-type study, H/L appeared to benefit less 
from a PARTICS approach (Calhoun 2012).Therefore, we will perform a subgroup analysis in 
which we analyze AA and H/L separately using the definitions above regarding race/ethnicity 
assignment.Regarding smoking, according to the CDC’s 2010 Behavioral Risk Factor 
Surveillance System, about 21% of people with asthma are active cigarette smokers (CDC 
2010). Active smokers are well known to have increased asthma morbidity compared with non-
smokers (Lange 1998, Marquette 1992, Polosa 2013, Shavit 2007, Sippel 1999, Siroux 2000). 
More importantly, active smokers have a decreased therapeutic response to ICS as measured 
by asthma control scores, FEV1, and airway reactivity (Pederson 1996, Chalmers 2002, 
Lazarus 2007). Further, a study showed that this reduced therapeutic response to 
corticosteroids also occurs in former smokers with a greater than 10 pack-year smoking history 
(Chaudhuri 2003). In that study, both active smokers and former smokers had reduced FEV1, 
daytime symptom, and rescue medication use responses to corticosteroids as compared with 
those who smoke less than 10 pack-years. We will analyze current (within one year) or former 
smokers (> 10 pack-years) vs. non-smokers (no smoking within 1 year and <10 pack-years). 
We know that initial patient screening in BELT eliminated 40-50% of the patients who appeared 
qualified based on current or prior (>10 pack-year smoking history). Thus, we expect that 40-
50% of the patients in our current, pragmatic study will be current or former smokers. 
 
Additional subgroups will include patients with high FeNO vs. low and Eosinophil count 
high vs. low.  Regarding the FeNO subgroups measurement of FeNO at baseline, FeNO is a 
good marker of type 2 inflammation (Silkoff 2017). Type 2 inflammation is (i) driven by type 2 
helper T and innate lymphoid cells, (ii) through the actions of the cellular mediators interleukins 
4, 5, and 13, (iii) which results among other effects in eosinophil infiltration (Fahy 2015). FeNO 
is associated with all three of these features of type 2 inflammation. It correlates with the 
presence of the cellular drivers of type 2 inflammation (Liu 2015), and with high expression 
levels of interleukins 4, 5, and 13 (Peters 2014). FeNO also correlates with eosinophil 
infiltration as detected through the several ways of sampling for airway inflammation, including 
sputum (Gibson 2000), bronchoalveolar lavage fluid (Warke 2002), and bronchial biopsies 
(Ricciardolo 2012). Knowing that ICS therapy is particularly effective at targeting type 2 
inflammation, and that FeNO is a marker of type 2 inflammation, it is not surprising that FeNO 
is also a marker of responsiveness to ICS therapy, as noted by the American Thoracic Society 
(Dweik 2011).  
 
We will conduct a binary analysis with pre-specified thresholds (20 ppm and 30 ppm).  
In addition, we will conduct ROC analysis to identify optimal threshold for sensitivity and 
specificity.  These analyses will be conducted in relation to our primary outcome 
(exacerbations) and our secondary outcomes.  We will examine these outcomes in our intent-
to-treat and our per-protocol populations.  We will also test for heterogeneity based on 
race/ethnic status, smoking status, and additional factors enumerated in our primary protocol 
 
Peripheral blood eosinophils identify asthmatics that are most responsive to Patient 
Activated Reliever-Triggered Inhaled CorticoSteroid (PARTICS).  The PARTICS approach 
utilizes a patient-centric, provider-friendly approach to using inhaled corticosteroids.  Inhaled 
corticosteroids (ICS) are the most effective medications for the treatment of asthma (Adams 
2005, GINA guidelines 2014).  The PARTICS approach relies on the fact that asthma is 
responsive to ICS (Haahtela 1991).  Evolving data suggest that while the majority of asthma 
patients respond to ICS (Martin 2007), a significant minority might not (Woodruff 2009).   It 


21 
 
appears that the majority that responds has a type of inflammation that is closely associated 
with eosinophils and is labeled Type 2 inflammation (Fahy 2015, Peters 2014).  While this area 
is evolving, a recent review has suggested that blood eosinophils may be one of the best 
biomarkers to identify patients likely to respond to ICS or therapies directed at Type 2 patients 
(Pavord 2017).   There has been enthusiasm about blood eosinophils since the sample is easily 
obtainable and the assay is available in ANY clinical laboratory.  We will determine whether 
peripheral blood eosinophil count serves as an effect modifier of the relationship between 
treatment (PARTICS vs. usual care) and the study’s primary outcome (number of asthma 
exacerbations per year). We will stratify participants based on a pre-specified peripheral blood 
eosinophil count threshold of 300/uL. This threshold is based on a frequently-used cutoff for 
‘eosinophil-high’ status in the anti-eosinophil therapy literature (Giannetti 2016). 
 
As discussed in section III.E, Biostatistical analysis, we will be adequately powered for both 
these subgroup analyses. 
 
Additional exploratory subgroup will be considered including the following factors: 1) 
modality in which questionnaires have been returned; 2) patients’ attitude towards ICS from the 
validated BMQ (skeptical (low necessity, high concerns), indifferent (low necessity, low 
concerns), ambivalent (high necessity, high concerns), accepting (high necessity, low 
concerns)); 3) presence of depressive symptoms (yes/no); 4) health literacy status (low or 
marginal versus high); and 5) Discrimination stressors from the everyday discrimination scale 
(SHORT). 
 
C.  Participant Recruitment, Screening, Enrollment, and Follow-up 
 
1. Eligibility Criteria 
 
INCLUSION CRITERIA 
● Black or Hispanic based on self-identification (Hispanic if identify as both) 
● Male and female, ages 18-75 years 
● Ability to provide informed consent 
● Clinical history consistent with asthma for > 1 year. 
● Prescribed ICS as daily maintenance therapy 
● Participant must also have an ACT score of 19 or less, or a history of one or more 
exacerbations in the past year that required patient report of systemic corticosteroid use. 
 
EXCLUSION CRITERIA 
● Life expectancy less than one year 
● Known allergy to the ICS inhaler used in the study 
● Having COPD or other chronic lung disease other than asthma; with the exception of 
the following:  
• Dx of COPD in a never smoker without any other lung disease or any other 
disease that might cause airway obstruction such as: Cystic Fibrosis, 
Connective Tissue Disease, premature birth, organ transplantation, 
bronchiectasis, sarcoid, and obliterative bronchiolitis 
• Dx of COPD in former smoker with normal PFTs done after the person quit 
smoking 
• Dx of COPD in current smoker with normal PFTs done in past 24 months  


22 
 
• Dx of COPD IN CURRENT OR FORMER SMOKER with obstruction on 
PFTs:  normal diffusing capacity in past 24 months and demonstrated 
reversibility of 12% or more at any time  
● Regular systemic corticosteroid use daily or every other day for any reason—
including asthma or other medical reasons 
● Use of systemic corticosteroid, or visit to the doctor’s office, emergency department 
(ED) or urgent care, or overnight hospitalization for an asthma exacerbation in the 
past month (can wait and re-check eligibility after one month) 
● Use of biologics (injections or infusion medicines): with the exception of the following: 
• the patient has been on a stable dose of a biologic for at least 6 months and,  
• must have had an exacerbation at least 2 months after starting on 
a biologic to be considered eligible OR  
• must have a current ACT score <=19 to be considered eligible. 
 
● Bronchial thermoplasty less than 6 months ago (can re-check eligibility 6 months 
after procedure) 
● Another family member living in the same household already enrolled in study 
 
All sites will initially identify potentially eligible patients through specific searches of their EHR or 
data repository of EHR data designed to support research. Before contacting any patients, the 
provider or the practice Medical Director (who has been given permission to recruit on behalf of 
the practice) gives permission to contact the patient (this is the same for all contact scenarios). 
When an identified patient does not have a scheduled visit, the research coordinator will send an 
informational letter about the study that would ask if he/she is interested in hearing more about 
the study. The research coordinator’s information will be listed for the patient to call if interested. 
Patients who do have a scheduled visit will receive a phone call from the research coordinator 
giving a brief overview of the study and asking if they would like to hear more about the study 
during the clinic visit. If the research coordinator was unable to get in touch with the patient by 
phone the coordinator would approach the patient during the clinic visit (if approved by the 
medical provider. Patients who are sent a letter and don’t respond will be considered opt out. 
Patients who are called and do not want to learn more about the study will be considered opt out 
unless they indicate they would like to be contacted a later date. Patients who are seen in the 
clinic and do not want to participate, will be considered opt out unless indicating that they would 
like to be contacted at a later date. 
 
Efficacy trials generally include only 5% of eligible asthmatics (Herland 2005, Travers 2007). In 
contrast, we have set broad eligibility criteria including allowing patients with a COPD diagnosis 
who meet the following criteria with regard to the COPD diagnosis:  patient is a never smoker 
without any other lung disease or any other disease that might cause airway obstruction such 
as: Cystic Fibrosis, Connective Tissue Disease, premature birth, organ transplantation, 
bronchiectasis, sarcoid, and obliterative bronchiolitis; a former smoker with normal PFTs done 
after the person quit smoking; a current smoker with normal PFTs done in the past 24 months;  
a current or former smoker with obstruction on PFTs with normal diffusing capacity in the past 
24 months and demonstrated reversibility of 12% or more at any time. This study includes 
smokers and COPD is a common co-diagnosis in patients from communities where smoking is 
prevalent. This approach is much more pragmatic and inclusive of patients who are likely to 
benefit from the intervention.  
 
Furthermore, from our BELT study, we know that if we enroll patients on ICS who are not well 


23 
 
controlled using a standard asthma control instrument, or who are on an ICS/LABA, that one 
third will experience exacerbations over the next year. Additionally, patients with a history of 
exacerbation are at high risk for others (Miller 2007). In contrast to prior efficacy studies, we are 
not excluding current smokers (up to 25% of asthmatics), past smokers (10%- 25% of 
asthmatics and an even higher proportion of those turned away in our prior studies), or those 
with other comorbidities, or those who use other medications. We exclude only patients who 
cannot provide consent or who are not able to physically participate. We have included 
provisions for low literacy by providing oral materials for consent and a voice response system 
option in English and Spanish for those with limited literacy. 
 
 
2. Recruitment and Screening 
 
The Vanguard process is designed to track with the full study protocol as closely as possible to 
provide a piloting of the processes. As such participant recruitment will follow all of the methods 
outlined for the full study, as follows. Participant initial screening will primarily take place through 
searches of EHR data with an invitation to consider the study coming from the patient’s practice. 
This could be in person at the time of a visit, through a letter, through a phone call or through a 
secure message in the site’s EHR. Sites may use some or all of these techniques as best fits 
their patient population. For patients that respond with interest the study coordinator will do a 
brief screening during a real-time interaction, either face to face or via a secure telehealth 
connection. If the individual remains interested, the patient will then interact with the online 
enrollment system.  
 
Full study difference: Sites with the ability to enroll patients at home will offer that option to 
patients who are interested in enrolling.  
 
  
 
(a) Patient Enrollment System (PEERS)- 
 
This system will be identical for the Vanguard process as it is for the full study. See section 
II.F for a description of the uses for this system, called Patient Engaged Electronic 
Reporting System (PEERS). 
 
3. Randomization Scheme 
 
• In the Vanguard study, 36 patients from 4 clinical sites (2 sites enroll AA patients, and 
the other 2 sites enroll H/L patients). Thirty two English speaking patients will be 
randomized at the 3:1 ratio (with 6 patients randomized to the intervention arm and 2 
patients randomized to the enhanced usual care arm at each site. In other words, the 
Vanguard randomization scheme will only be stratified by site, and will not be stratified 
by race/ethnicity. In addition, 4 H/L Spanish speaking patients will be in placed in the 
intervention group to be able to sufficiently test the intervention materials. 
 
• 
Full study difference: patients will be randomized stratifying by site, race/ethnicity (AA vs. 
H/L) using permuted blocks of size 4 and 8 through central randomization available online 
using the same system which will collect consents. Participants will be randomized in a 1:1 
ratio of intervention to enhanced usual care. 


24 
 
 
4. Allocation Concealment 
 
We will minimize selection bias by concealing the allocation sequence from those 
assigning participants to intervention groups until after consent has been executed and the 
patient has been entered into the central database. The allocation will be determined through 
web-based communication. 
 
5.  Blinding/medications 
 
In keeping with a pragmatic trial, this will be an unblinded trial. Since the strategy is 
patient-activated, we will not enroll more than one patient per household. After knowing the 
treatment arm randomized to, each patient will watch a video that instructs him/her on how to 
get the medication he/she is assigned to receive. Although each individual patient or site 
investigator could know the randomized treatment arm a patient is assigned to, the 
randomization scheme for the full study will be kept confidential from all the investigators. 
Randomization scheme will be generated by the unblinded statistician at Duke Clinical 
Research Institute, and will be implemented by an authorized party who has no involvement in 
the conduct of the study. This blinding measure aims to eliminate any possibility that the study 
data is viewed aggregately by randomized treatment before the completion of the trial by 
anyone outside of the DCRI unblinded statistical team. In order to ensure all the study 
investigators are unbiased when making decisions during the conduct of the study, it is 
important to keep them blinded about the possible study results by treatment. 
 
6. Sample size: 
 
● Vanguard: 36 patients (16 AA and 20 H/L) from four sites that represent our study 
sites’ geographic, health system and practice size diversity. 
 
● Full study: Up to 1210 patients (1:1 randomization) will be enrolled in the study.  
 
 
7. Follow-up Intensity 
 
Aligned with the goals of a pragmatic trial, we have tried to minimize trial follow- up intensity so 
as to make the findings as applicable as possible. There are no required study visits after the 
enrollment visit. The patient monthly questionnaires are brief (5-10 minutes required) and will  
include reminders for both groups. Please reference the separate attachment for exact text to be 
used for the reminder included at the end of the survey. They will be completed by both the 
intervention and the usual-care group. Additionally, we have adding a modality of assessment of 
patient use of medications non-invasively by examining patient prescription refills in systems 
where patients receive medications or are centrally reimbursed. We are assessing provider 
intensity of compliance with NAEPP guidelines non-invasively through materials combining 
information from the 
monthly patient questionnaires and information regarding drug prescribing in the EHR. o 
 
 
 
Vanguard: Patients will be asked to complete a baseline survey at 
enrollment 
o At 28 days they will receive a reminder to complete the next monthly survey through 


25 
 
their preferred method using their preferred reminder approach. 
o If they have not completed their monthly survey by day 30 they will receive a 
second reminder using the same method. 
o If they have not completed their survey by day 34 they will be added to a list for 
the central research team to call and help them complete the process either 
immediately over the phone or by having them engage their preferred completion 
method. 
o If patients have not completed their survey for 60 days or longer, they will be 
considered as having missed visit(s). One question will be added to their next 
Asthma Exacerbation Questionnaire (AEQ) about the number of asthma 
exacerbations since their last survey. Since the primary outcome of the full study 
is the intensity of asthma exacerbations during 15 months of follow-up, this added 
question will help capturing all the asthma exacerbations happened during follow-
up period, even one or more monthly surveys are missed by patients. 
o This will be repeated each month. The next survey will be scheduled to be sent 
out on the same day of the month (for instance 3rd Tuesday) thereafter. 
o If the initial survey falls on a fifth day of the month the process will be moved to 
the 4th day of the month. 
o Participants will be asked to participate in short phone calls to assess ability to 
follow study instructions and study processes at 1, 6, and 12 weeks (see Appendix 
C). 
 
• 
Full study difference: There will be no phone calls to assess ability to follow study 
instructions and study processes at 1, 6, and 12 weeks. In addition, the  Full study will 
have up to 15 months of follow up questionnaires versus 3 months in the Vanguard. 
o At 26, 28 and 30 days they will receive reminders to complete the next monthly 
survey through all available methods provided by the patient, until they have 
completed their survey. 
o At day 27, the local site study coordinator will call the patient to make sure s/he 
received the monthly survey reminder. 
o If they have not completed their survey by day 32, they will be added to a list for 
the central research team to call and help them complete the process either 
immediately over the phone or by having them engage their preferred completion 
method. 
o If the telephone follow-up process does not produce an adequate response, we 
will consider mailing a paper survey to patients who do not respond 
o Each monthly survey sent to patients will be based on 30-day periods starting 
from the Baseline survey. The first month survey will be sent at 30 days, the 
second month survey will be sent at 60 days, and so on.   
o We completed African American enrollment. We are extending Hispanic/Latino 
enrollment for 3 months until April 30, 2020, but not extending the project period. 
If a patient is enrolled in February 2020, they would be followed for 14 months, 
March for 13 months, April for 12 months. 
8. Adherence to the intervention 
 
• 
Vanguard: will test these systems through our Vanguard cohort. To further assess the 
patients’ understanding and acceptance of PARTICS, we will use inhaler monitors 
provided by Propeller Health (Madison, WI) attached to the patient’s own SABA and the 
study-provided ICS. These devices record the number and time of each actuation and 
synch through phone or wireless plug-in wall modules. This information will allow us to 


26 
 
assess how often the SABA is used by each patient and the percentage of times that the 
study ICS is used in conjunction with the SABA and to cross-reference that information to 
the patient self-report on the questionnaires. We will cross-reference these data with ICS 
fulfillment data from TEVA’s Specialty Pharmacy, Shared Solutions Pharmacy. 
 
• Full study difference: There will be no sensor attached to the inhaler/s therefore data 
collected from a sensor with regards to inhaler usage. 
 
We will assess clinician adherence with NAEPP guidelines in the care of the enrolled patients. 
Specifically, we will assess prescribing of daily controller medication rates for all enrolled 
subjects (all with have persistent asthma), rates of deteriorations with more than 2 days of 
symptoms which resulted in office visit but no use of oral steroid bursts, rates of step-up therapy 
following more than one exacerbations or deterioration within 6 weeks, rates of step-up therapy 
when patient monthly questionnaires report uncontrolled asthma by ACT or Asthma APGAR for 
3 or more consecutive months and patient has an office visit during that time and step down 
following 6 or more months of no EMR-documented asthma problems or 6 consecutive months 
of patient reported controlled asthma on the monthly ACT or Asthma APGAR reports and an 
office visit at the end of that period (e.g. within the next 3 months). Documenting the prescribing 
of daily controller medications, use of oral steroid bursts and step-up and step-down therapy will 
also require links to the enrolled patients individual medication lists from the EMR and where 
possible to pharmacy fulfillment data.  
This is a pragmatic trial, so we will be using practices that would be used in routine care to help 
patients adhere to their treatment arm. We will send two messages to all treating clinicians of 
patients enrolled in the PARTICS intervention arm. The first message is embedded within the 
EMR, and notifies the clinician that their patient is participating in the study, and asks them not 
to change the patient’s study medication instructions without contacting the PREPARE study 
team. The second message is a letter to all treating clinicians with basic information about the 
study, so clinicians do not interfere with the instructions that are given to the intervention 
patients in the study. The exact text for these messages are uploaded in a separate attachment. 
 
9. Enrollment and Restriction of participants 
 
Vanguard: We will enroll 36 patients at 4 sites to test the study design process. 
Full study difference: We will enroll up to 1210 patients. Using a very conservative estimate that 
50% of those approached who are eligible will enroll (2400 leading to 1210) we will need 2400 
eligible patients to be approached. Considering our reduced entry criteria and the EHR’s ability 
to identify patients taking the required medications, we assume 80% of those identified will 
qualify when screened (3000 leading to 2400). 
 
 
10. Source and volume of patients 
 
All participating sites have searched their respective Electronic Health Records for patients who 
meet inclusion criteria. Each site is expected to recruit based on results of the EHR search. 
Recruitment ranges from 20-200 depending on the site. Section IV.F lists all sites and expected 
enrollment rate. Recruitment should be improved compared with classic RCTs because this 
study does not require extensive reporting expectations of participants (monthly surveys are 
streamlined, can be completed through multiple methods, and are linked with reasonable 
reimbursement for time spent answering them). 


27 
 
 
The Vanguard activities will assist in identifying major barriers to recruitment not already 
accounted for to allow for adjustments of the study protocol. During our initial engagement 
activities with the African American and Hispanic/Latino patients and other stakeholders, we 
have begun identifying potential barriers to dissemination and implementation of our results. 
Below are examples of barriers identified by each stakeholder group and suggested solutions 
developed by the stakeholders and our dissemination work group. Our Vanguard process will 
further facilitate our understanding and approach to addressing barriers. 
 
11. Justification of expected participation rate 
 
Vanguard: The four sites selected and agreeable to recruit during the Vanguard phase have 
reported high counts of patients who meet criteria. This was necessary because the Vanguard 
patients will not be eligible for the Full study. Also, having high counts of eligible patients will 
enable the sites to recruit 8 patients each in a short period of time. 
 
Most of the sites have successfully recruited asthma patients for previous studies (e.g. the BELT 
trial). Site-provided numbers of AA or H/L individuals with asthma on an ICS are available from 
their EHR. A tabular summary of these sites is included in Consortium Contractual 
Arrangements. We have identified a total of >20,000 eligible patients. Based on previous 
studies, we believe that we are well within capacity for that recruitment, which we believe will 
only require 3000 EHR identified patients. Further, study design will improve our ability to enroll 
identified potential participants. One, our relaxed exclusion criteria will allow for fewer exclusions 
of identified patients. For example, BELT, sites recruited ~14% of EHR identified patients 
(1100/~8000). The main reason interested patients were excluded from BELT related to current 
or past smoking (~40% of EHR identified patients). Using these patient numbers we have 
budgeted for each site to recruit no more than 10 and 15% of all initially eligible patients into the 
study. Two, another common reason for not participating in BELT was the 50% chance of 
receiving an “experimental drug” and having to change current medications. This will not be the 
case for PREPARE since both treatment arms will continue using their same controller 
medications, and the experimental arm will test the use of a non-experimental drug (ICS) using a 
new medication administration strategy (PARTICS). Three, BELT included a 
genetic analysis which turned many potential participants away from enrolling. Assuming only a 
10% increase through avoiding these last two BELT related recruitment issues would bring the 
recruitment rate to ~25% ((0.14/0.6*1.10). Overall sites can recruit at approximately one half to 
one quarter of this rate (AA 600/12,871 = 4.7%, H/L 600/7170 = 8.4%) and still fulfill their 
recruitment expectations. Furthermore, if needed we can add two more sites to the 14 who have 
already committed to the study. Site specific estimates are supplied in the Participating Sites 
and Resources section. 
 
Full study difference: Up to 20 clinical sites with experienced investigators and co- investigators 
will recruit up to 1210 patients meeting eligibility criteria. 
 
12. Maximizing adherence to the enrollment plan 
Vanguard: the duration of the Vanguard process is only three months and participants will be 
contacted at 1, 6 and 12 weeks to be asked about the study process and logistics. We expect 
this frequency of contact will result in high adherence. Further, the Vanguard process is 
explicitly designed to test all of our protocol processes and is specifically relies on participant 
feedback. We expect that this relationship between participants and study coordinators will 
result in high adherence. 


28 
 
 
Full study difference: Participants will not be called at 1, 6 and 12 weeks. However, weekly 
calls between site recruiters and the trial management team will help keep recruiting practices 
the same from site to site. Most importantly, the use of videos and computer “face-to-face” 
consenting using centralized coordinator staff from health care system will reduce variability. 
 
13. Literacy and Minority Issues 
 
The PREPARE study focuses on minority populations, limiting its enrollment to AAs and H/Ls. 
To ensure that literacy does not interfere with trial recruitment or data collection, all written trial 
material (English and Spanish) will be designed for a low- literacy audience. We will prepare 
video-based materials in English and Spanish for those who have trouble reading. English or 
Spanish videos will contain members of the group with which the patient self-identifies. All 
materials will be trialed and refined in the Vanguard process, in conjunction with feedback from 
our patient advocates and patient stakeholders. 
 
14. Strategy for Balancing Internal Validity and Generalizability 
 
We propose a randomized, unblinded, pragmatic trial with minimal barriers to patient entry. It is 
being conducted in vulnerable populations, in multiple real world settings, with minimal invasive” 
or behavior-altering monitoring, no required follow-up visits, and easy application—all aimed at 
broadening applicability, easing dissemination, and supporting sustainability. Our considerations 
are as follows: 
 
(a) Degree of flexibility and complexity of intervention 
 
Vanguard: in keeping with our desire to maximize generalizability and ease dissemination, we 
have maximized the flexibility by which the experimental intervention is applied. We have also 
minimized the degree of provider expertise needed to apply and monitor the experimental and 
comparison interventions. The intervention provides maximum flexibility to patients since they 
control the frequency and timing of doses in the experimental intervention. Additionally, other 
medications, including other asthma medications are not restricted. This represents a minimally 
complex session for providers with low time commitment and provides CME credits, thus 
enhancing opportunities for successful dissemination and sustainability. 
 
This phase will call for additional phone calls to monitor the study process. These phone calls 
are also low complexity. 
 
Full study difference: There will be one phone call within one month of enrollment to ask the 
patient about receiving the survey reminder and filling out the survey. 
 
 
Vanguard: will test and assess our questionnaires and collection systems through our Vanguard 
cohort not patient outcomes. 
 
Full study difference: There will be no assessment of questionnaires and collection systems. The 
outcomes are obtained from a mix of patient self-report on the monthly questionnaires, 
electronic records, and prescription refill information. Other than the first, they represent no 
burden for the patient or provider. Based on feedback from our patient advisors, we have 


29 
 
minimized the burden of the patient questionnaires by providing multiple modalities for 
completion. Many of the instruments have been validated across modalities. 
 
(b) Recruiting and Enrolling a Representative Population and Avoiding Selection Bias 
 
We are focusing on AA and H/L populations since they are highly affected by asthma and 
represent some of the greatest challenges in terms of therapy implementation. We are striving to 
obtain a representative population by reasonable geographic distribution across multiple 
different health systems. In concert with a pragmatic trial, we have set our inclusion criteria quite 
broadly with few exclusions. We plan to enroll patients with low literacy by having all our 
consenting and explanatory materials in video formats and apply to IRBs for permission for 
video/verbal consent. Patients will be identified through searches of provider databases. 
 
A few different basic approaches to recruitment will be utilized. For those patients with 
scheduled visits, attempts will be made to contact them before the office visit to see if they are 
willing to spend extra time to learn about the study. At the office visit, the patient will be asked if 
he or she is interested in hearing more about the study and offered parking or other 
accommodation (patient-partner recommendation) to stay to review the video information and 
consent materials. If the patient consents, he or she will be entered into the trial. Sites will also 
be asked to contact patients who appear to be eligible but make only infrequent office visits 
through letters or phone calls from their offices. These individuals will be asked to call the study 
coordinator to learn more about the study. Most individuals who are interested in learning more 
about the study will be asked to schedule a visit with the study coordinator at their usual care 
setting.  
 
We will further modify and refine our recruitment and enrollment methods via patient partner 
advice. By including patients during office visits as well as through community outreach, the 
study will minimize biases towards those patients with higher compliance with office visits or 
higher severity of disease requiring more frequent visits. 
 
Advertising 
 
A flyer with information about the study will be posted on appropriate research boards at study 
recruitment facilities. This same flyer will be sent via email to research study distribution lists that 
are designed for patient recruitment, posted in local newspapers, and disseminated at 
community centers, such as community churches and local community centers.  
 
 
15.   Other Full study changes 
 
No additional differences from the Vanguard though these areas will be explored during 
the various phone interactions to collect study process information. 
 
D.  Study Procedures 
 
1. Informed Consent 
 
a. Vanguard: Our informed consent documents are meant to be brief while providing the 
patients with the information required determining their desire to participate in the study 
and meet the requirements of all involved IRBs. Informed consent form will be uniform 


30 
 
throughout the sites except as required by a site's IRB; a central IRB will apply to all sites 
where this is feasible. Multiple approaches to completion of informed consent will be 
available to facilitate enrollment. Most patients will be consented online, using a study 
consent form embedded in the PEERS data collection, prior to patient registration which 
may include a web (visual) conference between the subject and the study staff who will 
review all study details similar to an in-person visit. The consent component of the PEERS 
system has been used for multiple previous studies. Data collected prior to consent is 
anonymous and remains so if the patient decides not to participate in the study. Once the 
patient provides consent not only is that information stored but selected responses from 
prior to the consent process can be used to supplement the intake survey data. 
 
If a site’s IRB requires modifications to the consent forms, a separate consent for that site 
will be provided which will then link the participants to the central PEERS system. All 
subjects will be provided with the informed consent form/web site when the study site 
investigators have determined they may be an acceptable candidate for randomization. 
An invitational video will be followed by an eligibility questionnaire. Participants not found 
to be eligible will be requested to voluntarily and anonymously provide their gender, race 
and ethnicity for tracking purposes for the final study CONSORT diagram. For eligible 
patients the consent process will include the aims of the study, the data collection, follow-
up requirements, and all potential risks and benefits of the study. A research coordinator 
will be available to discuss the study with the subject or answer questions. 
 
Informed consent will be obtained before any study data is collected in an identifiable 
manner. All participants’ interactions with the system are tracked anonymously prior to 
consent. Documentation of this process will be required, the subject will e-sign the 
informed consent document or sign a paper consent form if required by the local IRB. 
Electronic signatures will be maintained by the PEERS system and documentation of 
each enrolled participant’s consent will be provided to the AAFP NRN by each site 
obtaining it. Paper consent forms will be maintained at the site as part of the subject's 
research records (which may be separate from their medical records) as well as a copy 
provided to the AAFP NRN and to the participant. No participant will be enrolled without 
documentation of informed consent and no waivers of this process will be sought or 
granted due to the use of the addition of a medication in the intervention. The PEERS 
system has been used for many studies with online consent approved by over 15 IRBs 
across the country. 
 
(b) Full study difference: The patient will not have to agree to the Propeller User Agreement 
because there will be no sensor/s used in the full study. 
 
 
2. Study Questionnaires 
 
(a) PREPARE questionnaires 
 
Asthma Exacerbation Questionnaire (AEQ): 
 
Our primary outcome, the rate of asthma exacerbations per year, is defined as the number of 
exacerbations, emergency room visits, or hospitalizations requiring oral or parenteral 
corticosteroids, per patient per year. It will be captured by subject self-report via a monthly 
asthma exacerbations questionnaire (AEQ). Reports will be substantiated by verification in the 


31 
 
EHR or direct patient interview. Multiple clinical trials demonstrate convergent validity with other 
measures of asthma-related health status (Busse 2011, Peters 2010, Lemanske 2010) and their 
responsiveness to intervention (O’Byrne, 2005). We previously developed, tested, and used the 
AEQ as part of the BELT trial, in which we enrolled >1,000 AA patients. The AEQ is sensitive but 
not specific, meaning it overestimates the number of true exacerbations and therefore requires 
confirmation, but is not likely to miss exacerbations. Therefore, we will use the medical records 
or, if necessary, contact all patients whose form suggested an exacerbation to confirm. We will 
categorize these exacerbations as to whether they resulted in a hospitalization or emergency 
department visit. 
 
Asthma Control Test (ACT) 
 
The ACT is easy to use, patient completed, and assesses the frequency of shortness of breath, 
use of rescue medications, the effect of asthma on daily functioning, and overall self-
assessment of asthma control. The ACT has been evaluated in independent study population 
samples and can be self-administered in person or at home (Schatz 2007a), by telephone 
(Schatz 2007b) and by mail (Schatz 2007c). The ACT has been recommended by the NAEPP 
and the NIH Asthma outcome workshop (NAEPP 2007, Cloutier 2012) because of the extensive 
validation data for these tools, using the widest range of criterion and construct measures, 
including demonstration of responsiveness to therapy and a minimal clinically important 
difference (MCID). The MCID is defined as the smallest difference in a given score of interest 
which patients perceive as beneficial and which would support a change in the patient's 
management (Jaeschke 1989). The MCID for the ACT has been defined as 3 for individuals 
over time and between populations (Schatz 2009) and cut-off values for uncontrolled asthma: 
 
ACT ≤ 19 (Nathan 2004), and “very poorly controlled” asthma: ACT ≤ 15 have been established. 
(Schatz 2006, Nathan 2004). 
 
Asthma APGAR 
 
The Asthma APGAR is a next generation control assessment that is linked to tools for primary 
care physicians to suggest next steps. (Yawn 2009). The tool has been shown to produce similar 
control status to the ACT. (Rank 2014) using 3 questions and considering a score of >2 as 
inadequate control. The same tool is used for children and adults. By allowing one version for all 
ages and to require only three responses, the Asthma APGAR may be easier to use that older 
longer control assessments. In addition, implementing the Asthma APGAR in practice has been 
shown to reduce asthma exacerbation related emergency department and hospitalizations by 
50%. (Yawn 2016 JAMA in press). 
 
Asthma Symptom Utility Index (ASUI) 
 
The ASUI is probably the symptom scale most frequently used in asthma studies including large 
multicenter clinical trials (Boushey 2005). The ASUI’s psychometric properties are well 
documented and support the reliability and construct validity of the instrument, including internal 
consistency reliability and test-retest reliability. The minimum clinically important difference has 
been determined as 0.09 points (Bime 2012). 
 
Days Lost from Work or School 
 


32 
 
Days lost from work and school will be collected using a validated questionnaire developed and 
utilized as part of the National Health Interview Survey (NHIS 2014). Our patient partners felt 
that this was a very important outcome they would be interested in. 
Demographics  
Eligibility  
Co-morbidities  
Asthma medications 
Smoking status 
Exacerbations in past 12 months 
Health Literacy-Brief Form 
 
The 3 question version of the health literacy assessment will be used. This has been compared 
to the longer TOHFL which is not validated for self-administration and is lengthy. The short 
version of the Watson scale had a AUC of .79 compared to the TOHFL for clinic patients. 
(Wallson JGIM 2013). The questions are designed to be self- administered. 
 
The Beliefs about Medication Questionnaire (BMQ –Asthma Specific) 
 
The BMQ Asthma Specific is a measure of patient beliefs about their asthma and asthma 
medications. There are two scales in the BMQ: one that assesses patients' beliefs about the 
necessity of controller (i.e., ICS) medication for managing their asthma (Necessity scale), and 
another scale which measures worries and concerns about possible negative consequences of 
using their medication (Concerns scale). The BMQ is a validated instrument has been widely 
used in asthma and other chronic illnesses and has been shown to be a robust predictor of 
adherence with chronic therapy. (Menckeberg 2008) 
 
Patient Health Questionnaire (PHQ)-2 
 
The PHQ-2 asks two questions that screen for depression and has been shown to be a valid and 
reliable measure. The PHQ-2 has up to 97 percent sensitivity and 67 percent specificity in 
adults, with a 38 percent positive predictive value and 93 percent negative predictive value 
(Whooley, 1997). 
 
Dose counter data for rescue ICS and SABA  
 
Vanguard specific questions: 
• 
Satisfaction with therapy (intervention only) 
• 
Assessment of enrollment process 
• 
Assessment of receiving 1st inhaler—intervention only 
• 
Assessment of monthly questionnaire process 
• 
Assessment of QVAR refill process—intervention only 
• 
Overall assessment of study participation 
• 
Which inhalers are you using for rescue? 
• 
If you have seen your clinician, did you discuss your rescue medicines? 
• 
Did seeing your clinician result in you making any changes in recommendations 
from those given by the study materials? 
• 
Is the pouch helpful? 
• 
Do you carry the pouch with you outside of the house? 


33 
 
• 
How frequently do you carry the pouch with you outside the house? 
• 
Have you talked to any other person about your rescue inhalers—such as family, 
friends, others with asthma? 
• 
Did they give you any different advice? 
• 
Did that change what you are taking for rescue inhalers? If so, how? 
 
Discrimination Scale 
 
The short version of the ‘Everyday Discrimination Scale’ consists of 5-questions with answer 
choices that range in a Likert scale. It has an alpha = 0.77 and has been used in tested in 
multiple other chronic diseases, such as cardiovascular disease. Its results have been used in 
those disease to support a positive association between degrees of perceived discrimination and 
prevalence of chronic disease. This scale has not been used in a large-scale study of African-
American/Black and Hispanic/Latino patients, and therefore, our results would be novel. These 
could help determine the underpinnings of the increased asthma-related morbidity and mortality 
rates observed in these communities. 
 
Payer’s Scale 
 
Health system use metrics of patient’s overall health status and health related quality of life 
when determining which therapies to recommend or include in their pharmacy benefits. We have 
included questions commonly considered important in the decisions to facilitate our 
dissemination activities at completion of this trial. 
 
COVID-19 Questionnaire (short) 
 
It has been reported that COVID-19 is disproportionately affecting minority populations in terms of 
its direct effects related to the frequency and the morbidity of those infected. To understand the 
effect on our at risk PREPARE study population of African American/Blacks and Hispanic/Latinos, 
we have developed and added a short questionnaire, to the current monthly surveys for our study 
patients regarding COVID19: 
• 
Have they been diagnosed with COVID-19 
• 
Did they have a test 
• 
Symptoms 
• 
Psychosocial – (job, ability to get asthma meds, etc.) 
 
 
(b) Questionnaires administered, by study phase and visit 
 
1. Vanguard [Complete] 
 
Tool or domain 
Baseline 
1 week 
6 weeks 
12 weeks 
Eligibility 
X 
Demographics 
X 
Co-morbidities 
X 
Asthma medications 
X 
X 
Exacerbations 
X 
X 
Smoking status 
X 
X 


34 
 
Lost days of work or school 
X 
X 
Beliefs about Medications 
Questionnaire—asthma 
X 
Health Literacy-Brief Form 
X 
PHQ-2 
X 
MARS-5 adherence 
X 
Perceived stress 
X 
Asthma Symptom Utility 
Index 
X 
X 
Asthma APGAR (control) 
X 
X 
Asthma Control Test 
X 
X 
Ask-12 (adherence 
likelihood) 
Vanguard telephone interview questions: 
Inhaler dose counter # Usual 
rescues 
Maintenance (non-pouch) 
QVAR (intervention) 
X 
X 
X 
Address change 
X 
X 
Satisfaction with therapy 
(intervention only) 
X 
Assessment of enrollment 
process 
X 
Assessment of monthly 
questionnaire process 
X 
X 
Assessment of QVAR refill 
process—intervention only 
X 
X 
X 
Overall assessment of study 
participation 
X 


35 
 
2. Full Study  
 
Tool or domain 
Baseline 
Monthly 
Final 
Survey 
Eligibility 
X 
Demographics 
X 
Co-morbidities 
X 
Asthma medications 
X 
X 
X 
Exacerbations 
X 
X 
X 
Smoking status 
X 
X 
X 
Lost days of work or school 
X 
X 
X 
Beliefs about Medications 
Questionnaire—asthma 
X 
Health Literacy-Brief Form 
X 
PHQ-2 
X 
MARS-5 adherence questions 
X 
X 
Perceived Stress Index 
X 
Asthma Symptom Utility Index 
X 
X 
X 
Asthma APGAR (control) 
X 
X 
X 
Asthma Control Test 
X 
X 
X 
Payers Scale 
X 
Everyday Discrimination Scale (SHORT) X 
Satisfaction with therapy 
(intervention only) 
X 
Refill information 
X 
X 
Address change 
X 
Permission to contact for additional 
questions related to PREPARE 
 
X 
Permission to contact for future studies 
 
X 
COVID-19 questionnaire (SHORT) 
X 
X 
 
3. Unbiased and systematic data collection: 
  
Vanguard: 
● To maximize compliance and reduce bias, these questionnaires can be completed 
through various ways matched to participant preference and literacy level--mailed 
questionnaire, email, text, telephone, smart-phone, and website. Our patient partners 
emphasized that such varied techniques are necessary to assure that we do not bias 
our results to those interested in responding via specific modality. We will also 
reimburse participants $20/questionnaire to compensate patients for their time for 
completing each questionnaire. Trial staff will follow up with participants who do not 
complete their monthly questionnaires. We used these techniques in the BELT trial in 
which we enrolled >1,000 AA patients and achieved >75% survey completion using 
only paper and phone techniques. Patients will be notified to complete monthly 
survey by their method of choice. If patient has requested a paper survey, it is mailed 
to him/her. If the patient has not completed the survey in 7 days a reminder is sent 


36 
 
(post card). If the patient has not completed the survey in 7 more days then patient is 
added to central research team queue to be contacted directly either by phone, email 
or text. The patient will stay on this list until the survey has been completed/received. 
 
● Additional questionnaires asking about the study process will be administered (as 
shown above). Procedurally, participants enrolled in the Vanguard assigned to the 
treatment arm will be asked at 6 weeks to request an ICS refill. Participants will either 
be asked verbally or get a post card at enrollment to call to test the system for 
requesting an ICS refill. Further, they will be asked to call for ICS refills when their 
ICS inhaler reaches the 100 (out of 120) remaining puff threshold. This is to facilitate 
refill requests being placed during the short Vanguard process. In addition, we will 
track patients’ usage of their inhalers with a sensor made by Propeller Health. 
Patients in the intervention group will have a sensor attached to both the rescue 
medication and ICS that they will keep in the pouch provided to them. The patients in 
the control group will receive a sensor to track usage of their rescue medication (a 
pouch is provided for the patient to carry their rescue inhaler). The sensor system 
includes a hub that will be plugged in at the patient’s home and will transmit data to a 
secure database at Propeller Health. Once a month the data will be sent to the data 
coordinating center. Otherwise, there will not be other procedural or data collection 
differences between the full study and the Vanguard process. 
 
 
● Full study differences: There will be no additional questionnaires as described in the first 
paragraph above. All follow-up will be via phone as outlined in the previous section, “Follow 
Up Intensity.”  
 
4. Medications and reimbursement 
 
Vanguard: We will use a real-life distribution system (Teva’s specialty pharmacy, Shared 
Solutions through electronic scripts in the EHR). Teva will collaborate with us to implement 
the study and distribute and monitor drug disbursement. Shared Solutions Pharmacy will 
act as our central pharmacy. Therefore will de facto be able to demonstrate that the delivery 
is feasible, sustainable, and scalable across the United States. 
 
There will be no cost for the ICS inhaler. The Teva pharmaceutical company has agreed to 
donate ICS (beclomethasone diproprionate HFA, QVAR. Patients will order refills from 
Teva’s specialty pharmacy, Shared Solutions. 
 
Full study differences: The QVAR inhaler will change to the QVAR® RediHaler™  
 
 
5. Fractional exhaled nitric oxide (FeNO) test: 
 
During the study visit, we will ask participants to exhale into a machine that determines nitric 
oxide gas levels in their breath. This procedure was not conducted in the Vanguard phase, and 
will only be conducted during the full study. 
 
6. Blood draw (Eosinophils): 
 
During the enrollment visit, we will ask each participant if s/he agrees to have blood drawn.  


37 
 
The blood draw is to determine Eosinophil counts which are known to be associated with 
response to Inhaled Corticosteroids. The test used will be a complete blood count with 
differential (CBC with differential). The amount of blood needed for this test is 3 mL, collected in 
a purple top tube. This will be the only blood draw for the participant throughout the study. This 
procedure will only be conducted during the full study. 
 
 
 
E. Participant and Patient Retention 
 
Vanguard: Participant retention will be monitored through the monthly survey process. 
During the survey completion process no attempt will be made to alter a participant’s 
medication use, whether in the intervention or enhanced usual care arms. Participants will 
receive two automated reminders followed by in person follow up in an attempt to complete 
the monthly surveys. Participants will be asked to provide a contact person that is likely to 
know how to contact the patient should their phone or address change. The local site staff 
will also be asked to help locate patients lost to contact. At regular intervals across the study 
a small number of gift items will be provided to a randomly selected individual that has 
completed the last three monthly questionnaires. Patients will also be paid $20 for their time 
in completing the each of the monthly questionnaires, as well as once at the end of the 
Vanguard when patients return their sensor, using the ClinCard research debit card system. 
If patients receive overages on their smartphone bills as a result of answering the 
questionnaires, they will receive $5 per questionnaire on their ClinCard. In addition retention 
in the Vanguard process will be assisted with multiple brief phone contacts to assess study 
processes. 
These contacts will not take place in the full study as they would represent a type of case 
management and thus an intervention in their own right. 
 
• 
Full study differences: Patients who fill out their monthly survey within 6 days of receiving 
their first reminder on day 26, will be entered into a lottery/raffle. They will have a chance 
to win one of three $100 prizes each month. Sites located in Florida will not participate in 
the lottery due to state restrictions. 
 
In addition, we will be implementing a few additions to focus on patient retention and 
engagement during the study. We will: 
• 
send an appreciation card semi-annually to patients to keep in contact with 
them.  
• 
send a quarterly text message reminder (to all patients who have enabled text 
message reminders) about their treatment arm to encourage adherence to 
their medications and remind them about completing their monthly surveys.  
• 
send announcements via text message about winners of the lottery prizes 
(excluding any personal information), to help motivate patients to complete 
their surveys in a timely manner.  
Exact text for these outreach methods are uploaded as separate attachments. 
 
 
• Data Collection and Quality 
 
Vanguard: there will be some additional questions in the monthly surveys otherwise the system 
will be identical. 


38 
 
 
1. Database Design and Administration 
 
The electronic data capturing system PEERS will be designed and programmed by the 
University of Colorado Denver, Department of Family Medicine (UCDFM). The data collection 
system will be reviewed by the study team, undergo User Acceptance Testing (UAT) and Quality 
Assurance (QA) before being made available for data entry. 
Throughout the study, the system will be monitored both by UCDFM and the Statistical DCC at 
Duke Clinical Research Institute (DCRI), with quality issues being identified, logged, and action 
plans developed. 
 
Access to the data collection system and database should be strictly controlled and well 
documented. Personnel at UCDFM and the Statistical DCC of DCRI will have no right to delete 
or change data. Only the site and central site users will have this ability. Data cleaning will be 
done by automatic or manually created queries to the site users who will need to confirm and 
change data in response. All the data changes will be tracked by the system and stored in a 
database audit trail which can be accessed as needed. 
 
Our database will include the following major covariates: age, gender, prior corticosteroid bursts 
in past year (Y/N), ICS/LABA prescription, and current smoking (Y/N). Age and gender will be 
self- reported and can be checked against medical records. Corticosteroid bursts in the past 
year are subject to recall issues. However, patient-reported bursts have been shown to correlate 
with the likelihood of prospective 
bursts (Miller 2007). 
 
In addition, where available we will search the patient’s prescription records for bursts of 
prednisone. With regards to smoking, while imperfect we will use the validated questions used in 
national surveys in section 7 of the CDC Behavioral Risk Factor Surveillance System (CDC 
2013). ICS/LABA use will be confirmed through the medical record. 
 
No complex data linkages will be required for this project. All patients will be consented, so we 
can link records using ‘clear text’ methods. Furthermore, all existing health data will come from 
the sites, and thus will be linked prior to being transferred to the research team. Given the small 
number of patients per site, if any concerns were to arise, questionable linkages can be 
manually checked. We will use EHR data to supplement the evaluation of asthma care by 
participating clinicians. This will include a limited de- identified data set related to asthma 
diagnosis and care (e.g. rates of controller therapy for patients with persistent asthma and rates 
of use of oral steroids for asthma exacerbations in the non-enrolled patients) for all patients for 
the practice with asthma and linking of EHR data to study participants for similar assessed. In 
addition, to determine if COVID 19 has an impact on asthma and asthma care we will extract 
COVID PCR and/or serology data when available. Pharmacy fulfillment data will be cross-
checked by date of birth. For the general population of asthma patients, no record linkages are 
planned. 
 
Outcomes will primarily be identified through monthly patient questionnaires. The responses to 
these questionnaires will serve as a trigger to undertake further review of medical records data. 
Discrete EHR data may be misleading in a study of this nature. 
 
Exacerbations will be identified from patient reported data in the monthly questionnaires. That 
data will include acute increases in asthma symptoms that result in an asthma related 


39 
 
hospitalization or being given a prescription for oral steroids during an asthma related 
emergency room visit, clinic visit or telephone consultation. The occurrence of the hospitalization 
or visit and the prescribing of oral steroids will be confirmed by querying the patient’s EHR. Most 
of our sites have confirmed that ED and hospital visits are usually included within their EHR. 
However, if the information is not available, e.g. hospitalization not document in the clinic record 
or patient self treating with oral steroids previously prescribed for home use, the information will 
be confirmed by a call to the patients by a study nurse or coordinator requesting more specifics 
such as the exact date and the name of the prescription and duration of use or the name and 
duration of stay at a hospital. 
 
All exacerbations will be reviewed by a team of 3 physicians blinded to the patient study 
assignment. A study nurse or coordinator will obtain the documents required for review and 
make sure that any information related to study arm assignment, intervention or enhanced usual 
care, is redacted. Drs. Pace, Carroll and Cardet will do the initial review. If all 3 agree that it is or 
is not an exacerbation that decision will be accepted. If they do not have unanimous agreement, 
the event and all information will be sent to the adjudication team, Drs. Israel, Fuhlbrigge and 
Yawn to make a final decision. All physicians assessing or adjudicating exacerbations will be 
blinded to randomization. 
 
The Policy Stakeholder Group requested additional data elements for secondary analyses-- total 
number of asthma related visits made to the enrolling site, ED visits, hospitalizations, and total 
asthma medication usage. The Policy Stakeholder Group was interested in how PARTICS might 
affect visits not associated with an exacerbation and thus not captured with our original data 
collection plan. In addition to asking patients o their monthly questionnaires, we will also ask all 
sites to provide site-generated billing data for their patients from one year prior to the date of 
consent 12 to15 months following consent (depending on when the patient was enrolled). It will 
be adjusted for a 12 month rate. Thus, we will be able to compare between-groups visit 
frequencies as well as within-group visit frequencies over time. The impact on total asthma 
medication could influence the ease of acceptance of this strategy during dissemination. 
 
Full study differences: The additional questionnaires used in the Vanguard (as noted above in 
pages 38-39) will not be included in the Full study monthly questionnaires. 
 
2. Data Monitoring and Site Auditing 
 
The PEERS system will be programmed such that patient intake, baseline and monthly 
questionnaire data is required to be completed prior to advancing to the next section. Thus, 
patients who complete the consent, enrollment, baseline and monthly data collection processes 
should have complete data. All outcome data will be selected from radio button or pick list 
questions and thus data will be codified at the time of capture. The PEERS system will also 
provide an administrative section for each site as well as the local research team. This section 
will provide patient contact information following consent. Allow messaging between the sites 
and the AAFP NRN staff and allow study staff to collect patient data using a computer assisted 
survey process when needed. Sites are primarily being asked to enroll patients. The eligibility 
criteria will be built into the consent process. The enrollment rate will be tracked using the 
administrative processes for the AAFP NRN within PEERS. If a site uses a paper method for 
any consents then an administrative page will be created to allow the local site to complete the 
eligibility criteria after consent is obtained. These sites will be monitored by a daily PEERS 
report to the central AAFP NRN staff. If a site appears to be struggling with recruitment the 
AAFP NRN staff may make a site visit to see if they can assist with rethinking the recruitment 


40 
 
process. 
 
3. Methodology for Collecting Patient Consent and Questionnaire Data 
 
The Patient Engaged Electronic Reporting System (PEERS) has been developed and enhanced 
over the past 15 years by the University of Colorado, Department of Family Medicine (CUDFM.) 
The system is licensed to the DARTNet Institute and will be customized and provided to the 
study through a purchased services agreement between the AAFP and DARTNet. The system is 
a HIPAA compliant, multi-modal, fully localized patient data collection and study management 
system. The system is used for both clinical care and research. The system is a table driven 
data collection system with advanced within questionnaire data management as well as between 
questionnaire data management. Many of the advanced features will not be necessary for this 
project. 
 
At enrollment, following consent, patients will provide all available contact methods (phone 
number, email, text) and will receive reminders on all methods provided. All messages are 
HIPAA compliant (no clinical information is included) and provide a link the appropriate login 
system (browser/mobile browser for email or text message and interactive voice response 
system for phone messages.) Patients may move between data collection systems as they wish. 
 
PEERS is hosted in the CUDFM data center (which also serves as the HIPAA compliant data 
center for all DARTNet activities.) This center is secured environment with 24 hour police 
monitoring, password controlled entry that is monitored as well as both local and central police 
alerts for open/ajar doors. The entire center is located behind the University of Colorado Palo 
Alto firewall with advanced intrusion detection software and monthly remote server auditing for 
security. The data environment is located behind a second, research/clinical firewall maintained 
by the CUDFM informatics staff. All data transmissions for end users are encrypted. The 
CUDFM maintains daily incremental back-ups, weekly system images and monthly full file level 
back-ups. Off- site and cloud back-up storage is maintained with a 12-month rotation system. 
 
4. Database Lock 
 
The study database will be locked after the data are reviewed by both CUDFM and the 
DCRI statistical team to ensure that the datasets provided for analyses are complete and 
accurate. The final datasets will be exported into SAS and provided to the DCRI statistical team 
through a secured website. 
 
F. Engagement Plan 
 
1. Stakeholder Groups 
 
Patients, patient advocacy groups, providers, including pharmacists, professional 
societies, healthcare policy experts, and content experts have all been engaged from the 
beginning in formulating our question, identifying the study groups (AA and H/L adults), 
selecting the intervention (PARTICS) and the Asthma IQ, choosing outcomes (exacerbations 
and missed work and school days), and suggesting the exploratory aims and analyses for this 
PREPARE study. Our stakeholders, especially our patient partners and their advocates have 
been, and will be, integral parts of the study of the study team. Below, we describe their 
involvement in planning the proposal up to now, review how the study governance includes 
them going forward using the Vanguard cycle as an example, and explain their proposed 


41 
 
involvement in the subsequent parts of the study including data interpretation, results 
presentation and dissemination. We have been working with 6 stakeholder groups. Three 
separate groups were created for patients including AA partners, H/L partners, and advocacy 
groups. The patient partners have been working with us over the past year. We have also 
included provider groups (those participating in the study), professional society stakeholders 
from the major lung and allergy societies, health policy partners (including insurance, national 
pharmacy, population management, and Center for Medicare/Medicaid Services 
representatives), and clinical trial specialists including those with experience recruiting AA and 
H/L populations. 
 
2. Organizational Participation of the Stakeholders 
 
The patients and other stakeholder groups are tightly interwoven into the study 
governance. They represent 8 out of 9 groups (8 out of 13 individuals) on the Executive 
Committee that meets monthly to monitor and govern the study. In addition, each of the 
stakeholder groups has a specific co-Investigator liaison on the Operations Committee (OC) 
(responsible for supervising operations). These liaisons are responsible for managing 
interactions with each stakeholder group. Due to the importance of the patient voice in this 
research, we are employing Ms. Rodriguez-Louis, an AA/Hispanic asthma educator as a 
specific manager of these interactions assisted by Dr. Fagan, an expert in community outreach. 
A Spanish interpreter (Hebbert) has been provided, if desired by any H/L stakeholder. Ms. 
Rodriguez-Louis will be a member of the Executive Committee as well as the Operations 
Committee. All stakeholders will be invited and reimbursed for attending the 2 day study start-
up meeting to engage all participants and to hear patient voices. In addition, there will be a 2-
day meeting in year 5 for the whole team to work on analysis, interpretation and development 
of understandable messages. Before and between the in-person meetings, the groups will meet 
regularly by conference call and webinar to assure they are fully engaged in following the study 
progress and dealing with problems that arise in the conduct of any study. Further, we are not 
only incorporating the voice our patient stakeholders in our study, we are actually incorporating 
actual patient subject voice into designing our study as described in our Vanguard study 
process. During the final 2 years, our stakeholders will spend considerable time helping us 
develop the dissemination goals and strategies that they have already begun to consider. All 
partners and stakeholders are compensated for their time and attendance at equal rates. 
Patient input will be channeled through two different mechanisms throughout this trial. Dr. Juan 
Carlos Cardet, a native of Puerto Rico, and Ms. Jacqueline Rodriquez, an African-American 
educator, will be the Operations Committee representatives to the H/L and AA patients. With 
the assistance of our patient facilitators, they will meet regularly and an on ad hoc basis 
(frequency will depend on the phase of the study with their respective groups to seek their 
feedback and communicate their input for the Operations Committee. Additionally, the groups 
will have direct representation on the Executive Committee of the study. Suzanne Madison, 
Margie Lorenzi, and Barbara Kaplan will respectively represent the AA, H/L, and patient 
advocacy committees to the Executive Committee. The Executive Committee sets the policy for 
the entire study, approves all protocols, approves all budgets and extraordinary expenditures, 
established new committees, and reviews all publications and communications. Additionally, all 
committees and subcommittees to be established will either include representatives of the 
patient stakeholder committees, e.g., dissemination, or include specific liaisons who will be 
responsible for meeting with, and channeling, stakeholder input. 
 
G. Project Milestones and Timeline 
 


42 
 
Work in the first nine months will focus on obtaining initial IRB approvals, developing 
training materials, and preparing the data collection systems, the patient contact systems, and 
reminder systems for surveys. 
From Q3 of Year 1 – 1st month of Year 2, we will enroll the Vanguard cohort, extensively 
evaluate and work with our stakeholders to interpret the data from the Vanguard assessments. 
The Vanguard data will be important in the stakeholders’ work to finalize the protocol, and 
modify and finalize patient and clinician education materials. 
At the end of year one and in Q1 of year 2 site recruitment will be completed, training and IRB 
approval of the final protocol will occur. 
The first patient will be enrolled at the end of Q1 of Year 2, and enrollment will end during Q1 
Year 4 with follow up of last patient completed by Q1, year 5. 
For Vanguard 5 months after the contract, and complete it within 6 months Throughout the 
period of patient enrollment and follow up, we will work with our patient and other stakeholders 
to address implementation issues such as slow recruitment, incomplete patient retention, 
problems with training materials, low response to monthly surveys and other issues that arise. 
The patients will help identify and resolve barriers around these issues and help us modify 
processes as required. 
In year 4, Dr. Yawn will begin working with the stakeholder groups to finalize dissemination 
goals and specific strategies to facilitate widespread uptake of PARTICS (See Dissemination 
and Implementation). 
Data cleaning and analysis will occur in Q2 4of Year 5. 
Interpretation of the results as well as manuscript preparation and final crafting of 
understandable patient messaging and other early dissemination activities will be finalized in 
Q3 and Q4 of year 5 with a final face to face stakeholders’ meeting in Q3 or 4 of year 5. 
 
A final report of the study will be completed in month 60. 
 
III. Study Outcomes and Statistical Analysis 
 
 A. Patient-centeredness of PREPARE outcomes 
 
This study is designed to use real-world patient-reported outcomes (exacerbations, 
asthma control, quality of life, missed activities) that are of demonstrated importance to 
patients, providers, payers, and policy makers. Below we describe the patient-centeredness of 
our primary and major secondary outcomes. 
 
B. Primary Outcome 
 
Vanguard: We will be doing multiple assessments about the implementation and 
operationalization of the study processes. We will use descriptive statistics and qualitative 
analyses. Questionnaires administered to participants are included in the appendix. 
 
Full study differences: We will be analyzing questionnaire data to address our hypotheses. 
There will be no assessments with regards to study processes as in the Vanguard phase. 
 
Rate of asthma exacerbations per year is the primary outcome of this trial. It has been 
argued that exacerbations are the most important asthma outcome, because they constitute the 
greatest risk to patients, and are a cause of anxiety to patients and their families. All of our 
patient partners agreed that exacerbations have major impacts on their lives and would be 


43 
 
interested in using PARTICS if it would prevent or significantly reduce exacerbations. In 
addition to their effects on patients, exacerbations result in a great stress on health care 
providers (Lane 2006, Skrepnek 2004, Andersson 2003) and are of high importance to payers 
and health care policy makers. Exacerbations increase the risk of asthma mortality (Jorgensen 
2003) and generate the greatest cost to the health care system (Reddel 2009, Lane 2006). 
Asthma exacerbations are recognized as a common clinical manifestation in patients with all 
levels of asthma severity (Pauwels 1997, O’Byrne 2001). National consensus guidelines have 
defined an asthma exacerbation as a worsening of asthma reported by the patient of a degree 
that requires treatment with corticosteroids (Revicki 1998). 
The standardization of how we define asthma exacerbations was the focus of both an 
ERS/ATS Task Force (Reddell 2009) and a workshop sponsored by the NIH (Fuhlbrigge 2012). 
 
Our primary outcome, the rate of asthma exacerbations per year, is defined as the number of 
exacerbations, emergency room visits, or hospitalizations requiring oral or parenteral 
corticosteroids, per patient per year. It will be captured by subject self-report via a monthly 
asthma exacerbations questionnaire (AEQ). Reports will be substantiated by verification in the 
EHR or direct patient interview. Multiple clinical trials demonstrate convergent validity with other 
measures of asthma-related health status (Busse 2011, Peters 2010, Lemanske 2010) and 
their responsiveness to intervention (O’Byrne 2005). We previously developed, tested, and 
used the AEQ as part of the BELT trial, in which we enrolled >1,000 AA patients. The AEQ is 
sensitive but not specific, meaning it overestimates the number of true exacerbations and 
therefore requires confirmation, but is not likely to miss exacerbations. Therefore, we will use 
the medical records or, if necessary, contact all patients whose form suggested an 
exacerbation to confirm. We will categorize these exacerbations as to whether they resulted in 
a hospitalization or emergency department visit. Using all sources of data available, an 
independent group of physicians (who are blinded about patient’s randomized treatment) will 
adjudicate and classify all possible asthma exacerbation events to determine if an exacerbation 
is truly a primary endpoint event. All adjudications will be based on a document with pre- 
specified rules for adjudication. 
 
C. Secondary Outcomes 
 
1. Asthma Control: Asthma Control Test (ACT) score 
 
Asthma control represents the degree to which impairment (impact of asthma on 
patient’s daily life) is minimized and the goals of therapy are met. The National Asthma 
Education and Prevention Program's Expert Panel Report 3 (NAEPP 2007), of which Drs. Israel 
and Yawn were members or reviewers, 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. With the input of our stakeholders we will use the ACT (rather than the ACQ) for 
monthly outcome measures of asthma control. The Asthma Control Test (ACT) (described in 
D.III.8) measures asthma control— attainable only by patient report—and was developed to 
have low patient burden (Nathan 2004). Scores from the ACT allow providers to rapidly 
determine whether a patient’s asthma is controlled or not (Nathan 2004). The ACT is self-
reported and has been validated in multiple settings (office setting, mail, & by telephone) 
(D.III.8-Validation of Scales). 
 
The ACT is easy to use, patient completed, and assesses the frequency of shortness of breath, 
use of rescue medications, the effect of asthma on daily functioning, and overall self-
assessment of asthma control. The ACT has been evaluated in independent study population 


44 
 
samples and can be self-administered in person or at home (Schatz 2007a), by telephone 
(Schatz 2007b) and by mail (Schatz 2007c). The ACT has been recommended by the NAEPP 
and the NIH Asthma outcome workshop (NAEPP 2007, Cloutier 2012) because of the 
extensive validation data for these tools, using the widest range of criterion and construct 
measures, including demonstration of responsiveness to therapy and a minimal clinically 
important difference (MCID). The MCID is defined as the smallest difference in a given score of 
interest which patients perceive as beneficial and which would support a change in the patient's 
management (Jaeschke 1989). The MCID for the ACT has been defined as 3 for individuals 
over time and between populations (Schatz 2009) and cut-off values for uncontrolled asthma: 
ACT ≤ 19 (Nathan 2004), and “very poorly controlled” asthma: ACT ≤ 15 have been 
established. (Schatz 2006, Nathan 2004). Asthma APGAR will be used as a secondary 
assessment of control to see if the three questions with a shorter time reference and therefore 
less risk of recall bias can be used to replace the ACT. (Rank, MCP 2014). 
 
2. Preference Based Quality of Life: Asthma Symptom Utility Index (ASUI) 
The ideal outcome measure for any comparative effectiveness analysis captures the risks 
and benefits for each of the interventions from the patient's point of view. The use of a preference-
based instrument, the Asthma Symptom Utility Index (ASUI), captures this important information 
(Revicki 1998). The measure is entirely patient experience focused. To develop this measure, 
patients were asked to assign a relative value to different health states. The ASUI has two 
important features that highlight its importance to patients: 1) the ASUI captures the tradeoff of the 
positive and negative aspects of interventions from the patient’s point of view, and 2) the ASUI 
measures the severity and impact of asthma symptoms. For asthma, the type and severity of 
asthma symptoms can differ between individuals or differ in a given individual over time. In addition, 
certain symptoms may be more troublesome than others to patients, and certain treatments might 
be more or less desirable. Whereas a patient with severe asthma might not appear to improve in 
terms of having significant symptom free days, s/he might improve in the severity and or frequency 
of the symptoms, something that is not captured by symptom-free day scales. The ASUI is probably 
the symptom scale most frequently used in asthma studies including large multicenter clinical trials 
(Boushey 2005). The ASUI’s psychometric properties are well documented and support the 
reliability and construct validity of the instrument, including internal consistency reliability and test-
retest reliability. The minimum clinically important difference has been determined as 0.09 points 
(Bime 2012). 
 
3. Days Lost from Work or School or Usual activities 
 
As highlighted by our patient partners in our focus groups, days lost from work and school 
are a great concern for asthma patients. At the request of the patient partners, we have included 
this outcome measure. Days lost from work and school will be collected using a validated 
questionnaire developed and utilized as part of the National Health Interview Survey (NHIS 2014). If 
a patient does not work or go to school they are asked a question about days he/she was unable to 
carry out usual activities due to asthma. Our patient partners felt that this was a very important 
outcome that they would be interested in. 
 
4. FeNO 
 
Fractional exhaled nitric oxide (FeNO):  Exhaled nitric oxide gas will be measured during the 
study visit. Asthma is an inflammatory disease of the lung. The PREPARE trial relies on the fact 
that in many cases asthmatic inflammation is of the eosinophilic (or Type 2) form of inflammation. 


45 
 
Corticosteroids are particularly effective in targeting Type 2 inflammation.  While inhaled 
corticosteroids (ICS) were initially thought to be a therapy for all asthmatics, studies now suggest 
that up to half of asthmatics may have non-type 2 inflammation and thus may be less responsive to 
ICS (Woodruff 2009).  Thus, it is possible that PARTICS may be most beneficial for a particular 
group of patients – those with Type 2 mechanisms of inflammation.   
 
 
5. Blood draw/Eosinophils 
 
 
Peripheral blood eosinophils may identify asthmatics that are most responsive to Patient 
Activated Reliever-Triggered Inhaled CorticoSteroid (PARTICS).  Eosinophil counts can be 
calculated by a complete blood count with differential.  We will determine whether peripheral blood 
eosinophil count serves as an effect modifier of the relationship between treatment (PARTICS vs. 
usual care) and the study’s primary outcome (number of asthma exacerbations per year). We will 
stratify participants based on a pre-specified peripheral blood eosinophil count threshold of 300/uL. 
This threshold is based on a frequently-used cutoff for ‘eosinophil-high’ status in the anti-eosinophil 
therapy literature (Giannetti 2016).  
 
 
D. Exploratory Outcomes 
 
1. Asthma deteriorations: 
Asthma deteriorations are defined as episodes of increased asthma symptoms for two 
or more days which resulted in patient determined increases in usual asthma medications 
without hospitalization, emergency department visit or prescription of oral steroids. In the 
previous mentioned BELT study (Wechsler 2015), we found that some patients chose not to 
seek medical care despite significant levels or length of increased symptoms due to 
transportation or financial barriers or health beliefs. However, these individuals did report 
increased use of the medications previously prescribed for their asthma. Evaluating both 
exacerbations and deteriorations may provide a more complete picture of the impact of the 
intervention on changes in asthma control and acute increases in symptoms. 
 
2. The Asthma Medication Ratio (AMR) 
 
This is a metric used by HEDIS to assess quality of asthma care in healthsystems. It is 
calculated as the rate of controller therapy refills over the controller therapy plus the rescue therapy 
refills over a period of one year. In a subset of enrolled patients, we will use the available pharmacy 
reported fill data from the patient’s health care system plus the ICS fill data from Teva for the 
intervention group to calculate AMR in the enhanced usual care and intervention arms. 
 
3. Asthma APGAR: 
 
The Asthma APGAR has been validated against the ACT in White children and adults 
but has not been validated against the ACT in African American or Hispanic Latino populations. 
We will use this opportunity to assess the validation to consider whether or not this brief control 
assessment could be used in African American/Black or Hispanic/Latino populations. 
 
4. Total health care utilization and asthma-related healthcare utilization: 
 
To assess the potential impact of use of PARTICS on the patient’s health care utilization 


46 
 
will be evaluated during the follow up months of the study for all enrolled patients and 
comparing those in the enhanced usual care with those in the intervention group. We will also 
collect utilization data for the 12-month period before enrollment to assess changes in health 
care utilization within the enhanced usual care and within the intervention group for the period 
prior to enrollment and the annualized total health care utilization for the enrollment period. 
 
Utilization will be based on review of the patient’s insurance claims record for those 
sites with access to insurance data and health care system’s billing data and EHR for all visits 
and procedures at any site (e.g. outpatient, urgent care, emergency department, hospital-
based) for integrated delivery systems. For those clinics that are part of a system that includes 
pharmacy fulfillment data and/or insurance claims data, we will include all prescription 
medications that the patient obtained from the pharmacy. 
 
Asthma-related health care utilization will be considered to include all visits and 
procedures which include asthma as a diagnosis in the outpatient and urgent care setting and 
for which asthma is a first or second diagnosis for emergency department or hospitalizations. 
While this is not likely to be completely accurate picture of the amount of time spent on asthma 
during particularly out-patient visits, it is a conservative estimate and unlikely to involve a 
systematic difference in billing procedures between the two study arms or before and during 
study enrollment. 
 
5. Medication Data: 
 
For patients randomized to the intervention group, the amount of QVAR use (estimated in total 
refills per period) due to PARTICS treatment will be reported by summary tables. Information 
on all other medication use will be available only in subset of patients for whom pharmacy 
fulfillment data is available from their health system. When available, the total number of 
dispensed inhalers for all of the patients’ usual maintenance medications and usual rescue 
medications will be reported in summary tables. 
No formal statistical tests are planned. 
 
E. Biostatistical Analysis, Statistical Design, and Sample Size 
 
Vanguard data validation 
 
The data transfer process will be tested in the Vanguard study. Data collected from 
Vanguard process will be transferred from the Patients Engaged Electronic Reporting System 
(PEERS) developed by the University of Colorado, Department of Family Medicine (CUDFM) to 
DCRI. The verification of data transfer integrity will be performed at DCRI according to DCRI 
SOP. 
 
Unexpected data inconsistencies within and between data sources will also be examined 
and reported. It will help to determine if additional data queries or validation rules will need to be 
developed to ensure the data quality in the full study. 
 
Randomization data from PEERS system will be compared with the original 
randomization scheme generated by DCRI to make sure the PEERS system randomization 
data match the randomization scheme created by DCRI. The randomization slots actually used 
by Vanguard patients will also be examined to make sure the randomization process works as 


47 
 
planned in the Vanguard study. 
 
Data collected through Vanguard process will be summarized by randomized treatment 
using appropriate descriptive statistics. Descriptive summaries of the continuous variables will 
be presented in terms of mean, standard deviation and percentiles (e.g., median, 25th and 75th 
percentiles), while discrete variables will be summarized in terms of frequencies and 
percentages. Due to the small sample size of the Vanguard study, no formal statistical tests will 
be performed. 
 
Data report will focus on the Vanguard specific questions that survey about the study 
enrollment process, intervention process, monthly questionnaire process, and medication refill 
process. In addition, the screen failure data, patients’ adherence barrier data from ASK-12, 
reasons of patients’ drop-out or premature discontinuation, data on missed visits will also be 
carefully examined and reported. These data will help the study team to identify the barriers of 
patient enrollment, treatment compliance, and patient and physician adherence. 
 
Full study differences: Formal statistical analyses will be performed. 
 
1. Overview 
Statistical analysis will be performed at the Statistical Data Coordinating Center at Duke Clinical 
Research Institute (DCRI). The study will use a randomized, parallel design to test the addition 
of PARTICS to provider-educated care as compared to continuation of provider-educated care. 
All major treatment comparisons between the randomized groups in this trial will be performed 
according to the principle of “intention- to-treat” (ITT); that is, subjects will be analyzed according 
to the treatment arm they were randomized to regardless of their compliance with the study 
medication. 
 
Data collected in this study will be documented using summary tables with appropriate 
descriptive statistics for continuous variables and binary variables. 
Annualized rates of count outcomes will be summarized using the annualized mean occurrence 
based on the Poisson model. In addition, survival curves will be constructed for all time to event 
endpoints using Kaplan-Meier methods. 
 
Unless otherwise specified, the statistical analyses procedures for comparisons of the two 
groups will be as follows: 1) Two-sample t test or Kruskal-Wallis test for continuous parameters; 
2) Chi-square test of independence for binary comparisons unless the number of events is less 
than 10, in which case Fisher’s exact test will be used; 3) Cochran Mantel-Haenszel Modified 
Ridit Scores for non-time-to-event categorical variables with >2 categories (nominal variables 
will be compared using the General Association p-value; ordinal variables will be compared 
using the Row Mean Score p- value); 4) Andersen-Gill adaptation of Cox regression for time-to-
event variables with more than one occurrence. 5) Log- rank test for first occurrence of time-to- 
event variables. All statistical tests and/or confidence intervals, as appropriate, will be performed 
at α=0.05 (2-sided) unless specified otherwise. SAS statistical software (version 9.1 or higher) 
will be used in analyses, unless otherwise noted. 
 
2. Background Data and Baseline Characteristics: 
 
Baseline demographic and clinical characteristics, including age, gender, socioeconomic status 
(SES), ethnic groups (Hispanic/Latino or African American), smoking status, BMI, medical 


48 
 
history/comorbidities, asthma history, and asthma medication use (e.g., ICS/LABA use vs. ICS 
use) will be summarized for each randomized treatment arm of the study. Asthma exacerbations 
during the 12 months prior to randomization will also be reported. 
 
In addition, data on patients’ attitude towards ICS (by the Beliefs about Medications 
Questionnaire - BMQ), healthy literacy level (by S-TOFHLA questionnaire), depression level (by 
Patient Health Questionnaire—PHQ-2), treatment adherence likelihood (by ASK-12 
questionnaire) will also be tabulated by randomized treatment groups. 
 
Asthma exacerbations, Asthma Control Test (ACT) scores, lost days of work or schools within 
one month prior to randomization will also be reported using summary tables. 
 
Only descriptive statistics will be reported for the baseline data. Continuous variables will be 
presented in terms of mean, standard deviation, and percentiles (e.g., median, 25th and 75th 
percentiles), while discrete variables will be summarized in terms of frequencies and 
percentages. 
 
3. Treatment Compliance 
 
Treatment Compliance will be monitored throughout the study. Numbers of patients non- 
compliant with treatment or crossing-over will be documented using counts and rates over time. 
 
Sensitivity analyses will be performed for patients who have treatment cross- overs. 
 
The primary analysis will be based on an Intention-to-treat analysis, but we will also conduct a 
Per Protocol analysis with available data. 
 
4. Statistical Analysis for Primary Outcome 
 
The primary aim of the study is to determine the impact of PARTICS on asthma outcomes in a 
minority population consisting of African American and Hispanic/Latino adults. The primary 
outcome of this study will be the intensity of asthma exacerbations during the months of follow- 
up between those patients randomized to addition of PARTICS to provider-educated care vs. 
those who continue with provider-educated care alone. 
 
Rate of asthma exacerbations per year will be reported for two treatment groups. Annualized 
rates of count outcomes will be summarized using the annualized mean occurrence based on 
the Poisson model. 
 
Exacerbations rates during follow-up will be compared using the Andersen-Gill adaptation of 
time-to-event Cox proportional hazards model with robust standard errors to account for 
potential multiple occurrences of the outcome in each patient (Andersen Gill, 1982). This model 
was selected over the more commonly used time to first event Cox model for two reasons. First, 
we believe that total experience during follow-up matters more to patients than the onset of the 
first exacerbation. Second, the power is increased when multiple events can be included. The 
covariates in the primary comparison will include: study center (to account for any geographic 
variation in patterns of care), h/o exacerbations in the past year (y/n), on ICS/LABA prior to 
randomization (Y/N), race/ethnicity, smoking status (as defined for subgroups), age, BMI (body 
mass index), and gender since all may influence the rate of exacerbations or the response to 
corticosteroids. The primary effect will be based on the randomized treatment arm indicator 


49 
 
variable. 
 
Time from randomization to first asthma exacerbation will be compared using the log-rank test. 
In addition, survival curves will be constructed for this time-to-event endpoint using Kaplan-Meier 
method. 
 
5. Secondary Outcome Analyses 
 
Secondary outcome variables include asthma symptom utility index (ASUI), asthma control as 
measured by the Asthma Control Test, and the number of days lost from work or school. For 
outcomes measured as continuous variables, a linear mixed model will be employed to compare 
the treatment arms. The dependent variable will be change from the baseline value. The model 
will use data from all available assessments and the predictors (included as fixed- effects) will 
include randomized treatment arm, continuous time of assessment as a linear and quadratic 
term and the interactions of the treatment arm with the time variables. Independent random- 
effects will be included for intercept and time variables. The model will adjust for all the variables 
adjusted for in the primary analysis. 
 
6. Subgroup Analysis 
 
Subgroup analyses for the primary efficacy outcome will be performed on the ITT 
population in order to explore whether the treatment effect is consistent across subgroups. Our 
goal is to determine the impact of PARTICS on asthma exacerbations in two pre-specified main 
subgroups determined by 1) race/ethnic group (African American vs. Hispanic/Latino) and 2) 
smoking status [i.e., participants who are previous (>10 pack- years)/current (or within 1 year) 
smokers vs. those who have not smoked (in the past year and <10py)] 3) patients with high 
FeNO vs. low and 4) patients with high eosinophil counts vs. low. Based on our prior 
experience, about 50% of our population will be smokers or ex- smokers. 
 
Subgroup analyses to evaluate variation in treatment effect will be performed on the 
basis of tests for interaction using the same Andersen-Gill version of the Cox proportional 
hazards model as used in the primary analysis. The model will be including terms for treatment 
arm, subgroup, and treatment by sub-group interaction and adjust for all variables included in 
the primary model. Additionally, treatment effects within each categorical subgroup will be 
examined separately using analogous Andersen-Gill model. Event rates by treatment arm and 
hazard ratios with 95% confidence intervals will be reported for each subgroup. 
Forest plots will be generated displaying the estimated hazard ratios and 95% confidence 
intervals for each subgroup will be presented. Variation in treatment effect will be assessed on 
the basis of tests for interaction in the Andersen-Gill version of the Cox proportional hazards 
model described above. Treatment effects estimated within each categorical subgroup will be 
considered exploratory/hypothesis generating. Thus, no adjustment for multiple testing will be 
employed. 
 
Additional exploratory subgroup analyses will be performed investigating the effect of 
the following factors: 1) modality in which questionnaires have been returned; 2) patients’ 
attitude towards ICS from the validated BMQ (skeptical (low necessity, high concerns), 
indifferent (low necessity, low concerns), ambivalent (high necessity, high concerns), accepting 
(high necessity, low concerns)); 3) presence of depressive symptoms (yes/no); 4) health 
literacy status (low or marginal versus high); and 5) patient adherence barriers from the 
validated ASK12 questions 1,2,3 and 11 related to measures of inconvenience, forgetting and 


50 
 
cost. 
 
7. Exploratory Analyses 
 
In addition to the exploratory subgroup analyses mentioned above, we will also explore 
whether patient characteristics such as BMI, ICS/LABA use vs. ICS use, co- morbidity (such as 
history of heart disease, cancer, stroke, diabetes, chronic kidney disease, 
COPD/emphysema/chronic bronchitis, HIV/AIDS, and hypertension), and prior exacerbations 
(e.g., exacerbation within 12 months prior to randomization) affect the apparent effectiveness of 
PARTICS by examining the interaction of these factors with treatment. In addition, we will 
explore whether self-perceived discrimination affect outcomes regardless of treatment 
assignment. 
 
The effect of provider adherence and patient adherence on the effectiveness of the 
PARTICS intervention will also be investigated. We will collect information from patients 
regarding their medication use and have added “non-invasive” ways to monitor what actually 
happens after they are randomized to either the enhanced usual care group or the intervention 
group. To this end, we will collect and incorporate the following into our descriptive information 
and into our exploratory analyses: 1) Information on the refills of the ICS in PARTICS “non-
invasively” through the renewals at the pharmacy; 2) Information on PARTICS “adherence” by 
cross-referencing the ICS data above with patient monthly report of usage on their 
questionnaires and SABA pharmacy fulfillment data if available; 3) Information on PARTICS 
effects on other asthma medication use by comparing medication use between the intervention 
and non-intervention groups by examining monthly self-report and cross- referencing to 
pharmacy fulfillment data; 4) Measure of provider compliance with guidelines, by assessing 
whether providers adjust medications according to NAEPP guidelines. We will 
obtain this information “non-invasively” by examining EHR medication prescribing information at 
asthma related visits (none required by study). For each of these visits, we will refer to the 
patient’s self-reported asthma control score of the prior month (provided by the patient monthly 
questionnaire). We will examine medication prescribing at that visit from the EHR to assess the 
frequency with which providers stepped up, or stepped-down, care according to guideline 
recommendations (NAEPP, 2007); Patient adherence and provider adherence between the two 
treatment groups will be compared. 
 
The analyses on the exploratory outcomes will also be performed. The rate on asthma 
deteriorations will be reported by treatment groups. The composite endpoint of asthma 
deteriorations or exacerbations will be analyzed using the same Andersen-Gill version of the 
Cox proportional hazards model as used in the primary analysis. The Asthma APGAR data will 
be analyzed using the same mixed model approach as described above in the Asthma Control 
Test (ACT) score analyses. 
 
 
Data on the Asthma Medication Ratio (AMR) during the follow-up months, the total 
health care utilization (i.e., total number of visits made to the enrolling sites, total number of ED 
visits, and total number of hospitalizations), and asthma related health care utilization (i.e., 
number of visits made to the enrolling sites, number of ED visits, and number of 
hospitalizations for which asthma is a first or second diagnosis) will be summarized. 
Differences between two randomized treatment groups on these variables will be compared 
using either t-test or Kruskal-Wallis test if full follow-up is available on everyone or Poisson or 
Negative Binomial regression models with time as an offset to account for differential duration 
of follow-up. 


51 
 
 
 
 
8. Sample Size and Power Considerations 
 
Sample size and power calculations were performed using PASS software (Hintze 
2011), using the similarity of inference between the Andersen-Gill models and Poisson 
regression. 
 
For the primary efficacy outcome, power calculations were based on an estimated 
primary event intensity of 0.4 per year (0.5 per 15 months) in the control arm (as seen in the 
BELT study), 15 months of follow-up for each individuals with an annualized rate of uniform 
loss to follow-up of 25% (31.25% in 15 months of follow-up) and a two-sided significance level 
of 0.05. With these assumptions, 1200 up to patients (600 per arm) yields 80% power to 
declare a reduction of 23.5% in the intensity of exacerbations as statistically significant. 
Even if the event rate were lower at .35 we would still have 80% power to detect a 25% 
difference. This difference is clinically meaningful and is well within the 25-50% (and more likely 
40-50%) (O’Byrne 2006, Rabe 2006, Buhl 2012, Papi 2013, Calhoun 2012)) reductions noted 
with such studies. 
 
For subgroup analysis, using these same assumptions, with group size of 600 (300/arm), 
at a power level of 80% we would be able to detect an expected change of 32%, still well within 
the noted effects. 
 
Power for secondary outcome comparisons were also calculated. Based on results 
observed in the BELT study, we expect the standard deviations in ASUI scores to be 0.23 in 
each arm. Thus, we will have 80% power to detect a difference of 0.04 in ASUI scores between 
treatment arms. Assuming standard deviations of 4.9 in each treatment arm on the ACT 
questions score, we will have 80% power to detect a difference of 0.96 in ACT scores. 
 
9. Interim Analysis 
 
It is anticipated that our independent safety officer will review the accumulating data at 
approximately 6-month intervals. Interim data analyses of the key safety and outcome data will 
be performed in a blinded fashion for each of these data reviews. The primary objective of 
these analyses will be to evaluate the accumulating data. Our independent safety officer will 
review the clinical outcome rates, patient recruitment, compliance with the study protocol, 
reasons and patterns of the missing data, adverse event rates and other factors that reflect the 
overall progress and integrity of the study. 
 
Before each independent safety officer review session, a blinded summary safety data report 
will be provided to the safety officer. The extracted data files and the analysis programs for 
each independent safety officer report will be archived and maintained at the Statistical Data 
CC for the life of the study. 
 
We will monitor the event rate as it accumulates in a blinded fashion to help us determine if we 
will achieve sufficient power. We will also review the baseline characteristics of enrolled 
participants to make sure we have enrolled the population defined in the protocol. 
 


52 
 
10. Addressing missing data 
 
Every effort will be undertaken to limit premature discontinuations and ascertain 
completeness of data collection. Based on patient partner and patient advocate feedback, we 
are providing multiple methods of delivering the forms and multiple ways for participants to 
respond, including mail, email, telephone, text, smartphone app, website, and voice- response 
systems. We will also implement procedures designed to retain patients and increase 
responses. We will reimburse participants for completing forms with levels that our patient 
advisors felt would encourage completion. For any positive responses regarding exacerbations, 
we will call to verify and, where available, obtain medical records. We will also use the systems 
we used in our prior BELT study with AA participants to monitor missing data. Forms that are 
>10 days delayed result in attempts to re-contact the participant through all available consented 
modalities. 
 
In concert with intent-to-treat principles, we will continue to attempt to obtain information 
on patients who failed to return questionnaires. Sites will have access to medical records, 
claims data and prescription refills. Thus, unless the patient has withdrawn consent, we will be 
able to continue collecting information on the primary outcome through these alternative 
means. We will obtain the following information for dropouts: 1) reason for dropping out; 2) 
primary determiner of dropout; 3) degree of participation. We will use a traditional consort 
diagram to track the randomized patients. Full sample size will be presented in all tables and 
figures with clear annotation of the numbers used for each analysis. 
 
For the primary analysis (Andersen-Gill model) subjects discontinuing the study 
prematurely will be censored at the time of discontinuation. This approach might lead to biased 
results if discontinuation does not occur at random. Thus, two sensitivity analysis will be 
undertaken to examine the sensitivity of inference when data is missing at random and not at 
random: 1. Inverse probability weighting. In this approach, contribution of each subject to the 
risk set calculated at time t will be inversely weighted by the estimated probability of remaining 
uncensored up to time t. This probability will be estimated using a Cox proportional 
hazards model fitted to time to censoring with variables potentially prognostic of both, failure 
and censoring, both baseline and time- dependent (such as most frequent major protocol 
deviations, certain AEs etc.), entered as covariates. In order to reduce potentially high 
variability of the resulting treatment effect estimators due to sampling variability in weights, the 
weights will be “stabilized” by multiplication of probabilities of remaining uncensored up to time t 
estimated using baseline covariates only. 2. Pattern-mixture approach. As per Little 2012. we 
will assume that for participants who drop out, the hazard of an outcome deviates from that of 
participants who do not drop out by an offset--r1 for treatment and r0 for placebo. We will then 
explore the effect of this deviation on the findings for various choices of the offsets in the two 
study groups. If the treatment effect is qualitatively maintained for the range of offsets that are 
considered to be clinically plausible, then the findings will be considered to be robust. 
 
In other analyses, missing data will be handled by using multiple imputation. Ten 
imputed data sets will be generated with imputation methods based on the regression or Monte 
Carlo framework. Final results will be based on averages from the ten imputed data sets with 
appropriate estimator employed of the variance. The variables included in the imputation model 
as covariates will be pre-specified. 
 
 


53 
 
IV. Research team 
 
A. Overview 
Our team of academic researchers combines expertise in asthma and asthma care, 
designing and implementing clinical trials and pragmatic studies in primary care settings, 
engaging patient partners, and other invested stakeholders. Three team members participated 
in the NAEPP 2007 asthma guidelines (Israel, Yawn, Fuhlbrigge), and all have worked in 
asthma research for many years. Germane to this trial, Israel, Yawn, Pace, Pencina, and 
Fuhlbrigge have collaborated on a large-scale asthma trial in 17 diverse practice settings in 
which they recruited more than 1,000 AA participants (BELT trial). Dr. 
Israel is a recognized expert in asthma clinical trial design. He brings together collaborators 
with expertise in: 1) asthma clinical epidemiology and outcomes measurement (Fuhlbrigge); 
2) execution of practice-based trials in asthma practitioner- based settings (Yawn, Pace); 3) 
organizational infrastructure and telecommunication- based patient outreach and data handling 
(Pace); 3) understanding barriers to adherence in asthma (Dr. Rand) 4) experienced 
engagement facilitators and asthma educators (Rodriguez-Louis, Fagan); 5) an investigator 
who is a native of Puerto Rico (Cardet); and 6) trial analytics (Pencina). Teva pharmaceuticals 
has agreed to provide almost $1 million of drug (QVAR® RediHaler™ (beclomethasone 
dipropionate HFA) and Teva has agreed to handle drug distribution and provide pharmacist 
stakeholders. Below we briefly describe the expertise of the primary researchers. 
 
B. Clinical Coordinating Center at Brigham and Women's Hospital 
The primary research facility is the Brigham and Women’s Hospital (Harvard). 
 
C. Practice Based Research Networks: American Academy of Family Physicians (AAFP) 
National Research Network (NRN): 
 
The AAFP NRN is one of the largest practice-based research networks in the country 
which has focused primarily on pragmatic clinical trials (PCTs) for the past seven years. The 
AAFP NRN will serve as the clinical coordinating center for this project. 
Network studies have resulted in over 90 publications in the past 14 years with a number of 
papers under review and in development. The AAFP NRN has received funding from NIH, 
AHRQ, CDC, and numerous foundations and industry sources. Virtually every PBRN study 
involves multiple clinical locations with pilots often engaging 8 to 12 sites and full PCTs 
engaging 20 to 40 sites, thus the AAFP NRN staff routinely supports multi- site trials. The AAFP 
NRN experience includes the Americans In Motion-Healthy Interventions trial, a 3-year, multi-
million dollar trial examining the impact of the AIM-HI approach on improving diet, exercise and 
emotional well-being on weight, physical fitness, psychological health as well as physiologic 
and metabolic parameters in over 650 obese individuals cared for in 24 family medicine offices 
across 15 states (Pace 2013). A second project conducted with the Olmsted Medical Center 
Research Office (incorporated into the AAFP NRN sub-contract for this project) supported 30 
family medicine offices in recruiting, treating and tracking over 2200 recently post-partum 
women for depression symptoms for a year after enrollment (Yawn 2012). This study was only 
the second to demonstrate improved outcomes with the treatment of post- partum depression. 
Finally, the entire research core recently completed the BELT study which tracked 1100 African 
American individuals with asthma for up to 18 months across 20 sites. The AAFP NRN, in 
conjunction with the core study team, have demonstrated their ability to effectively coordinate 
large, multi-site PCTs. The AAFP NRN has demonstrated its ability to coordinate multiple 
clinical sites for a number of large projects. 
 


54 
 
D. Johns’ Hopkins Adherence Center 
Dr. Cynthia Rand is a nationally known expert in the area of medication adherence and 
the barriers that exist to improving treatment adherence. Dr. Rand has been involved previously 
in a number of asthma studies and will join the research team to guide the work with patient 
stakeholders and the clinical sites to address identified barriers to adherence to the patient 
reliever-activated use of ICS. 
 
E. Data Coordinating Center and Statistical Analysis at Duke (Duke Clinical Research 
Institute (DCRI)) 
(DCRI) is a not-for-profit academic research organization (ARO) located in Durham, NC, 
created by Duke University. DCRI will provide analytic and statistical support and manuscript 
writing support. DCRI’s mission is to facilitate greater academic involvement in clinical research 
by serving as a leading center of clinical data management and analysis. Dr. Michael Pencina 
has extensive experience in designing and performing epidemiological studies and clinical trials 
and is currently a Professor of Mathematics/Statistics, Biostatistics and Epidemiology at Duke 
University. Dr. Pencina was the lead biostatistician for the BELT study and has led analysis of a 
number of other asthma related trials. DCRI has provided methodological and data analytic 
support for hundreds of large clinical trials. DCRI will also manage the reports and responses to 
the independent safety officer. Drs. Israel and Pencina have a long and productive working 
relationship. 
 
F. Clinical Sites 
 
Montefiore/Albert Einstein PBRN NYCRNG recruiting estimate 100 patients 
 
Has worked with the entire research team on the previously described BELT grant 
demonstrating their ability to recruit patients with asthma for a project of this nature. This site 
utilizes primarily FQHCs as clinical sites with both African American and Latino populations. 
The group has been involved in a number of large trials, including ACCORD and ALL-HAT. The 
research team and the clinical sites are experienced in conducting clinical trials and have a 
proven track record of working well within multi-site clinical trials. 
 
 The Department of Family Medicine at University of Florida Gainesville recruiting estimate 100 
patients 
 
The Department has practice sites in several communities, providing training in urban and rural 
medicine and health care for underserved areas in the State. Dr. Ku-Lang Chang was a co-
investigator in the BELT study. He successfully recruited African American individuals with 
moderate to severe asthma and will serve as site PI for this study. The Department and Dr. 
Chang have also been involved in a number of phase III and IV drug trials. There are several 
clinical sites that are used. They have identified just under 1000 potentially eligible patients 
from the EHR. 
 
 The MetroHealth System, recruiting estimate 100 patients – 
 
A large FQHC that covers Cleveland and delivers care at 16 locations mainly through primary 
care offices, but does have both adult and pediatric pulmonary clinicians. 
MetroHealth is an integrated healthcare delivery system affiliated with Case Western Reserve 
University and is the primary safety-net healthcare provider in northeast OH with over 1 million 
outpatient visits per year and over 500 physicians. The MetroHealth System consists of one 


55 
 
tertiary care medical center and over 20 satellite clinics throughout Northeast OH. The site is 
working with the AAFP NRN on a comparative effectiveness grant from Health Resources and 
Services Administration (HRSA) looking at atypical anti-psychotics in children, hypertension in 
children and obesity. The site has both large African American and Latino populations. The 
MetroHealth System takes care of thousands of people with asthma in primary care, pediatric 
and adult asthma clinics run by pulmonologist and clinics run by allergy and immunology 
physicians. The site has identified 1900 African Americans and Latinos with asthma on an ICS. 
 
The Departments of Internal and Family Medicine at University of North Carolina Chapel Hill (UNC) 
recruiting estimate 200 patients – 
 
Dr. Tamera Coyne Beasley will lead recruitment activities for this project through Internal 
Medicine, Family Medicine and Pulmonary sites. UNC has worked extensively with Dr.Pace 
through AHRQ Task Orders as well as a partner in the DARTNet Institute Collaborative. As a 
large, research oriented institution UNC has extensive experience in participating in and 
running large research trials. In fact, the investigative team at UNC just completed a PCORI 
asthma study for which they recruited over 100 adult patients. The UNC patient population for 
this project is predominately African American. EHR data has identified over 2800 potentially 
eligible African American and Latino individuals. 
 
Mount Sinai Divisions of Pulmonary Medicine and General Internal Medicine, recruiting estimate 100 
patients 
 
They are parts of a major research institution where both the co-investigators and clinical sites 
have directed or participated in numerous research projects involving patient consent. Dr. 
Wisnivesky has been the PI and currently serves as the PI for a number of pulmonary related 
projects. Dr. Wisnivesky has focused his research on asthma medication adherence barriers, 
barriers to ICS use and health literacy related to asthma therapy (Ponieman 2009, Sofianou 
2013). He has been involved in a number of clinical trials and successfully recruited patients 
with asthma for these trials. Dr. Wisnivesky and Dr. Israel have been colleagues for years but 
this will be the first research project they have conducted together. 
 
Division of Allergy and Immunology at the University of Puerto Rico, recruiting estimate 100 patients 
– 
 
The Division of Allergy and Immunology at the University of Puerto Rico is the project lead and 
has been involved in three asthma projects over the past eight years recruiting from 
approximately 1250 patients for each project, including a genome wide association project 
related to asthma and a study of ethnic differences in bronchodilator responsiveness (Galanter 
2008, Naqvi 2007). The Division also provides patient care in five other local community 
primary care practices and will utilize these sites as needed to supplement patient enrollment. 
Dr. Nazario and Dr. Cardet are colleagues that have known each other for some time. 
 
University of Alabama Birmingham recruiting estimate 100 patients – 
 
It has and has worked with the AAFP NRN on several projects over the past four years 
including studying novel approaches to ease the burden of collecting patient consent (Mudano 
2013), Cities for Life 
(http://www.aafpfoundation.org/online/foundation/home/programs/education/citiesforlife.h tml), 
a community wide project to improve patient use of community resources for lifestyle changes, 


56 
 
and the EDGE project. UAB is a large research oriented institution which conducts numerous 
patient consented studies in any given year. Dr. Trevor recently completed a study of use of 
pulmonary rehabilitation for patients with asthma (Trevor, in press) as the PI. She has also 
been a co-investigator in studies with Dr. Israel and other industry studies she has run out of 
the UAB clinical system. Dr. Trevino leads the Asthma Clinic for the Adult Pulmonary Division. 
She has reached out to the UAB Department of Family Medicine which will recruit patients as 
well. The population is predominately African American and the adult pulmonary clinic cares for 
over 1500 potentially eligible patients with the Department of Family Medicine adding to this 
total. 
 
University of Illinois, Chicago recruiting estimate 50 patients – 
 
UIC is a major academic research institution. The PI for this project, Dr. John Hickner, has 
worked with Dr. Pace and Dr. Yawn on a number of previous projects, including a project with 
Dr. Israel to examine the impact of primary office spirometry (Yawn 2007). Other projects with 
Dr. Pace include two patient safety reporting projects funded by AHRQ and a recent 
international project to examine the needs of primary care clinicians for point of care lab testing. 
Dr. Hickner a previous director of the AAFP NRN and has been involved in a large number of 
clinical trials. His site will utilize Family Medicine, Internal Medicine and Pulmonary clinics if 
required for patient recruitment. 
 
 Emory University recruiting estimate 50 patients – 
 
Emory is a major academic research institution. Dr. Lutz, the PI for this project, was the 
Director of the Ambulatory Sentinel Practice Network (ASPN), the precursor network to the 
AAFP NRN. Dr. Pace has worked with Dr. Lutz since his time at the University of Colorado 
stretching back over 20 years. Dr. Lutz has directed a number of large clinical trials while with 
ASPN including an HIV surveillance trial and an international otitis media trial (Calonge 1991, 
Froom 1990). 
 
 Howard University recruiting estimate 100 patients– 
 
Howard is one of the original predominately Black Medical Schools in the US and has worked 
closely with Georgetown to advance clinical research. Patients for this project will be recruited 
through the Department of Community and Family Medicine and their affiliated clinical locations 
across Washington, DC and Maryland. The DC Primary Care Research Network (DCPrimNet) 
includes 44 clinical sites with over 14,000 clinical visits per week. The network will provide sites 
for this project and has completed four previous research projects. 
 
University of South Florida recruiting estimate 100 patients – 
 
The University of South Florida Allergy and Immunology Clinical Research Center is a 
nationally recognized center of excellence in asthma research. They have proven themselves 
to be able to successfully recruit for multiple previous studies. Dr. Casale was the PI on a 
recent project with the AAFP NRN (Dr. Pace co-I) studying the impact of the Asthma IQ system 
on quality of care. Dr. Casale and Dr. Israel are also close colleagues. Dr. Casale and the USF 
team have been involved in a large number of clinical trials, recent studies include an 
evaluation of tiotropium versus LABA in asthma (Kerstjens 2015), and studies of TLR9 agonists 
for asthma therapy (Casale 2015). 
 


57 
 
University of Central Florida recruiting estimate 20 patients – 
 
UCF is a new medical school and does not have an extensive research history. UCF is 
interested in getting started in participating in clinical trials, given the local population with the 
second highest number of individuals from Puerto Rico living in the surrounding area in the US, 
the research team has invited them to participate as a clinical site. With the small enrollment 
number the site has agreed to accept a lower start-up payment and the total cost per patient 
recruited is not any higher than other sites. Dr. Pasarica has participated on clinical trial 
research teams as part of her PhD activities. This site will recruit from the faculty practice as 
well as clinical faculty practices in the Kissimmee area. The AAFP NRN staff is very familiar in 
supporting and helping primarily clinical sites become successful research sites and will provide 
extensive support to the PI and study coordinator at this site. 
 
University of Mississippi recruiting estimate 65 patients – 
 
The UMMC is a research oriented academic medical center with a culture of conducting clinical 
trials. Dr. Marshall, site PI, has been involved in a number of previous asthma studies and his 
center has proven its ability to recruit patients in previous work. Past trials include a placebo 
controlled study of omalizumab (Novartis, Marshall, G), an NIH study on mindfulness and 
asthma (5R21AT002938-02 Pbert) and DoD study on improved decision support (USM- 
MRCSSC-12162005-68D/NNS06AA68D Faruque). Dr. Marshall and Dr. Israel are colleagues 
but have not worked together in a research capacity previously. 
 
G. Back-up sites 
 
Given the budget structure for this project where the majority of a site’s budget is 
dependent on successful recruitment there was a logical limit to the number of clinical sites that 
could be included. With 1200 patients required for appropriate power we have budgeted for up 
to 1385 patients being consented. This will allow for some patients who are found to not be 
eligible after being enrolled and patient drop-out within the first month of the study. 
The budget for enrolling patients is fixed and will follow the sites that are successful in their 
enrollment. To be sure this project successfully meets its enrollment goal (the biggest single 
problem in most clinical trials) we have also budgeted to be able to on-board 2 additional sites 
should enrollment fall short. There are currently two other medical systems that have 
expressed interest in participating that we were not able to include at this time. Jacobi Medical 
Center in New York City was a component of our last application and Wayne State University 
asked to be included in this application. Both locations have been told that if there are any 
enrollment problems they will be added to the clinical performance sites. 
 
H. Site Management and Monitoring 
 
This study will be completed at multiple sites serving a variety of functions. The primary 
research facility is the Brigham and Women’s Hospital (Harvard) with clinical site coordinating 
support from the American Academy of Family Physicians National Research Network, data 
coordinating center (DCC) and statistical support from the Duke Clinical Research Institute and 
the clinical enrollment site all around the Eastern and Southern US. Please note that sites are 
primarily paid by actual enrollments. Enrollment will be competitive. While submitted budgets 
are based on anticipated enrollment, payments will be made based on actual enrollments. Site 
capacities vary from 20 patients to 200 patients, thus site budgets vary greatly. The smallest 
site is receiving a lower start- up amount so the per patient cost at this site is actually slightly 


58 
 
lower than two other sites. The number of patients available per site is shown below and also in 
the Performance Sites and Resources section. 
American Academy of Family Physicians National Research Network (AAFP NRN) will be 
engaged to support these study sites for successful completion of the Asthma IQ program by all 
enrolling clinicians, as well as issues of site implementation support. They will also be 
responsible for the systems to collect monthly patient reported outcome data including 
confirmation of asthma exacerbations through contact with the clinic sites or the enrolled 
patient. The study sites will be responsible for patient enrollment procedures including informed 
consent, collection of patient baseline data and providing prescription for ICS to be sent to the 
central pharmacy for those randomized to PARTICS. Clinical sites will enter their collected data 
onto the AAFP NRN’s maintained study database. 
The clinical sites will provide continuing asthma care to all enrolled patients as they deem 
appropriate incorporating the on-line instructional component of the Asthma IQ asthma 
management system. 
 
 
I. Research Staff--Site Interactions 
 
Drs. Pace, Israel and Yawn have conducted a number of clinical trials together over the 
past 12 years as outlined in sections above. 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 the plan to deal with recruitment challenges. The sites provide 
extensive feedback to the research team and adjustments to the protocol may be made. For 
this project this 2 day meeting will also include the all stakeholder groups outlined in 
Engagement and Appendix. 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. Informed consent is practiced 
and ideas for distance consent will be reviewed. 
Typically a few months before the in person meeting the AAFP NRN staff will begin 
working with each site’s study coordinator to complete any local IRB submissions that are 
required. Given the new emphasis on ceding IRB approval if at all possible we will definitely 
initially ask each local IRB to consider ceding to the Harvard IRB which 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 interactions more meaningful at the face to face meeting. 
After the face-to-face meeting 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 IHC system, on web-based video consent processes, another review of enrollment 
criteria, how to interface with Teva 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, Carroll 
and Yawn) will contact and talk with each site PI to be sure he or she is comfortable with all 
processes. (Dr. Carroll is the current Director of the AAFP NRN and experienced in clinical 
trials.) 
After recruitment begins the AAFP NRN staff will schedule weekly meetings with each 
site study coordinator and help them trouble shoot any issues that arise as well as maintain 
communication between sites. The senior staff will touch base with the site PIs at least monthly 
for the first 4 to 6 months and then may spread these contacts out if the site is having no issues 


59 
 
and is effectively recruiting for the study. 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 list serve 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. 
Finally, travel funds have been included in years 2 to 4 for site visits to provide on- site 
support and review for sites that are experiencing problems or if enrollment concerns are 
expressed by the AAFP NRN or local site staff. This combination of support and tracking has 
proven very successful over time and is routine operating procedure for all AAFP NRN 
supported studies. 
 
V. Drug supplies 
Teva Pharmaceuticals will provide free inhaled corticosteroids (QVAR® RediHaler™ 
beclomethasone dipropionate HFA), and has agreed to act as our central pharmacy and set up 
electronic prescriptions for electronic health records, and to have two pharmacists (one serving 
predominantly H/L customers and the other AA customers) participate. The Vice President of 
Retail Sales will be one of our stakeholders. Teva has agreed to provide almost 
$1 million of drug and has agreed to handle drug distribution and provide pharmacist 
stakeholders. 
 
VI. Patient Partners/Stakeholder Feedback 
 
A. African-American Patient Partners 
 
Through our patient engagement facilitators, we met with this focus group twice and we 
held conference calls with this group as well to assure that we had heard their feedback. Their 
feedback has been important to us and has caused us to alter important parts of the grant. 
These patients have agreed to participate throughout the grant. They have provided 
biosketches and letters of agreement. As outlined in Engagement, this group will meet as often 
as biweekly depending on the phase of the Grant (e.g., Increased during Vanguard planning 
and interpretation, and less during study conduct). Ms. Rodriguez-Louis, from the operations 
committee, is responsible for meeting with them regularly to obtain feedback and assure 
involvement. Additionally, Ms. Suzanne Madison, will serve as their representative on the 
Executive Board, which sets all policies for the study and approves protocols and committees. 
She will also report back to this committee. All committee members are compensated at the 
same rate as stakeholders of all committees. 
 
B. Hispanic/Latino Patient Partners 
With the assistance of a Spanish translator, we also met with this focus group twice and 
we held conference calls with the potential members. These patients have agreed to participate 
as outlined, including attending the face-to-face initial meeting and the concluding-
interpretation- dissemination meeting. They have provided biosketches and 
letters of agreement. This patient group will also meet as often as biweekly depending on the 
phase of the grant (e.g., increased during Vanguard planning and interpretation, and less 
during study conduct). Dr. Cardet, from the operations committee, a Puerto Rican native with 
immediate family on the island, is responsible for meeting with them regularly, with the 
assistance of facilitators and translators, to obtain feedback and assure involvement. 
Additionally, Ms. Margi Lorenzi, will serve as their representative on the Executive Board. She 


60 
 
will also report back to this committee. 
These committee members are compensated at the same rate as stakeholders of all 
committees. 
 
C. Patient Advocacy 
Two of the major organizations involved in Asthma Patient advocacy have agreed to join 
us. Ms. Kaplan will represent advocacy to the Executive Committee (EC). Dr. Yawn will be their 
liaison to the Operation Committee (OC). 
 
D. Healthcare Providers 
We have included representatives of the provider groups participating in the studies as 
well as pharmacists and staff. Dr. Wisnivesky will represent this group. He has extensive 
experience dealing with both AA and H/L populations in his venue in NYC. Dr. Yawn will be 
their liaisons to the OC. 
 
E. Professional Societies 
 
We have included representatives of the major lung, allergy, and family medicine 
professional societies. Our members include past-presidents of these societies. Dr. Finn, past-
president of the American Thoracic Society, with a particular interest in outcome disparities, will 
represent this group to the EC. Dr. Israel will be their liaison to the OC. 
 
F. Health Policy Experts 
 
We have included a broad range of policy experts including medical officers of health 
insurance units, a member of the Center of Medicaid Services, and population management 
experts. Dr. Westfall will represent the group to the EC and Dr. Fuhlbrigge will be their OC 
liaison. 
 
G. Expert Scientific Advisors 
 
We have included experts in asthma clinical trial design and the Operational lead of the 
AA BELT study. We have also included Drs. Burchard and Celedon who have extensive 
experience recruiting and retaining H/L populations with asthma. Dr. Israel will be their liaison 
to the operations committee and Dr. Wechsler will be their representative. 
 
VII. Protection from Risk, Adverse Events, Asthma Exacerbations, and Safety Monitoring 
 
A. Human Subjects Involvement and Characteristics 
 
1. Human Subject Enrollment 
 
Human subjects will be involved in the proposed study. One thousand two hundred and 
ten 1210 African American (AA) and Hispanic/Latino (H/L) adults, ages 18 years and older will 
be enrolled in this study. Up to 20% of Hispanic adults consider themselves Black/Hispanic 
(see section XII, Table 1). Any potential subject identifying themselves as both Black and 
Hispanic will be included in the Hispanic group. All enrollees will have a clinical history 
consistent with asthma and a prescription for an inhaled corticosteroid (ICS), either as a stand-
alone controller medication or in combination with a long-acting beta-agonist (LABA). If they 


61 
 
meet the enrollment criteria (see section II.C.1 Eligibility Criteria XII, Table 2), they will be 
randomized to one of two treatment options, either standardized provider educated care or 
standardized provider educated care plus as needed combination ICS+short-acting beta-
agonist (SABA) (PARTICS) for acute symptoms. 
 
African American and Hispanic/Latino adults with asthma experience a disproportionate 
rate of asthma exacerbation compared to other racial/ethnic groups. We will be examining the 
comparative effectiveness of PARTICS among AA and H/L men and women ages 18 years and 
older with a clinical diagnosis of asthma; no patients from other racial or ethnic groups will be 
enrolled. Detailed inclusion and exclusion criteria are listed in section II.C.1 Eligibility Criteria. 
The data collected from the subjects in this study (basic demographic and monthly 
information on asthma control and exacerbations) will be entered into a database maintained 
by the University of Colorado Department of Family Medicine (UC- DFM) and then de- 
identified and stored on local server for later data cleaning and secure transfer to Dr. Michael 
Pencina at Duke University for data analysis. The majority of study sites have been identified 
and included in this application (See Sites and Resources). The American Academy of Family 
Physicians National Research Network (AAFP NRN) will be engaged to support these study 
sites for successful completion of the Asthma IQ program by all enrolling clinicians, as well as 
issues of site implementation support. They will also be responsible for the systems to collect 
monthly patient reported outcome data including confirmation of asthma exacerbations through 
contact with the clinic sites or the enrolled patient. The study sites will be responsible for patient 
enrollment procedures including informed consent, collection of patient baseline data and 
providing prescription for ICS to be sent to the central pharmacy for those randomized to 
PARTICS. Clinical sites will enter their collected data onto the AAFP NRN’s maintained study 
database. The clinical sites will provide continuing asthma care to all enrolled patients as they 
deem appropriate incorporating the on-line instructional component of the Asthma IQ asthma 
management system. 
 
2. Sources of Materials 
 
One blood specimen will be collected at enrollment for a CBC with differential. Data on 
all subjects will be collected and entered into the AAFP NRN’s Integrated Health Connect (ICH) 
study database. This database includes identifiable information as it is directly accessed by the 
study patients and utilized by the research staff to track all enrolled patients. When data are 
transferred to Dr. Pencina at Duke for analysis, study patients will be identified by a unique 
identifier without any patient names or addresses. Site study coordinators and the research 
staff at the AAFP NRN, in the course of following and collecting data from the subjects, will 
have access to the subjects' personal information and may have access to medical records for 
confirmation of exacerbations, emergency room visits and hospitalizations. The data captured 
in the IHC database will include information on race/ethnicity and sex, relevant medical history, 
asthma medication usage, asthma- related quality of life, information on co-morbid conditions, 
asthma control, missed school and work days and asthma symptoms, and asthma 
exacerbations. Whenever feasible, the subjects will enter their own information directly into an 
online survey utility both during the enrollment process and for the monthly surveys. When 
needed, support from the coordinator or a voice assist system will be available at enrollment 
with comparable support for the monthly survey completion. Support for these utilities will be 
provided by the UC-DFM, an AAFP NRN partner, and will meet all HIPAA privacy and security 
requirements including strong passwords and secure URLs. These data will then be transferred 
into the study database at the U of Colorado Denver Department of Family Medicine. The data 
to be collected and the manner of de-identification will be discussed with the enrolled patients 


62 
 
as part of the informed consent process. 
 
B. Risks to Human Subjects 
 
1. Change in medications 
 
We are adding prn SABA/ICS (PARTICS) to the patient’s current therapy. All other changes in 
patient medications will be made by the patient’s personal clinician. Thus, we are not introducing 
any new medication class to patients’ regular daily controller therapy regimen. At baseline, 
patients will either be on ICS/LABA combination, or on ICS monotherapy, and will be asked to 
continue their current therapy. 
 
Patients randomized to the intervention arm will be given a prescription filled by central 
pharmacy and delivered to the patient for an extra ICS inhaler (beclomethasone 
dipropionate/QVAR® RediHaler™). Included with the ICS inhaler will be a Velcro band to attach 
to their SABA rescue inhaler to facilitate easy access to both “rescue” medications. Patients will 
be instructed to take an inhalation of ICS whenever they take a puff of SABA for acute symptom 
relief but not when the SABA is used as exercise pretreatment. To minimize the risk of overuse 
of ICS, subjects who are currently having an asthma exacerbation will be considered to be 
uncontrolled on their current therapy and will be asked to see their physician to re-evaluate 
treatment options before enrolling in the study. Shared Solutions will contact the central staff if a 
patient calls for a third refill of QVAR® RediHaler™ (beclomethasone dipropionate HFA) in a 
month. The central staff will notify the site and the provider will be alerted. All subjects will be 
informed that the alternative to participation in the trial is to continue their baseline asthma 
therapies. 
 
2. Inhaled Corticosteroids Risks 
 
All subjects will already have been on daily ICS maintenance therapy prior to enrollment in the 
study. ICS therapy is currently commonly used for asthma but not approved for use as rescue 
therapy—ICS as rescue therapy is what the intervention group will be asked to do (PARTICS). 
Participants assigned to the intervention group will be provided with the ICS beclomethasone 
dipropionate (QVAR® RediHaler™ (beclomethasone dipropionate HFA)) and asked to use one 
puff of it for every puff of albuterol used for rescue. Overall corticosteroid dosing may be 
increased in the intervention group, especially in the short term. However, data from efficacy 
studies of the PARTICS approach suggest that total inhaled corticosteroid dose will actually 
decrease as providers decrease the ICS dose due to improved patient control. Additionally, 
since we are targeting a group that has a high risk of exacerbation (1/3 or more based on our 
prior studies) for many subjects the total yearly dose of corticosteroids will be decreased even 
further due to avoidance of oral corticosteroid bursts resulting from the decreased rate of asthma 
exacerbations with PARTICS. 
 
All subjects will be informed that beclomethasone dipropionate/QVAR® RediHaler™ 
(beclomethasone dipropionate HFA) can most commonly produce: 
• 
hoarseness, 
• 
throat irritation, and 
• 
yeast infection of the mouth or throat (known as thrush or oral candidiasis, 
 
We will advise participants to rinse their mouths with water and spit the water with each inhaler 


63 
 
use in order to avoid these side effects. We will inform participants that other less common risks 
with use of beclomethasone dipropionate/QVAR® RediHaler™ (beclomethasone dipropionate 
HFA) may occur, although many of these side effects usually occur when corticosteroids are 
taken orally, not inhaled, and have been reported in children. These include: 
 
• 
Osteoporosis 
• 
Glaucoma 
• 
Cataracts 
• 
Adrenal gland suppression 
 
 
Pregnancy is not a contraindication to asthma controller therapy, including ICS. Improved 
asthma control has been shown to be associated with improved pregnancy outcomes. We will 
advise all women to seek maternity care as soon as they are aware of the possibility of 
pregnancy and to inform their physician or nurse midwife of their participation in this study. 
 
We will advise participants to consult with their doctor or nurse about any changes to their asthma 
treatment regimen, and to discuss with their doctor or nurse if they think they may be experiencing 
any effects due to using beclomethasone dipropionate/QVAR® RediHaler™. 
 
 
3. Asthma Questionnaires Risks 
 
There are no risks associated with questionnaires and patients will be reimbursed for their time 
in the amount of $20 for each of the monthly surveys they return and $50 for completion of the 
enrollment process and demographic questionnaires at baseline. 
 
4. Procedural Risks 
 
Fractional exhaled nitric oxide (FeNO) testing: Exhaled nitric oxide gas will be measured during 
the study visit. This procedure involves exhaling into a device that measures FeNO. The 
associated risks are minimal. It is possible that a participant could become lightheaded from 
blowing into the machine, but this is uncommon since participants are instructed to not blow 
forcefully into the machine. 
 
Blood eosinophil count: a blood draw of 3mL, or less than one teaspoon, will be taken from 
participants during the study visit, and a complete blood count with differential will be performed 
on the sample. The associated risks are minimal. It is possible that the participant will have 
some light bruising at the blood draw site, which will subside in a few days. 
We will not conduct any other study specific procedures aside from data collection and medical 
record review. 
 5. Blood Draw Risks: 
The patients will be asked if s/he is willing to have 3 mL’s of blood drawn during enrollment to 
process a CBC w/differential. The blood draw is minimal risk.  However, the blood draw may 
cause a small amount of pain or bruising. Rarely, people faint when their blood is drawn.    
 
C. Adequacy of Protection Against Risks 
 


64 
 
1. Recruitment and Informed Consent 
 
At study start-up, the research team will work with the Operations Committee and 
patient partners to draft an Informed Consent Template. Our goal will be to make the informed 
consent documents very brief while providing the patients with the information required to 
determine their desire to participate in the study and meet the requirements of all involved 
IRBs. Informed consent form will be uniform throughout the sites except as required by a site's 
IRB. We will work with sites to attempt to use a central IRB for all sites where this is feasible. 
We will work on multiple approaches to completion of informed consent to facilitate enrollment. 
Some patients will be consented online, using a study consent form URL and a web (visual) 
conference between the subject and the study staff who will review all study details similar to 
an in-person visit. 
 
If a site’s IRB requires modifications to the consent forms, a separate URL for that site 
will be provided which will then link the participants to the central IHC system. All subjects will 
be provided with the informed consent form/web site when the study site investigators have 
determined they may be an acceptable candidate for randomization. The form, the aims of the 
study, the data collection, follow-up requirements, and all potential risks and benefits of the 
study will be discussed with the subject by qualified study site personnel. Informed consent will 
be obtained before any study data is collected. Documentation of this process will be required, 
the subject will e-sign the informed consent document or sign a paper consent form if required 
by the local IRB. Electronic signatures will be maintained by the IHC system and 
documentation of each enrolled patient’s consent will be provided to the AAFP NRN by each 
site obtaining it. Paper consent forms will be maintained at the site as part of the subject's 
research records (which may be separate from their medical records) as well as a copy 
provided to the AAFP NRN and to the patient. No subjects will be enrolled without 
documentation of informed consent and no waivers of this process will be sought or granted 
due to the use of the addition of a medication in the intervention. The IHC system has been 
used for many studies with online consent approved by over 15 IRBs across the country. 
 
2. Risk of asthma exacerbation 
 
This study is directed toward the reduction of asthma exacerbations. Acute 
management of subjects’ asthma is not changed or mandated by the study and will be handled 
by the patient’s chosen clinician in their usual manner. Training clinicians with the Asthma IQ 
instructional component as support for standardized provider educated care has been shown to 
improve asthma control and may be associated with decreased risk of exacerbations. The use 
of PARTICS (combined ICS+SABA) for acute symptom relief is intended to further reduce the 
risk of exacerbations and no data have been published to show that the use of combined acute 
relief medications increases exacerbation potential. Data collection will include assessment of 
exacerbations, with confirmation through communication with the patient’s primary site of 
asthma care. Due to the pragmatic nature of the study, no 
additional interventions will be provided unless the patient has an allergic reaction to the 
components of the ICS used for this study. If such is the case both the patient and their care 
site will be notified to assure they have information on the exact medication to which the 
apparent allergic reaction occurred and the patient’s participation in the study will be 
discontinued since no other options for a different type of ICS are available within the study. 
 


65 
 
3. Risk of excess inhaled corticosteroid use 
 
As mentioned in the risk section, we anticipate, based on the efficacy data, that ICS use 
will actually decrease over the course of the study. Patients will be cautioned about steroid side 
effects and told to report them to their physician. We will also work with our sites, patients, and 
providers to review additional precautions. 
 
4.  Adverse Event Monitoring 
 
(a) Asthma-Related Adverse Events: 
Data collection will include assessment of exacerbations, with confirmation through 
communication with the patient’s primary site of asthma care. Due to the pragmatic nature of 
the study, no additional interventions will be provided unless the patient has an allergic reaction 
to the components of the ICS used for this study. 
 
(b) Non-Asthma Adverse Events 
 
We won’t monitor these due to the nature of pragmatic trials like this one. However, adverse 
events due to concurrent illnesses other than asthma may be grounds for termination from the 
trial if the illness is considered significant by the investigator or the patient’s personal physician 
or other clinician or if the patient is no longer able to participate effectively in the study. Patients 
experiencing minor intercurrent illnesses may 
continue in the study. Examples of minor intercurrent illnesses include acute rhinitis, sinusitis, 
upper respiratory infections, urinary tract infections, and gastroenteritis. 
Because this is a pragmatic trial, no restrictions on medications for treatment of these 
conditions will be made. 
 
(c) Serious Adverse Events: 
These are events that meet any of 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. Also includes any other adverse event that, based upon 
appropriate medical judgment, may jeopardize the subject's health and may require medical or 
surgical intervention to prevent one of the outcomes listed above. 
 
5. Management of Asthma Exacerbations 
 
This study is directed toward the reduction of asthma exacerbations. Acute 
management of subjects’ asthma is not changed or mandated by the study and will be handled 
by the patient’s chosen clinician in their usual manner. Training clinicians with the Asthma IQ 
instructional component as support for standardized provider educated care has been shown to 
improve asthma control and may be associated with decreased risk of exacerbations. The use 
of PARTICS (combined ICS+SABA) for acute symptom relief is intended to further reduce the 
risk of exacerbations and no data have been published to show that the use of combined acute 
relief medications increases exacerbation potential. 
Data collection will include assessment of exacerbations, with confirmation through 
communication with the patient’s primary site of asthma care. Due to the pragmatic nature of 
the study, no additional interventions will be provided unless the patient has an allergic reaction 
to the components of the ICS used for this study. If such is the case both the patient and their 
care site will be notified to assure they have information on the exact medication to which the 


66 
 
apparent allergic reaction occurred and the patient’s participation in the study will be 
discontinued since no other options for a different type of ICS are available within the study. 
 
6. Data and Safety Monitoring Plan 
 
We will appoint an independent safety officer from the Division of Pulmonary and Critical 
Care Medicine from Brigham and Women’s Hospital who has no other role in the PREPARE 
trial. This independent safety officer will be presented data in a blinded manner, and review 
safety data twice annually. 
 
The PI of the study will be informed of serious adverse events as soon as they occur and will 
notify the central IRB at Partners within 5 working days/7 calendar days. 
 
7. Risk to Data Confidentiality 
 
Potential risks to data confidentiality will be mitigated by requirements for the de- 
identification of study data before secure transfer from the University of Colorado data 
collection site to Duke and by security protocols for the IHC patient-reported outcomes data 
capture systems. All users of the IHC system will be tracked and only provided access in a 
secure fashion following established UC-DFM Standard Operating Procedures for this process. 
The IHC system is an enterprise level system that handles multiple research and clinical data 
collection processes across thousands of individuals simultaneously. This project will be totally 
isolated from all other ongoing research activities. Patients will only have access to their 
personal information, questionnaires appropriate for their current research activities and the 
educational video(s) associated with their arm of the study. Site research staff will only have 
access to the patients enrolled by their site. AAFP NRN staff will have access to patient contact 
data for all patients, as well as reports indicating questionnaire status for each individual. The 
IHC system will automatically lock the monthly questionnaire for three weeks following 
completion by an individual assuring that we do not have duplicate completion of one month’s 
questionnaire. The system will automatically remind individuals to complete 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 these data. 
 
8. Inclusion of Women and Minorities 
 
Only African American and Hispanic/Latino adults ages 18 years and older with asthma 
will be enrolled in this study, as the proposed research question focuses on the treatment of 
asthma specifically in this population. Based on past research experience and evidence from 
the medical literature, the researchers feel that this population is at significantly higher risk from 
asthma than other racial and ethnic groups and that further study in this specific population is 
needed. Therefore, no other racial/ethnic groups will be enrolled. 
Women will be enrolled with no exclusion for pregnancy if determined acceptable by the 
woman’s maternity care clinician(s). Statistics for studies of this type indicate that the 
percentage of women within the population to be enrolled will be approximately 60%. The study 
will seek to enroll approximately 50% of subjects of African American self- reported race and 
approximately 50% of Hispanic/Latino self-reported ethnicity with the provision as stated above 
that those reporting themselves to be Black and Hispanic will be enrolled in the H/L group. 
Enrollment of one group may be slowed or stopped if recruitment is faster or recruitment goals 


67 
 
are met for this group. The expected enrollment is detailed in the section XII, Table 1. 
 
9. Inclusion of Children/Adolescents 
 
Patients ages 18 to 21 will be included in this study. While they are labeled as “children” for 
study inclusion criteria by the National Institutes of Health and the Department of Health and 
Human Services, no special requirements for informed consent or parental permissions or safety 
concerns exist for this study among those aged 18 to 21 at all sites, except for the University of 
Puerto Rico—UPR requires assent of children ages 18 to 21 plus consent of a legal guardian. 
 
D. Potential Benefits and Importance of the Knowledge to be Gained 
 
1. Benefits to Human Subjects and Others 
 
We believe there may be a potential benefit to those patients randomized to the 
PARTICS arm but this is still unknown. The potential benefit would be decreased numbers of 
exacerbations (asthma episodes that require oral steroid bursts or hospitalizations) and 
possibly decreased symptoms and reduced need for extra asthma medications. It is also 
possible that implementation of the Asthma IQ training for standardized provider educated care 
may improve rates of asthma control and this benefit could accrue to patients in both arms of 
the study. 
Asthma has been resistant to various approaches to improve outcomes. Most 
approaches to date have focused in improving clinician implementation of current clinical 
guidelines and improving patient adherence with these treatment guidelines but when 
successful have been complex and difficult to widely disseminate. A few projects have worked 
at the community level to improve environmental conditions, but are also difficult to disseminate 
widely. 
The approach studied in this project puts the patient in control of the level of additional 
use of ICS controller medications. The potential for benefit to society and individuals with 
asthma in general is very significant as the PARTICS represents a new approach to asthma 
therapy. Current asthma controller therapy follows a rigid, provider- prescribed approach. This 
study will examine the potential benefits of a patient controlled approach added to typical use of 
daily controller medications. Multiple studies and quality improvement projects have attempted 
to reduce asthma exacerbations, a theoretically ambulatory care-sensitive condition, with little 
long term improvement in outcomes. Any chance to determine a method to close this gap in 
care and learn how better to treat these subjects in clinical practice presents a clear benefit to 
African American and Hispanic/Latino adults with asthma. 
Our proposed study seeks to inform a key health decision for people with asthma and 
clinicians who treat it-- should asthma patients use, and providers prescribe, a controller 
medication to be used each time a reliever is used in order to reduce asthma exacerbations? 
The PREPARE trial can help with that decision by assessing the ability of PARTICS to reduce 
exacerbation occurrences, reduce days lost from school or work, and reduce the consumption 
of ICS – all outcomes of high importance to patients. 
 
This health decision is particularly pertinent among AAs and H/Ls, who bear a disproportionate 
burden of asthma morbidity and are less likely to receive, choose, or be able to comply with 
guideline-driven care. If the study shows that the PARTICS approach reduces exacerbations 
and/or improves other outcomes important to patients, then this approach can easily be 
adopted by patients and their providers in the context of current care since it is intuitive and 


68 
 
takes advantage of current patient-driven patterns of reliever inhaler use. 
 
2. Knowledge to be Gained 
 
PREPARE will teach us whether a PARTICS strategy can reduce asthma exacerbations 
in a real-world setting with high-risk populations as has been demonstrated in efficacy studies. 
It will also teach us whether the PARTICS approach can be implemented in health care 
systems that treat substantial numbers of minority patients. Although PARTICS- type strategies 
have been shown to significantly reduce exacerbations in carefully controlled efficacy studies 
by nearly 50% it’s unclear patients will accept this strategy in real life outside the realm of an 
efficacy clinical trial. 
PREPARE will also teach us whether the rationale for the PARTICS approach is better 
understood and accepted by patients than current standards of care, and whether it can reduce 
potential barriers to asthma self-management, such as beliefs about medication, cost, 
forgetting medication, health literacy and depression. While our preliminary data suggests 
significant benefit of the PARTICS strategy across a diverse population, this trial will teach us 
whether particular subgroups of patients show a greater benefit from this approach. 
 
VIII. Data Sharing and Trial Information 
 
A. ClinicalTrials.gov 
 
This pragmatic trial requires registration on clinicaltrials.gov and registration will be 
done prior to enrollment of the first patient, during the first year of the project. 
 
 
B. Data Sharing Plan 
 
During the course of the PREPARE study, the Executive Committee (EC), which 
includes patients, patient advocates, and representatives of other stakeholder committees will 
establish a Data Sharing Committee (DSC) that will include at least two patient representatives. 
The DSC will develop a PREPARE Data Sharing Plan to be approved by the EC. This plan will 
include a detailed description of a post-project Data Request Process. 
Complete, cleaned de-identified copies of the final datasets will be maintained at a secure 
location to be determined by the Steering Committee. These datasets will be made available as 
outlined in the PREPARE Data Sharing Plan via the established Data Request Process within 
one year of completion of the study. Specifics of this plan will be proposed by the Data 
Coordinating Center and ratified by the Executive Committee and at minimum will include the 
following provisions: 
 
A specific Data Request form will be created that will need to be completed by all 
applicants requesting data and submitted to the PREPARE Data Sharing Committee. 
Required information to be provided on the Data Request form will include: 
 
--Details on the requesting individual(s) and their affiliated organization 
--Detailed specification of required data 
--Intended use of the data 
--Timeline for receipt of the data 
 
Applicants will need to provide funds to cover the costs of retrieving the data and 


69 
 
fulfilling the specifications of the request. The costs of the requests will be based on the number 
of hours to fulfill the request and the specific billing rate of the statistician performing the task. 
Data requests will require approval by a majority of the Data Request Committee, including the 
Principal Investigators. 
 
The PREPARE Data Sharing Committee will remain active following the end of the 
study and will meet periodically to review and evaluate specific data requests. 
Requests for data will need to come through one of the Data Sharing Committee members 
who, upon receiving the request, will schedule a meeting to review the request. Requests may 
be fully approved, conditionally approved, or denied, or additional information may be 
requested based upon specific criteria established in the 
 
PREPARE Data Sharing Plan. The PREPARE Data Sharing Committee decisions will 
be communicated in writing to the requesting individual and can be communicated verbally by 
the contacted Data Sharing Committee member as well. If approved, de- identified SAS 
datasets will be prepared in accordance with the data specifications requested. In addition to 
providing the above described data sharing resources, a complete copy of the de- identified 
datasets, along with the data dictionary will be placed in the public archives. 
 
 
 
IX. Nebulizer Qualitative Sub study 
 
Background: Preliminary data show a high rate of consistent nebulizer use in the overall study 
(~45%), regardless of treatment assignment. Most of the published research on nebulizer use is 
focused on the pediatric population. Given the significant proportion of participants who report 
using a nebulizer regularly in our PREPARE trial this exploratory sub-study represents an 
opportunity to add to the published literature on the topic of nebulizer usage in Hispanic and 
African American adults. 
 
Aim: This qualitative sub-study is to help us understand preferences, practices, and decision-
making about nebulizer use among a sample of African American and Hispanic/Latino asthmatic 
adults. 
 
Recruitment: a random sample of 40 patients who report using a nebulizer for rescue on their 
baseline questionnaire and report using a nebulizer in the past 4 weeks for rescue on at least 
one monthly survey will be interviewed.  We will include 20 AAs, 10 Usual Care, 10 Intervention; 
20 H/L, 10 Usual Care, 5 Spanish speaking; 10 Intervention, 5 Spanish speaking. We will 
exclude patients from two PREPARE sites not covered by Partners’ IRB: Atrium and UIC. 
 
All site PIs and/or Medical Directors will be contacted and asked permission for us to offer 
participation in this nebulizer sub-study to current PREPARE participants who self-report 
nebulizer use (as noted above).   
 
A random sample of 300 participants will be contacted by mail. We will send opt-out letters with 
an opt-in clause (uploaded as separate attachment) and an information sheet (uploaded as 
separate attachment) explaining the sub-study and asking them to contact us if they did not 
wish to be offered participation in this sub-study. Participants will be informed that calls will be 
recorded for study purposes and will request verbal consent prior to the interviews starting 
(phone script uploaded as separate attachment). When participants are reached, they will be 


70 
 
offered the option being interviewed at the time of scheduling a more convenient date/time for 
the sub-study interview. Research staff trained in qualitative research will conduct a 30 min 
telephone-based interview (interview uploaded as a separate attachment). 
 
Each participant will be called a maximum of 5 times with at least two of those times being an 
evening call. Messages will include a study specific call-back number and scripted message 
(message script uploaded as separate attachment). 
 
X.  COVID-19 Sub study 
 
Background: The PREPARE study has produced riveting data/manuscripts regarding the 
COVID-19 pandemic and its impact on this disproportionately affected population of African 
American/Black and Hispanic/Latinx adults with asthma. First, a clinical communication 
published in May 2021 finding a 40% reduction in asthma exacerbations from January - August 
2020 compared to January - August 2019 (during COVID-19) has had an overwhelming impact 
on researchers and the community. The finding was highlighted by several news agencies 
including the Atlantic. Additionally, a second manuscript has been accepted by JACI in Practice.  
Although we sampled only a subset of patients in the study, the findings showed that this 
population experienced changes in the quality of their asthma care and had increased 
socioeconomic stressors as a result of the COVID-19 pandemic and may be hesitant or 
unwilling to receive a COVID-19 vaccine. 
 
The patient partners, stakeholders and research team agree that there is much more to be 
learned about this population with regards to COVID-19. In specific, we would like to better 
understand what might have contributed to the reduction in asthma exacerbations that we are 
measuring as our primary outcome. This involves understanding what practices have been 
undertaken by our population and, in order to make recommendations, to understand some of 
the attitudes toward COVID-19-induced modifications.    
 
Aims: The aims of the sub study are to 1) explore subject behavioral changes which may have 
resulted in decreased exacerbations following the Covid19 pandemic. 2) explore patients’ 
attitudes towards measures to prevent the spread of Covid19 (mask wearing, vaccine, etc.) and 
3) investigate patient preferences towards telehealth vs. in person asthma clinic visits.    
 
Methods: A COVID-19 questionnaire will be sent to PREPARE patients who agreed to be 
contacted after exiting the study. Approximately 1,000 agreed to future contact. The REDCAP, 
HIPPA compliant, questionnaire link will be sent via email and/or text and follow up of non 
responders will be by phone. As in the full study, to compensate patients for their time, we will 
pay patients $25 for completing the questionnaire. Payment will be made through the BWH 
ADVARRA system.   
  
Each participant will be called a maximum of 5 times with at least two of those times being an 
evening call. Messages will include a study specific call-back number and scripted message 
(message script uploaded as separate attachment). 
 
 
List of Abbreviations 
 
AA: African Americans 
AAAAI: Academy of Allergy Asthma and Immunology AAFP: American Academy of Family 


71 
 
Physicians ACT: Asthma Control Test 
AEQ: Asthma Exacerbation Questionnaire AMR: Asthma Medication Ratio 
ARO: academic research organization ATS: American Thoracic Society 
ASK-12: Adherence Starts with Knowledge-12 ASUI: Asthma Symptom Utility Index 
BELT: Anticholinergic vs Long-Acting β-Agonist in Combination With Inhaled Corticosteroids in 
Black Adults With Asthma: The BELT Randomized Clinical Trial. 
BMQ: Beliefs about Medication Questionnaire CCPC: Disease Control and Prevention 
DCC: Data Coordinating Center 
DCRI: Duke Clinical Research Institute EC: Executive Committee 
ED: emergency department EHR: electronic health record 
ERS: European Respiratory Society H/L: Hispanic/Latinos 
ICS: inhaled corticosteroids LABA: long-acting beta-2 agonists 
MCID: minimal clinically important difference 
NAEPP: National Asthma Education and Prevention Program NIH: National Institutes of Health 
NRN: National Research Network OC: Operations Committee 
PARTICS: Patient Activated Reliever-Triggered Inhaled CorticoSteroid PCORI: Patient-
Centered Outcomes Research Institute 
PCT: pragmatic clinical trial 
PEERS: Patient Engaged Electronic Reporting System PHQ-2: Patient Health Questionnaire 
PREPARE: Patient Empowered Strategy to Reduce Asthma Morbidity in Highly Impacted 
Populations 
QA: Quality Assurance 
SABA: short-acting beta-agonist SES: socioeconomic status UAT: User Acceptance Testing 
UCDFM: University of Colorado Denver, Department of Family Medicine. 
 
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XII. FIGURES 
 
 
Figure 1. PREPARE Overall Study Structure 
 


86 
 
Figure 2. PREPARE Participant Flow Diagram 
Potentially eligible patient identified from EHR or during 
clinic visit 
Patient asked if interested in considering study 
If no, 
exit 
If yes - appointment set 
up for intake visit 
Patient views intro video 
If not interested, 
patient exit 
If interested, patient 
completed eligibility 
survey 
If not eligible, 
patient exit 
If eligible, patient 
reviews consent 
If patient 
If consent signed, patient 
doesn't not 
 completes registration 
consent, exit 
  
information 
Patient logs into PEERS system 
and completes Intake survey 
Study coordinator reviews Registration data and 
intake survey reviewing any unclear or skipped 
answers and completing these two areas 
Patient completes baseline 
survey 
Randomization revealed 
Enhanced Care patients 
Patient views correct 
educational video and selects 
pouch 
Study coordinator 
views/reviews inhaler 
technique 
Patient receives pouch ( by 
mail for video conf) 
Study coordinator 
views/reviews inhaler 
technique 
 
Patient receives pouch ( by 
mail for video conf) 
Patient completes monthly 
questionnaires 
Patient completes 
monthly 
questionnaires 
Study coordinator gives patients ICS or 
mails it; guarantees the prescription is in 
the EHR.
Patient views correct 
educational video and selects 
pouch 
Intervention patients 
Patient and study coordinator meet in 
person or by two way video conferencing 


87 
 
Figure 3. Project Milestones and Timeline 
 


88 
 
XIII. Tables 
 
Table 1: Estimated Final Racial/Ethnic and Gender Enrollment Table 


89 
 
XIV. APPENDIX 
 
A. Vanguard Interview Questions: Qualitative Interview - 12 weeks [complete] 
 
Instructions to interviewer: Please ask each of the questions to each person/interview you do. 
 
Each question has the core concept bolded; the core concept is the general topic of a piece of the 
study we are interested in. After each core concept is an open-ended question. Please start with 
these and give the participant time to answer them before diving in to the prompt/probe questions. 
Based on the participant’s answer to the open- ended question, it may not be necessary to ask 
each and every prompt/probe question. The prompt and probe questions are listed as guidance for 
you but it may not be necessary to ask them all. Please use your own judgment on this. 
 
Refer to the accompanying Tip Sheet for Interviewing (at the end of these questions) prior to your 
interviews if needed to help you prepare for the interview. 
 
 
Hello, am I speaking with [participant’s name]? My name is [Victoria] and I am a part of the 
PREPARE study team. 
 
Thank you for being available to speak with me today. I really appreciate it. 
 
This interview will probably take about 20 minutes. Is this still a good time for you? 
 
[Check also that connection is good, no background noise, and audiorecorder working properly]. 
 
Is it OK if I audiorecord this call? That would really help me be sure I remember everything you say 
and give my full attention to our conversation. 
 
The purpose of today’s interview is to learn more about your experience being a part of this study. 
Your ideas and feedback about ways we can improve our work for the future are very important to 
us. Please feel free to share your opinions as honestly and openly as you can. There are no “right” 
or “wrong” answers here. 
 
If you have any specific questions or concerns that come up in our discussion that I cannot answer, 
I will be sure to give you the contact information that you need to get those answers from other 
research team members. 
 
 
For enhanced usual care and intervention patients at 12 weeks: 
I would like to start off asking your general impression of being a part of this study? 
What worked for you? What didn’t work for you? 
What would you tell a friend with asthma about this study? 


90 
 
If you didn’t have to do these interviews would you consider doing this again for up to 15 
months? 
Do you think the payments for completing the questionnaires was reasonable? 
1. What can you tell me about any of the educational materials you saw or were provided 
as part of the study? Thinking back to the study video’s that you saw when you 
enrolled in the study. Have you watched any of the study video’s again since you were 
enrolled? 
- 
If yes -> which video’s did you watch again? (intro video, study video, inhaler 
video) *only intervention patients saw the study video* 
o What made you decide to watch the [use answer from previous] video 
again? Was it helpful? Did you watch it more than once? Did you 
show the video to any friends or family? 
- 
If No --> Why did you not watch them again? (too long? Too boring? 
Just forgot? --> too long/too boring etc- Any suggestions on improvements? 
Just forgot -->Anything we could do to remind you that they are available) 
 
Thinking back to the study packet you received when you enrolled in the study. Have 
you looked through the packet again since you were enrolled? 
- 
If yes -> What did you go to the packet to look for? 
o Where you able to find the information you needed? Was it helpful? 
Did you show the packet to any friends or family? 
 
- 
If No --> Why did you not look at it again? (too long? Too boring? Just forgot? 
--> too long/too boring etc- Any suggestions on improvements? Just forgot --
>Anything we could do to remind you that it is available) 
Did you ever look at the website for the study? 
If yes -> What did you go to the website to look for? 
o Where you able to find the information you needed? Was it helpful? 
Did you show the website to any friends or family? 
- 
If No --> Why did you not look at it? (too long? Too boring? Just forgot? --> 
too long/too boring etc- Any suggestions on improvements? Just forgot --
>Anything we could do to remind you that it is available) 
2. Now I’d like to ask you about your experience with the monthly questionnaire. (this is 
the survey that you completed every month with questions about your asthma and 
inhaler usage). 
 
Open-ended question: How was the experience overall? Option-tell me about your 
overall experience with the monthly questionnaires. Can you walk me through it as it 
happened for you? 
Did you get any reminders to complete your questionnaires? Did the reminder 
message come when you expected it? 
If it didn’t come when you expected it, can you tell me more about that? Was it 
helpful? Why or why not? 
Tell me about any difficulties you had completing the questionnaire. 
How easy or hard were the questions to answer? 
Were there any questions that seemed to repetitive (as if you were being asked 
the same thing over and over again) 


91 
 
Would it have helped if someone read the questions to you? 
What is your opinion on the length of the questionnaire? (Was it too long, too 
short, or just right?) 
Was there anything we didn’t ask that you think would be important for us to 
know? 
3. Now I’d like to ask you some questions about your inhalers/puffers. 
How many quick reliever/albuterol inhaler canisters do you currently have and 
use? Do you usually keep separate or different quick relief inhalers in multiple 
places like the car, work, home? 
Do you remember how many refills of your quick reliever/albuterol you have 
gotten since the start of the study? 
What do you usually call your albuterol inhaler? 
For usual care only: 
Did you fill in the medicine log when you got the new inhaler? 
Yes --> Was it hard to remember to do this? What could we do to make this easier? 
No --> What could we do to make it easier? 
Do you have any ideas on other ways (besides the medicine log) you could keep track 
of your inhalers during a longer study? Would a periodic reminder via text message/ 
phone call/ email help? Would a sticker on your pouch have helped you remember? 
1. Do you use a nebulizer? If no go on if Yes 
Have you used your nebulizer in the past week? (about how many times?) 
  
Past two weeks? (about how many times?)   
 
2. Overall, how do you feel your asthma has been since you started the study? Tell me 
about how you feel compared to before you started the study. Has there been any 
change? What if anything is different for you? Have you noticed any changes in your 
health? 
3. Are there things that you think we should change or improve about this study? Please 
give us any ideas you may have. 
4. Do you have any concerns or questions for me about the study? 
 
For intervention only: 
1. Now I’d like to ask you some questions about your study medicine QVAR. How many 
refills of QVAR have you gotten since the start of the study? Any difficulties with the 
refills? 
2. Now let’s talk about the part of the study that asks you to use the study medication 
QVAR. 
2a. Open-ended question: How was it taking an additional medication? 
Prompts/probes: 
2b. Was it hard to remember to use the QVAR® with the albuterol/quick reliever? 
If yes --> Is there anything that you think we could do that would help you 
remember? 
2C. How often do you think you used both inhalers together puff for puff? 
For example if you took 4 puffs of albuterol/quick reliever you then took 4 of 
QVAR®? 
2D. Did you fill in the medicine log when you got the new inhaler? 


92 
 
Yes --> Was it hard to remember to do this? What could we do to make 
this easier? 
No --> What could we do to make it easier? 
Do you have any ideas on other ways (besides the medicine log) you could keep 
track of your inhalers during a longer study? Would a periodic reminder via text 
message/ phone call/ email help? Would a sticker on your pouch have helped 
you remember? 
3. Have you used your nebulizer in the past week? (about how many times?) 
  
Past two weeks (about how many times?   
 
If yes --> did you use your QVAR after using the nebulizer? 
If yes -> how many puffs did you use? 
If no (or not 5 puffs) -> why did you not use 5 puffs of QVAR (hard 
to remember, too many puffs, etc). What could we do to make it easier to 
remember or less scary? 
4. During the study, did you make a visit for your asthma to a healthcare provider? This 
includes your regular asthma doctor or someone covering for your regular doctor, urgent 
care and Emergency department. 
If yes 
- did you mention the PREPARE study to them? 
o If yes- tell me more about that, what did they have to say? Did 
they have questions? Were you able to answer those 
questions? 
o If No- tell me why not? What could we have done to make it 
easier to remember to tell providers about the PREPARE 
study? 
- 
Did you show them your stickers, yellow card, or any other 
information about the study? 
o If yes- tell me more about that? Did they look at them? Ask 
any questions? Was the card/sticker/website helpful? 
o If no- tell me why not? What could we have done to make it 
easier to remember to share your card/sticker? 
- 
Did the provider talk with you about how you were taking the QVAR? 
o If yes- tell me more about that ? Did they adjust your dose? 
Did they tell you take it differently than you had 
been taking it? Did they seem concerned about how you were 
taking the QVAR? 
If No- skip to next question. 
5. Do you think that using the 2 inhalers medicines was better for you asthma? 
- 
If yes- can you give me an example of why you thought it was better? 
o If it were an option would you continue to use the two 
medications together? 
- 
If no- tell me why you didn’t think the extra inhaler helped? 
o If it were an option would you continue to use the two 
medications together? 
6. Overall, how do you feel your asthma has been since you started the study? Tell me 


93 
 
about how you feel compared to before you started the study. Has there been any 
change? What if anything is different for you? Have you noticed any changes in your 
health? 
7. Are there things that you think we should change or improve about this study? Please 
give us any ideas you may have. 
8. Do you have any concerns or questions for me about the study?