Clinical trial NCT01967173
Conditions: Asthma
Keywords: Asthma Fluticasone Salmeterol
Sponsor: Milton S. Hershey Medical Center
Start date: 2014-02-01; Completion date: 2017-07-01
Enrollment: 574 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to find the best asthma treatment to add for Blacks who have asthma that is not well controlled on a low dose of inhaled steroid. This study will also try to find out if Black adults and children differ in how they respond to the medications used in this study.

Detailed description:
BARD is a 66 week prospective, randomized, double-blind, crossover trial in Blacks (individuals who self-report Black ancestry) who have inadequately controlled asthma while taking low-dose inhaled corticosteroids (ICS). BARD will examine the efficacy of increasing the dose of ICS with or without the addition of a long-acting beta agonist (LABA) to determine whether individual patients respond better to one treatment than another and, if so, whether the responses are different for children and adults or if they are related to genetic ancestry.

Arms: arm 1: Flovent Diskus® 250 mcg,followed by Advair Diskus® 250/50 mcg, followed by Flovent Diskus® 100 mcg, followed by Advair Diskus® 100/50 mcg arm 2: Advair Diskus® 250/50 mcg, followed by Advair Diskus® 100/50 mcg, followed by Flovent Diskus® 250 mcg, followed by Flovent Diskus® 100 mcg arm 3: Flovent Diskus® 100 mcg, followed by Flovent Diskus® 250 mcg, followed by Advair Diskus® 100/50 mcg, followed by Advair Diskus® 250/50 mcg arm 4: Advair Diskus® 100/50 mcg, followed by Flovent Diskus® 100 mcg, followed by Advair Diskus® 250/50 mcg, followed by Flovent Diskus® 250 mcg arm 5: Flovent Diskus® 500 mcg, followed by Advair Diskus® 250/50 mcg, followed by Flovent Diskus® 250 mcg, followed by Advair Diskus® 100/50 mcg arm 6: Advair Diskus® 250/50 mcg, followed by Advair Diskus® 100/50 mcg, followed by Flovent Diskus® 500 mcg, followed by Flovent Diskus® 250 mcg arm 7: Flovent Diskus® 250 mcg, followed by Flovent Diskus® 500 mcg, followed by Advair Diskus® 100/50 mcg, followed by Advair Diskus® 250/50 mcg arm 8: Advair Diskus® 100/50 mcg, followed by Flovent Diskus® 250 mcg, followed by Advair Diskus® 250/50 mcg, followed by Flovent Diskus® 500 mcg
Interventions: intervention 1: Flovent Diskus® 100 mcg intervention 2: Flovent Diskus® 250 mcg intervention 3: Flovent Diskus® 500 mcg intervention 4: Advair Diskus® 100/50 mcg intervention 5: Advair Diskus® 250/50 mcg
Intervention descriptions: intervention 1: Flovent is an ICS intervention 2: Flovent is an ICS intervention 3: Flovent is an ICS intervention 4: Advair is an ICS/LABA combination intervention 5: Advair is an ICS/LABA combination

Protocol documents:
Prot_SAP_000.pdf: 
 
 
NHLBI AsthmaNet 
 
 
 
 
 
 
 
BARD - Best African American Response to Asthma Drugs 
 
 
 
 
 
 
 
 
 
Study Protocol 
Version 25.1 
July 21, 2017 
 


 ii
TABLE OF CONTENTS 
 
I. 
PRIMARY RESEARCH QUESTIONS: ......................................................................................... 1 
II. 
TRIAL OVERVIEW ....................................................................................................................... 1 
III. 
BACKGROUND AND SIGNIFICANCE ........................................................................................ 2 
IV. 
HYPOTHESES TO BE TESTED .................................................................................................. 7 
V. 
PROTOCOL SUMMARY AND SCHEMA ..................................................................................... 8 
VI. 
INCLUSION AND EXCLUSION CRITERIA (TO ENTER CHARACTERIZATION PERIOD) ...... 12 
A. Inclusion criteria at Screen Visit A (to enter run-in) ................................................................ 12 
B. Exclusion criteria at Screen Visit A (to enter run-in) .............................................................. 13 
VII. INCLUSION AND EXCLUSION CRITERIA PRIOR TO RANDOMIZATION .............................. 17 
A. Inclusion Criterion for Randomization: Lack of acceptable asthma control in run-in period ... 17 
B. Exclusion Criteria for Randomization ..................................................................................... 20 
VIII. RATIONALE & SPECIAL CONSIDERATIONS FOR SPECIFIC ASPECTS OF THE STUDY... 21 
A. Anticipated composition of study population .......................................................................... 21 
B. Definition of “Black” for this study: ......................................................................................... 21 
C. Genetic Analysis of Responses ............................................................................................. 21 
IX. 
SPECIAL CONSIDERATIONS INVOLVING THE STUDY POPULATION AND STUDY 
MEDICATIONS ................................................................................................................................... 26 
A. Justification of inclusion of participants who are symptomatic on low doses of ICS or 
ICS/LABA: ................................................................................................................................... 26 
B. Escalation of ICS dose: ......................................................................................................... 27 
C. Assessment of Black adults/adolescents vs. children, rationale for breakdown of age groups 
into age 5-11 years and 12 and older, and dosing issues: .......................................................... 27 
D. Steroid dose response in Blacks in relation to age: ............................................................... 27 
E. Combining adults and adolescents aged 12 and greater to develop data to inform guideline 
and treatment recommendations: ............................................................................................... 28 
F. HPA Axis Suppression: ......................................................................................................... 28 
G. Symmetry between adult/adolescent and pediatric studies: .................................................. 29 
X. 
PROTOCOL DETAIL AND VISIT STRUCTURES ...................................................................... 30 
A. Study visits and telephone contacts ...................................................................................... 36 
XI. 
OUTCOMES ............................................................................................................................... 43 
XII. GENOTYPING METHODS ......................................................................................................... 45 
XIII. STATISTICAL DESIGN AND ANALYSES ................................................................................. 45 
A. Randomization ....................................................................................................................... 45 
B. Masking ................................................................................................................................. 46 
C. Statistical Analysis Plan ......................................................................................................... 46 
D. Statistical Analysis Plan for Genetics .................................................................................... 57 
E. Power Calculations ................................................................................................................ 60 
F. Timeline ................................................................................................................................. 64 
G. Anticipated Results ................................................................................................................ 64 
H. Exploratory Analyses ............................................................................................................. 67 
XIV. DRUG SUPPLIES ....................................................................................................................... 70 
XV. ADHERENCE AND MONITORING ............................................................................................ 71 
XVI. INHALATION TECHNIQUES ..................................................................................................... 71 
XVII. PHENOTYPING AND SPECIAL STUDY TECHNIQUES ........................................................... 71 


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XVIII. 
SAFETY ASSESSMENTS ..................................................................................................... 73 
XIX. RISK/BENEFITS IN ADULTS/CHILDREN ................................................................................. 76 
A. Medication Risks: .................................................................................................................. 77 
B. Risks and Benefits of Study Procedures: .............................................................................. 78 
XX. TREATMENT FAILURE, DROP-OUT STATUS AND ASTHMA EXACERBATIONS ................ 80 
A. Criteria for assigning treatment arm failure during any one of the four treatment periods ..... 80 
B. Criteria for assigning drop-out status at any point in the study .............................................. 80 
C. Criteria for assigning treatment period drop-out status during any of the periods.................. 80 
D. Definition and management of asthma exacerbations ........................................................... 81 
E. Prednisone courses ............................................................................................................... 83 
F. Characterization of Asthma Exacerbations ............................................................................ 83 
G. Timing of Asthma Exacerbations and Trial Management ...................................................... 85 
XXI. ADVERSE EVENTS. .................................................................................................................. 86 
A. Definitions .............................................................................................................................. 86 
B. Adverse events unrelated to asthma ..................................................................................... 86 
C. Adverse events related to asthma exacerbations .................................................................. 87 
XXII. SAFETY MONITORING ............................................................................................................. 87 
XXIII. 
SUMMARY/IMPACT .............................................................................................................. 88 
XXIV. 
REFERENCES ...................................................................................................................... 90 
XXV. 
Appendix 1- PARTICIPATING PARTNERSHIPS............................................................... 107 
XXVI. 
Appendix 2: ACUTE ASTHMA ASSESSMENT QUESTIONNAIRE .................................. 108 
 
 


 1
I. 
PRIMARY RESEARCH QUESTIONS: 
 
 
In Blacks with asthma, aged 5 and older, who are inadequately controlled on low dose 
ICS, what is the preferred step-up therapy, and does the degree of African ancestry 
affect preference for different therapies?  
 
II. 
TRIAL OVERVIEW 
 
In this research study, we propose a 66 week prospective, randomized, double-blind, 
crossover trial in Blacks (individuals who self-report Black ancestry) with asthma aged 
12 and above, and separately, in Black children with asthma aged 5-11. Participants will 
be run-in on low dose ICS, and, if inadequately controlled, will randomly have their ICS 
dose increased and/or have a LABA added. In both groups we will examine, as a 
primary question, the efficacy of increasing the dose of ICS with or without the addition 
of a LABA. We will compare the response of these age groups to these step-up 
therapies. Due to safety and medication considerations, the trials in these groups are 
similar but not identical. Each study will allow us to answer our primary questions in the 
appropriate age group and the similarities will allow us to draw conclusions regarding 
whether the age groups differ in response. Both groups will have blood drawn for 
genomic analysis and ancestry markers, and we will determine whether the differential 
responses are related to genetic ancestry and whether there are areas of the genome 
that are associated with differential responses.     
 
 


 2
III. 
BACKGROUND AND SIGNIFICANCE 
 
Blacks suffer a disproportionate burden of asthma morbidity compared to Caucasians. 
As reported by the Centers for Disease Control, Blacks experience more asthma-related 
urgent care visits, higher rates of hospitalizations, and higher death rates (Akinbami 
2006). The prevalence rate of asthma exacerbations for self-identified Blacks is 19.2% 
higher than the rate of Caucasians with even higher rates of emergency room visits 
(Eisner 2001; Adams 2000; Griswold 2005; El-Ekiaby 2006). Hospitalization rates for 
asthma are almost 2.5 times greater in Blacks than in Caucasians (Akinbami 2006). 
Even more alarmingly, the death rate is 165% higher in Blacks than it is in Caucasians 
(Akinbami 2006). Whether this disparity is due to social, environmental, cultural, or 
genetic factors, remains unclear. 
 
One possible explanation for such racial differences in asthma is that Blacks respond 
differently to asthma therapies compared to Caucasians. Indeed, differential response 
to different therapies in Blacks compared to Caucasians has already been 
demonstrated in several other conditions, most recently in pulmonary hypertension- in 
which Blacks failed to demonstrate benefit with endothelin receptor antagonists 
compared with Caucasians (Gabler 2012)- and lupus–in which fewer Blacks who 
received belimumab responded to treatment compared to Blacks who did not receive 
belimumab (Mitka 2011). A similar differential response between Blacks and 
Caucasians is observed in asthma. According to national asthma guidelines, in patients 
inadequately controlled on low doses of inhaled corticosteroids (ICS), increasing the 
ICS dose or adding a long-acting beta agonist (LABA) are both preferred Step 3 
therapies based on studies that show they improve asthma control and decrease 
exacerbations (Shapiro 2009, Ind 2003, Kavuru 2000).  However, these studies were 
conducted in populations that were predominantly non-Black.  Multiple lines of evidence 
suggest that Blacks may not respond to escalation of medications as suggested in 
the studies used to formulate these guideline recommendations. Add-on of a LABA 
did not decrease exacerbations in self-identified Blacks and add-on LABA treatment 
was not as effective in these self-identified Blacks versus a mixed sample in improving 
other secondary indicators of asthma control (Bailey 2008) (see Table 1).   These 
findings were reconfirmed in the recently reported results of a study examining  
ICS/LABA vs. LABA in Blacks (Spector 2012). In a more recent study of Blacks (Brown 
2012), add-on LABA was compared to continuation of ICS. ICS dose was not increased 
in this study. While the rate of exacerbation was lower with added LABA, the magnitude 
of change of other indices was again not as great in Blacks as in studies of 
mixed/Caucasian populations (Table 1). Based on these studies, and on data 
suggesting that the Black population has a higher risk for steroid resistance (Chan 
1998) and reduced cellular sensitivity to corticosteroids (Federico 2005), some have 
hypothesized that Blacks have either a diminished response to LABA, or an increased 
need for, or decreased sensitivity to, ICS. Regardless of mechanism, these studies all 
suggest that a differential response to asthma therapies occurs in Blacks. 
 
 
 
 
 
 


 3
 
 
In that regard, a cross-sectional analysis of treatment responses in the studies 
conducted by the ACRN suggests that self-identified Blacks treated with LABA had a 
greater frequency of asthma treatment failures compared to Caucasians in the same 
trials (Fig 1) (Wechsler 2011).  
 
 
Further, in the BADGER trial conducted by the CARE Network, while more Caucasian 
children had a preferential  response to ICS+LABA as compared  to a 2.5-fold increase 
in ICS,  more self-identified Black children preferred increased ICS to addition of LABA  
(Fig 2) (Lemanske 2010). 


 4
 
Finally, we performed a post hoc analysis of data generated from the TALC trial (Peters 
2010). We evaluated a differential treatment response using a composite outcome 
measure similar to that used in the BADGER trial and identical to the one proposed for 
this trial. We found racial disparities in the response to add-on tiotropium bromide 
versus LABA, providing yet another example of differences in response to different 
therapies by race. Add-on tiotropium was superior to increasing the dose of ICS in 
Caucasians, but this was not the case in self-identified Blacks (Table 2), as reflected by 
the composite outcome measure of exacerbations, asthma control days and FEV1 
(Table 2). It is noteworthy that in this study, there was a trend towards preference of 
LABA/ICS vs. ICS in Blacks. The discordant findings in these different studies highlight 
the need for us to examine the question of asthma therapy in Blacks prospectively. 
TABLE 2 Response by Race in TALC
 
 
Genomic Ancestry: 
 
 As noted above, marked disparities exist in treatment-response phenotypes between 
self-identified Blacks and Non-Hispanic Whites. These differences have resulted in 
different treatment recommendations for Blacks with regard to hypertension and heart 


 5
failure, for example. However, many populations are admixed with varying degrees of 
different racial ancestry and are becoming increasingly admixed.   
 
In fact, current self-reported Blacks in public databases vary in the degree of African 
versus European white ancestry; average 71% African (SD +9.6) with a range of 29.4% 
to 96.5% in 392 African-Americans with asthma. An example of such variation is shown 
in the figure herein  
(labeled Figure 4- 
MDS Plot)  where the 
x’s represent 
asthmatics from the 
Severe Asthma 
Research Program 
and CSGA  asthma 
studies. The range of 
ancestry can be seen 
from this principal 
component analysis 
(where the blue 
cluster represents 
Africans (Yorubans) 
and the green cluster 
represents whites of 
European descent 
using standard data 
from HapMap.org). 
 
Considering the degree of variation in degree of African vs. European ancestry in self-
reported Blacks it has been postulated that self-reported measures may become 
increasingly imprecise when compared to true, genetically-measured ancestry. In fact, a 
recent study suggested just such a possibility in relation to lung function.   
Baseline lung function is a well-established characteristic that is markedly disparate 
between these ethnic groups, independent of asthma diagnosis. Current practice 
assigns predicted lung function on the basis of self-identified race.  However, Kumar 
and coworkers recently demonstrated that the degree of African ancestry as measured 
by genetic variants specific to ancestry called “ancestry informative markers” 
determined baseline lung function. Specifically, greater African ancestry was associated 
with lower baseline FEV1 and FVC (Genetics Figure 1). Further, calculations of 
baseline lung function based on genetic ancestry revealed that classic predictive 
equations actually misclassified asthma severity based on percentage predicted 
FEV1 in a subset of asthma subjects (Kumar 2010).  


 6
 
These data suggest that ancestry informative markers may be as good, or better, than 
self-identified racial ancestry as a marker with which to associate phenotypic variation 
between groups.   
  
In sum, these data suggest the following: 
1. Blacks respond differently to currently recommended asthma treatments 
than do Caucasians.  
2. As a result, current asthma guideline recommendations may not be 
appropriate for Blacks with asthma. 
3.  Genetic ancestry may be a superior method to identify subjects who 
may benefit from alternate treatment recommendations and step up in therapy.   
 
The data summarized above lead us to attempt to answer the following questions:   
- Do Blacks not completely controlled on low dose ICS respond to 
increases in ICS better than adding a LABA? 
- In Blacks, is a lack of response to low dose ICS/LABA due to inadequate 
dosing of the ICS component? 
- Are genetic analyses using degree of African vs. European ancestry 
useful in predicting responsiveness to the different therapies? 
- Do Black adults and children differ from one another with regard to 
responsiveness to ICS or LABA add-on therapies? 
 
 
The trial we outline below aims to address these questions.  The results of this study will 
have the potential to significantly impact the asthma guidelines because the resulting 
data will allow for evidence based recommendations for the use of asthma 
pharmacotherapy in Blacks. This study will also offer the opportunity to assess whether 
genetic ancestry markers can help us to predict the degree of differential pharmacologic 
response in Black individuals.   


 7
 
IV. 
HYPOTHESES TO BE TESTED 
Primary hypotheses in Adults/Adolescents ≥ 12 Years: 
1. 
In Black adults and adolescents with inadequately controlled asthma on 
low-dose ICS alone, the addition of LABA will not be more efficacious than 
increased doses of ICS in improving asthma control, regardless of the 
dose of ICS used with the LABA.  
2.  
A preference for LABA vs. ICS in Blacks in the study will be associated 
with a lesser degree of African ancestry (%African Black versus 
%European White) as determined by genetic markers of African ancestry.   
Primary hypotheses in Children 5-11 Years: 
1. In Black children with inadequately controlled asthma on low-dose ICS alone, the 
addition of LABA will not be more efficacious than increased doses of ICS in 
improving asthma control. 
2.  A preference for LABA vs. ICS in Black children will be associated with a lesser 
degree of African ancestry (%African Black versus %European White) as 
determined by genetic markers of African ancestry.   
 
Secondary hypotheses: 
1.  
Black adolescents/adults (≥12) will not differ from Black children aged 5-11 in the 
relative response to ICS and LABA examined in the primary hypotheses.    
2. 
The dose response curve to corticosteroids will not differ between Black 
adults/adolescents and children.  
Exploratory hypotheses: 
 
1.  
The variability in response to LABA and/or ICS will be related to differences at 
specific pharmacogenetic loci as detected by techniques such as admixture 
mapping.   
2.   
Patient 
characteristics, 
such 
as 
atopy, 
pulmonary 
function 
including 
bronchodilator reversibility, and methacholine responsiveness, along with 
selective biomarkers, such as sputum eosinophils, will be associated with the 
differential response to the study treatment among Black asthmatics across the 
ages. 
 
 
 


 8
V. 
PROTOCOL SUMMARY AND SCHEMA 
 
To attempt to answer the primary research questions raised above, we propose a trial 
examining and comparing the effect of step-up therapy in participants with asthma.  
Because the disparities in asthma burden occur in both children and adults, we will 
examine step-up in participants ≥ 12 years of age (FDA and NAEPP cut-offs for “adult” 
asthma recommendations) and separately in participants 5-11 years of age.  While of 
necessity, these trials are not precisely the same due to dosage restrictions in children 
and medication availability. Our goal was to create core parallels that would allow us to 
examine whether these age groups differ significantly in their patterns of response to 
add-on therapy, specifically the dose response of ICS and the impact of adding LABA to 
increased ICS therapy.   
 
Protocol Schema 
This is a prospective, randomized 66-week cross-over trial in both individuals 12 years 
of age and older and children (5-11 years of age) with inadequately-controlled asthma 
on low dose ICS. In individuals aged 12 and older, we compare the effectiveness of a) 
adding a LABA or b) increasing ICS dose 2.5 fold or c) increasing ICS dose 5 fold or d) 
adding a LABA and increasing ICS dose 2.5 fold (Figure 5a). In children aged 5-11, we 
compare the effectiveness of a) increasing ICS 2 fold b) increasing ICS 2 fold and 
adding a LABA c) increasing ICS 5 fold and d) increasing ICS 5 fold and adding a LABA 
(Figure 5b). Our goal is to identify the best option for add-on therapy in Blacks and to 
determine whether the response in Black individuals aged 12 or greater differs from that 
of Black children aged 5-11. 
 


 9
 
 
Run-in: Following successful completion of the eligibility assessment at Screen Visit A, 
participants will be entered into the run-in and switched from their therapy to low-dose 
ICS (100 mcg fluticasone propionate (FP) BID or equivalent in individuals aged 12 or 
greater; 50 mcg FP BID in children aged 5-11) (for individuals already on low-dose 
equivalent or requiring only 1 step down; see section VII.A for details regarding 
individuals who require a 2 step step-down process). They will be monitored closely for 
safety, and they will have a minimum of 2 weeks and a maximum of 10 weeks to 
demonstrate that they are inadequately controlled and appropriate for randomization 
(based on NAEPP guidelines criteria, see section VII.A below). As was done in the 
BADGER trial, participants will be continually monitored and randomized in the trial if 
uncontrolled. They will complete twice daily peak flow (PEF) measurements and e-
diaries using the Spirotel® device to monitor lung function and symptoms and will have a 
rescue plan in place. They will complete up to three additional screen/run-in visits at the 
performance site as follows: Following Screen Visit A, participants will be scheduled to 
return to the performance site in 2 weeks (+3 day regular window and +5 day extended 
window) to complete Screen Visit B which includes additional testing for 
characterization and eligibility confirmation and assessment for lack of acceptable 
asthma control. If the participant qualifies for randomization as described below, then he 
or she will be scheduled to return to the performance site between 24 hours and 2 
weeks later to complete Visit 1 and undergo randomization. If the participant does not 
qualify for randomization at Screen Visit B, then he or she will be scheduled for Screen 
Visit C in 4 weeks (+/-3 day regular window and +/-5 day extended window) with a 


 10 
phone call at the 2 week midpoint to assess for safety and lack of control. Those who do 
not qualify for randomization by Screen Visit C will be scheduled for Screen Visit D 4 
weeks later (+/- 3 day regular window and +/-5 day extended window) with another 
phone call at the 2 week midpoint to assess for safety and lack of control. The purpose 
of Screen Visits C and D is to upload the participant’s e-diary and review data for 
qualification for randomization on the basis of the ‘lack of acceptable control’ criteria 
outlined below, as well as to collect and replenish drug supplies. These visits are 
primarily administrative with no additional procedures taking place other than height 
measurements in the younger participants. If the participant qualifies for randomization 
at Screen Visit C or D, then he or she may be randomized and complete Visit 1 the 
same day, or he or she can be scheduled to return for Visit 1 as soon as possible, but 
definitely within 2 weeks. Visit windows are allowed in order to give the coordinator 
flexibility with scheduling the sputum lab and dedicating the necessary time in the clinic 
calendar to complete Visit 1. 
As described below, no participant will directly undergo a more than a 2 fold decrease in 
dose at the time of run-in. For example, adult participants who are on the equivalent of 
fluticasone 500 mcg BID or  fluticasone/salmeterol 250/50 will first have a 2 week trial 
on 250 mcg BID to ensure stability to enter the trial, prior to tapering down to 100 mcg 
BID to enter the run-in (See below, Inclusion Criteria).  
The 4-way crossover design will consist of random assignment to four specific treatment 
sequences for pediatric participants and four specific treatment sequences for 
adolescent/adult participants, as described in the Statistical Design and Analyses 
section.  
 
Treatment period:  Following the rolling run-in period with low-dose ICS, inadequately 
controlled participants will be randomized to addition of LABA, addition of LABA with 
increased ICS, or increased dose ICS (medium and high dose ICS) for 14 weeks. In 
those aged 12 and above at enrollment with inadequately-controlled asthma on low 
dose ICS (100 mcg fluticasone BID) we will compare the efficacy of different step-up 
therapies: adding a LABA vs. increasing the ICS dose 2.5-5 fold vs. increasing ICS 
dose 2.5 fold AND adding a LABA. In the pediatric subgroup, we will enroll participants 
aged 5-11 with inadequately-controlled asthma on 50 mcg fluticasone BID and compare 
the efficacy of adding a LABA AND increasing ICS dose 2-fold vs. increasing the ICS 
dose 2-5 fold vs. increasing ICS dose 5 fold AND adding a LABA. The last 12 weeks of 
each treatment period will be considered for analysis (to allow for drug washout from 
previous arm/wash-in for new treatment arm). Participants will come to the performance 
sites after 2 weeks to ensure adherence and safety and then at 6 week intervals 
thereafter in each treatment period. Participants will receive phone calls to ensure 
safety and to assess for any issues that may be ongoing at the 3-week point between 
visits.  
Of note, ICS doses to be used in the study are consistent with asthma guidelines. 
Increased ICS dosing will be different in individuals aged 12 or greater and children 
aged 5-11 as noted below (Table 3.) due to potential safety concerns of ICS in younger 
pediatric participants and due to availability of different drug preparations. 
 
 
 


 11 
 
 
 
To meet the total required sample size for this trial, participants, 291 Blacks aged 
greater than or equal to 12 at enrollment and 284 Black children aged 5-11 at 
enrollment, will be recruited across the Network, with attempts to recruit similar numbers 
at each clinical center partnership. With 18 strata (9 clinical center partnerships x 2 age 
groups), approximately 32 participants (32.3 adults/adolescents; 31.6 children aged 5-
11) will be randomized by each clinical center partnership.  
 
In sum, this is a 66-week randomized, double-blind, four-treatment, four-period cross-
over trial that will evaluate the differential improvement in control that is achieved 
following four separate treatment interventions in Black individuals whose asthma is not 
acceptably controlled on a low dose of ICS (per NAEPP guidelines). All participants will 
enter a run-in period lasting up to 10 weeks during which time they will receive a dose of 
1xICS (e.g. fluticasone 100 mcg BID in individuals aged 12 or greater and  50 mcg BID 
in children with asthma aged 5-11). During this period, running one week and two week 
periods to establish lack of acceptable asthma control will be evaluated using the 
definition described in Section VII.A. below. As soon as the participant meets the 
randomization criteria, he or she will be randomized into one of the treatment 
sequences described. Thus, it is possible for the participant to qualify for randomization 
prior to the end of the 10-week run-in period. This approach should maximize both 
participant safety and successful enrollment. During each period of the treatment phase, 
participants will receive an add-on therapy in the form of LABA, different strengths of 
increased ICS, or increased ICS and LABA. Each treatment period will be 14 weeks in 
length; the initial 2 weeks of each period will be considered to be the washout period for 
the previous treatment. The primary outcome measures of asthma control are asthma 
exacerbations (protocol defined), asthma control days (ACD) (see definition below), and 
the %predicted FEV1 at the end of the 14-week treatment regimen. Secondary 
outcomes are listed below.  
 
 
 
 
Table 3. ICS Dosing in Adults/Adolescents aged ≥12 and Children aged 5-11 
 
ADULTS/ADOLESCENTS 
 
 
 
 
CHILDREN 
1xICS=  
100 mcg FP* BID 
 
 
 
1xICS=  
50 mcg FP BID 
2.5xICS= 
250 mcg FP BID 
 
 
 
2xICS= 
100 mcg FP BID 
5xICS=  
500 mcg FP BID 
 
 
 
5xICS=  
250 mcg FP BID 
1xICS/LABA= 100/50 BID FP/salmeterol 
2xICS/LABA= 100/50 BID FP/salmeterol 
2.5xICS/LABA= 250/50 BID FP/salmeterol  
 
5xICS/LABA=250/50 BID FP/salmeterol 
* 
 
* FP=Fluticasone Propionate  


 12 
VI. 
INCLUSION AND EXCLUSION CRITERIA (TO ENTER 
CHARACTERIZATION PERIOD) 
A. Inclusion criteria at Screen Visit A (to enter run-in) 
 
1. Male and female participants, age 5 years and above at enrollment.  
2. Individuals who self-report Black ancestry (with at least 1 Black grandparent). 
Hispanics with at least 1 Black grandparent may be enrolled. Participants who 
have 1 Black grandparent but who do not necessarily self-identify as Black may 
also be enrolled.1  
3. Able to perform reproducible spirometry according to ATS criteria. 
4. Able to perform valid peak flow maneuver using the Spirotel® device. 
5. Clinical history consistent with asthma. 
6. Baseline FEV1≥40% of predicted and/or post-bronchodilator FEV1≥40% of 
predicted (post 4 puffs of albuterol at Screen Visit A). 
7. Asthma confirmed either by: (1) Beta-agonist reversibility to 4 puffs albuterol ≥ 
12% OR (2) PC20FEV1 ≤ 16 mg/ml (if FEV1≥ 55% predicted and ≥1.0 liter at 
baseline in adults or ≥70% in participants younger than 18) OR (3) an absolute 
relative change in %predicted FEV1 of ≥ 12% over two measurements 
documented by repeat spirogram over the previous year and done at an 
AsthmaNet performance site. 
(Participants will hold albuterol, montelukast, theophylline, ipratropium bromide 
(or other anticholinergics) and long-acting beta-agonists per instructions in the 
MOP prior to reversibility testing. Thus, if a participant is receiving these types of 
medications prior to Screen Visit A, he or she may be brought back to the 
performance site after following appropriate medication withholding to attempt 
qualification by reversibility criteria. If the participant does not meet this 
requirement, he/she may qualify if methacholine PC20  is ≤ 16 mg/ml at Screen 
Visit B.  Historical evidence of reversibility or methacholine PC20 may be used to 
meet the inclusion criteria if the source documentation is less than 1 year old and 
is from one of the AsthmaNet performance sites and was performed using 
AsthmaNet equipment, procedures, and methacholine. All participants will 
perform reversibility testing at Screen Visit A, regardless of source 
documentation status; all participants who qualify to perform methacholine 
challenge at Screen Visit B will perform the procedure, regardless of source 
documentation status.) 
8. To enter the run-in, participants must be either: A) inadequately controlled on 
low-, medium- or high-dose ICS monotherapy, or low- or medium-dose 
ICS/LABA, or B) well-controlled on low-, medium- or high-dose ICS 
monotherapy, or low-, medium- or high-dose ICS/LABA (see Study Visits, Screen 
A, at -10 weeks). Participants who require a 2 step step-down will first be 
stepped down to 2-2.5xICS dose for 2 weeks to assess control, as noted below.  
For purposes of assessing this criterion, inadequate asthma control will be 
defined as an ACT/c-ACT score <20; well-controlled asthma will be defined as an 
ACT/c-ACT score ≥20. 
9. Stable asthma controller therapy dose (ICS or ICS/LABA) for the 2 weeks prior to 
                                            
1 Genetically-related individuals (e.g., mother-child or sibling pairs) may participate. Family relationships will be 
tracked and adjusted for during analysis. 
 


 13 
Screen Visit A. 
10. Non-smoker (total lifetime smoking history < 5 pack-years if <18, or <10 pack-
years if ≥18 years of age; no smoking for at least 1 year). 
11. For participants ≥18 years of age: Ability to provide informed consent, as 
evidenced by signing a copy of the consent form approved by the Institutional 
Review Board of the participant’s respective study institution. 
For participants under 18 years of age: Ability of parent to provide informed 
consent, as evidenced by signing a copy of the consent form approved by the 
Institutional Review Board of the participant’s respective study institution. Verbal 
or written assent by the study participant will be documented according to local 
institutional guidelines. 
 
B. Exclusion criteria at Screen Visit A (to enter run-in) 
 
1. Inadequately controlled (per NAEPP guidelines criteria) on high dose ICS/LABA 
(e.g. Advair 500/50 BID). For purposes of assessing this criterion, inadequate 
asthma control will be defined as an ACT/c-ACT score <20; well-controlled 
asthma will be defined as an ACT/c-ACT score ≥20. 
2. Medical contraindication to LABA or history of adverse reactions to ICS or LABA 
preparations or any of their ingredients. 
3. Unwilling to provide a blood sample for DNA extraction and genetic analysis (part 
of co-primary aims of the study). 
4. Major medical problems prohibiting study participation, i.e. presence of chronic or 
active lung disease other than asthma or history of unstable significant medical 
illness other than asthma, including thyroid disease, diabetes mellitus, Cushing’s 
disease, Addison’s disease, hepatic disease, or concurrent medical problems 
that could require oral corticosteroids during the study or that would place the 
participant at increased risk. 
5. Systemic corticosteroid treatment for any condition within 4 weeks of enrollment 
at Screen Visit A. 
6. Current or prior use of medications known to significantly interact with 
corticosteroid disposition within the two-week period preceding Screen Visit A, 
including but not limited to: carbamazepine, erythromycin or other macrolide 
antibiotics (chronic use of macrolides excluded; intermittent use allowed with 2-
week washout prior to Screen Visit A), phenobarbital, phenytoin, rifampin, and 
ketoconazole.  
7. History of significant asthma exacerbation requiring systemic corticosteroids 
within 4 weeks of Screen Visit A or more than five courses of systemic 
corticosteroids in the past year. 
8. History of a life-threatening asthma exacerbation requiring intubation, mechanical 
ventilation, or resulting in a hypoxic seizure within the last 2 years. 
9. History of a respiratory tract infection within 2 weeks of Screen Visit A. 
10. Evidence that the participant (or family, in case of pediatric participants) may be 
nonadherent, or may move from the performance site area before trial 
completion. 
11. Inability to perform study procedures. 
12. If a female of child-bearing potential, failure to practice abstinence or use an 
acceptable birth control method. 
13. Pregnancy or lactation or planning to get pregnant during the course of the trial. 


 14 
14. Receiving hyposensitization therapy other than an established maintenance 
regimen defined as a continuous regimen for ≥ 3 months prior to enrollment. 
15. Participation in an intervention trial or use of investigative drugs in the past 30 
days or plans to enroll in such a trial during the study. 
16. Chronic use of any medication other than beta-agonists or inhaled 
corticosteroids, except:  
• oral contraceptives and other hormonal forms of contraceptives (i.e., 
DepoProvera-7, Norplant-7) 
• estrogen / progesterone replacement therapy for post-menopausal women 
• vitamins and calcium supplements 
• any nasal inhaled corticosteroid used at a stable dose throughout the 
entire study beginning at Screen Visit A 
• acetaminophen 
• non-steroidal anti-inflammatory medications (e.g., aspirin, naproxen, 
ibuprofen, Cox-2 inhibitors) 
• thyroid replacement medications 
• lipid-lowering medication 
• stable dose medical therapy for well-controlled hypertension and well-
controlled diabetes, except those meds specifically excluded in Table 4 
• medium and low potency topical cutaneous steroids  
• nasal saline spray 
• topical eye preparations for allergic eye symptoms (e.g. antihistamines, 
NSAIDs, or antiallergic compounds) 
• diuretics and specific antihypertensives (e.g. calcium channel blockers, 
clonidine, etc.) 
• acyclovir 
• antihistamines (48 hour washout for oral medications and 6 hour washout 
for nasal and ocular medications)  
• pseudoephedrine and oxymetazoline and other decongestants (48 hour 
washout for oral medications and 6 hour washout for nasal medications) 
• antibiotics for acne 
• stool softeners and bulk laxatives 
• H2 blockers and proton pump inhibitors for GERD 
• Imitrex for migraines 
• non-macrolide antibiotics 
• macrolide antibiotics used intermittently to treat acute adverse events 
• Propecia (finasteride) 
• SSRI class antidepressants 
• non-SSRI antidepressants 


 15 
• migraine analgesics (e.g., butalbital) 
• antianxiety agents 
• ACE inhibitors 
• Librax 
• CNS stimulants/appetite suppressants 
 
3. Use of any drugs listed in Table 4 (below) during the designated washout 
period prior to Screen Visit A or intention to take the drug during the study. 
 
 


 16 
 
Table 4.  Drugs to be withheld throughout the study 
 
Washout prior to Screen Visit A 
Leukotriene receptor antagonists 
≥ 1 week  
Inhaled steroids, except as provided in study 
None 
Intranasal steroids, except at stable dose throughout study 
None 
Oral steroids, except as provided in study for 
exacerbations 
≥4 weeks 
Injectable steroids 
≥4 weeks 
Cromolyn/Nedocromil 
≥1 week 
Oral beta-adrenergic agonists 
≥ 1 week 
Monoamine oxidase inhibitors 
≥ 4 weeks 
Beta-adrenergic blockers 
≥ 2 weeks 
Macrolide antibiotics (chronic use excluded; intermittent 
use for treatment of adverse events allowed – 2-week 
washout applies to both) 
≥ 2 weeks 
Inhaled beta-adrenergic agonists (intermediate-acting, 
e.g., albuterol, terbutaline, metaproterenol, pirbuterol, 
bitolterol), except as provided in study 
≥ 6 hours 
Inhaled long-acting beta-agonists (e.g., 
Salmeterol/formoterol), except as provided in study 
≥ 24 hrs  
Inhaled anticholinergics  
Short-acting:≥8 hours 
Long acting: ≥24 hours  
Short-acting theophylline (e.g., Slophyllin tablets) 
≥ 12 hours 
Long-acting theophylline (e.g., Theo-Dur, Slo-bid) 
≥ 24 hours 
Ultra long-acting theophylline (e.g., Theo-24, Uniphyl) 
≥ 48 hours 
Anti-IgE therapy (e.g., Xolair) 
≥3 months 
Drugs withheld prior to pulmonary function and/or 
methacholine challenge, per MOP 
Specified withhold time period 
Albuterol (study rescue) 
≥ 6 hours 
Salmeterol (blinded study drug) 
≥ 12 hours 
Methylxanthine-containing foods or beverages (e.g., 
coffee, tea) or medications 
≥ 4 hours 
Alcohol-containing foods or beverages 
≥ 4 hours 
 
 
 
 


 17 
VII. 
INCLUSION AND EXCLUSION CRITERIA PRIOR TO RANDOMIZATION 
 
Randomization criteria (after run-in with low-dose ICS (1xICS)) 
Participants will be randomized if they demonstrate compliance with study medications, 
e-diary completion, and PEF performance and lack of acceptable control of asthma 
during the run-in period (see below).  
 
A. Inclusion Criterion for Randomization: Lack of acceptable asthma control 
in run-in period 
For individuals aged 12 and older at enrollment, the run-in period consists of open-label 
treatment with 1 inhalation twice daily of FP 100 mcg/inhalation. For children 5-11 at 
enrollment, the run-in period consists of treatment with 1 inhalation twice daily of FP 50 
mcg/inhalation.   
Lack of acceptable asthma control during the run-in period is defined as: 
1. On more than 2 days per week for any 1 week period during the run-in, one or 
more of the following (rolling 1 week periods will be used to assess this criterion 
using data stored in the participant’s Spirotel® e-diary): 
a. Asthma symptoms (shortness of breath, wheezing, chest tightness, 
phlegm/mucus rated as mild, moderate or severe, or cough rated as 
moderate or severe)  
b. Use of inhaled bronchodilator for symptom rescue (≥1 puff) (does not 
include pre-exercise prophylactic treatment)  
c. Reduced peak expiratory flow (i.e. Peak flows in the red or yellow zone [< 
80% of the current PEF reference2]) 
i. The PEF reference value used to determine the yellow zone 
between Screen Visit A and Screen Visit B will be the pre-
bronchodilator PEF observed in the clinic at Screen Visit A. 
 
ii. The PEF reference value used to determine the yellow zone 
between Screen Visit B and Screen Visit C will be the highest of:  
1. pre-bronchodilator PEF observed in the clinic at Screen Visit 
A 
2. pre-bronchodilator PEF observed in the clinic at Screen Visit 
B 
3. pre-bronchodilator 
PEFs 
observed 
at 
home 
and 
electronically recorded by the Spirotel® device between 
Screen Visits A and B  
Note: The PEF reference value may not increase by more than 
20% from one visit to the next. 
 
iii. The PEF reference value used to determine the yellow zone 
between Screen Visit C and Screen Visit D will be the highest of:  
                                            
2 Updated PEF reference values will only be applied going forward in time; they will not be applied to PEF data 
collected prior to changing the value.  


 18 
1. pre-bronchodilator PEF observed in the clinic at Screen Visit 
A 
2. pre-bronchodilator PEF observed in the clinic at Screen Visit 
B 
3. pre-bronchodilator PEF observed in the clinic at Screen Visit 
C 
4. pre-bronchodilator 
PEFs 
observed 
at 
home 
and 
electronically recorded by the Spirotel® device between 
Screen Visits A and C  
Note: The PEF reference value may not increase by more than 
20% from one visit to the next. 
 
iv. The PEF reference value used to determine the yellow zone during 
the entire post-randomization treatment phase (for purposes of 
defining the participant’s action plan) will be the highest of:  
1. pre-bronchodilator PEF observed in the clinic at Screen Visit 
A 
2. pre-bronchodilator PEF observed in the clinic at Screen Visit 
B 
3. pre-bronchodilator PEF observed in the clinic at Screen Visit 
C 
4. pre-bronchodilator PEF observed in the clinic at Screen Visit 
D 
5. pre-bronchodilator 
PEF 
observed 
in 
the 
clinic 
at 
randomization Visit 1 
6. pre-bronchodilator 
PEFs 
observed 
at 
home 
and 
electronically recorded by the Spirotel® device between 
Screen Visit A and randomization 
 
The PEF reference value will not be updated after randomization 
for individuals who are age 21 or older at enrollment. Participants 
who are ages 5-17 at enrollment will have their height measured at 
each post-randomization visit, resulting in possible adjustments to 
their predicted PEF values. As such, participants in the 5-17 age 
range at enrollment will be subject to the adjustments based on 
predicted PEF outlined in item v. below for the duration of their 
study participation. Individuals who are between 18 and 21 years 
old at enrollment will have their height measured until they turn age 
21. They will be subject to the adjustments based on predicted PEF 
outlined in item v. below until they turn 21. 
 
v. If, at any time, the PEF reference value is lower than 50% of the 
predicted PEF calculated using published equations based on age, 
height, sex and race (as per AsthmaNet Spirometry Manual of 
Procedures), then the PEF reference value will be set to 50% of the 
predicted PEF. 
 
OR 
 


 19 
2. 
More than 1 night with awakening(s) due to asthma in a 2-week period 
 
Similar to the enrollment strategy utilized in the BADGER study (Lemanske 2010), 
individuals enrolled in this protocol can be characterized as falling into one of two 
groups at the time of Screen Visit A: 
• Step-neutral - currently receiving low-dose 1xICS dose = 200 mcg/day fluticasone 
equivalent in adults/adolescents, or 100 mcg/day in children age 5-11 
For individuals in the step-neutral group, the run-in will be up to 10 weeks in duration. 
These individuals will begin the run-in on 1xICS study medications.  
• Step-down - currently receiving controller therapy considered by the NAEPP 
guidelines to be at least 1 step above 1xICS (e.g. 2-2.5xICS or higher, or combination 
therapy of 1xICS/LABA or higher) 
For individuals in the step-down group who require a 1 step step-down approach (e.g. if 
baseline medication is 2-2.5xICS monotherapy or 1xICS/LABA combination therapy), 
the run-in will be up to 10 weeks in duration.  These individuals will begin the run-in on 
1xICS study medications. 
For individuals in the step-down group who require a 2 step step-down approach (e.g. if 
baseline medication is 5xICS monotherapy or 2.5xICS/LABA) the run-in will be up to 12 
weeks in duration. During the first 2 weeks, individuals will be stepped down to 2xICS (if 
age 5-11) or 2.5xICS (if age 12 and above). At the end of the 2-week period they will be 
seen at the clinic for Screen Visit A1 for upload of Spirotel® data, spirometry, and 
assessment of asthma control based on their Asthma Control Questionnaire (ACQ; 7-
item) score (Juniper 1999). If they demonstrate control (defined as ACQ score < 1.5 and 
no asthma exacerbation) on the reduced dose regimen, such individuals then will be 
tapered to 1xICS and Screen Visit B will be scheduled 2 weeks later. At Screen Visit B, 
they will be eligible for randomization according to the criteria outlined below. If 
individuals in the 2 step step-down group experience an asthma exacerbation requiring 
treatment with prednisone while on 2-2.5xICS or have an ACQ score ≥1.5 , they will be 
ineligible for further study participation and study termination procedures will take place.  
To be eligible for randomization, individuals must: 
1.  meet the definition of lack of acceptable asthma control above during any 1-week 
block (symptoms, rescue use, PEF) or 2-week block (nighttime awakenings) on 
1xICS study medications 
AND 
2.  demonstrate adherence with taking study medications (≥75% of scheduled doses) 
and completing e-diaries and PEFs (≥75% of days) during the visit interval during 
which lack of control criteria were met 
 
 


 20 
B. Exclusion Criteria for Randomization 
Participants who have an exacerbation on low dose ICS (1xICS) during the run-in 
period (i.e. worsening asthma symptoms resulting in treatment with systemic 
corticosteroids- see exacerbation definition in section XX below) may be eligible for 
randomization after the exacerbation has been appropriately treated with a 5-day 
course of prednisone per the guidelines in section XX.E below. The participant will 
remain on 1xICS during and following treatment of the exacerbation and will be eligible 
to be randomized 14 days (+7 day window) following the final dose of prednisone, 
unless the exacerbation is severe and requires hospitalization. In that case, the 
participant must be terminated from further participation in the trial due to safety 
concerns. 
If a participant experiences a second exacerbation that does not result in hospitalization 
on low dose ICS during the run-in, the same procedures will apply with respect to 
prednisone treatment and randomization.  
If a participant experiences a third exacerbation requiring treatment with prednisone 
during the run-in, then he or she will be terminated from further participation in the trial 
due to safety concerns.  
As noted above, individuals who are in the 2 step step-down group who experience an 
exacerbation while on 2-2.5xICS or have an ACQ score ≥1.5 at Screen Visit A1 are 
ineligible for further study participation. 
Thus, exclusion criteria for randomization include any of the following: 
1. Inadequate adherence (<75% of expected medication doses taken or <75% of 
diary recordings and PEFs completed)* 
2. Asthma exacerbation requiring hospitalization during the run-in 
3. Three significant asthma exacerbations on 1xICS during the run-in 
4. For those requiring 2 step step-down: Asthma exacerbation while on 2-2.5xICS 
during the run-in or ACQ score ≥1.5 at Screen Visit A1  
* Individuals who do not meet the adherence criteria after 2 weeks in the trial will be 
retrained and allowed to continue in the run-in for another 2 weeks. Screen Visit B will 
be deferred until adequate compliance is demonstrated. If, after 4 weeks in the run-in, 
the participant cannot meet the adherence requirements, then he or she will be 
terminated from further study participation. Individuals who show lack of adherence to 
medication dosing and/or e-diary and/or PEF completion on two separate evaluations at 
any point during the run-in will be terminated from further study participation. Depending 
on the circumstances, these individuals may be allowed to re-enroll starting at Screen 
Visit A at a later time. 
  


 21 
VIII. 
RATIONALE & SPECIAL CONSIDERATIONS FOR SPECIFIC ASPECTS 
OF THE STUDY 
A. Anticipated composition of study population 
The issue of best treatment for Blacks is of such great importance that we propose 
studying both adults/adolescents and children since it is not clear whether the results 
will be the same in these groups.  We are including both the adolescent/adult (≥12) and 
younger pediatric (5-11) Black population in this trial to ascertain whether the effects we 
will observe in Blacks aged 12 and older are different from Black children aged 5-11. No 
ICS dose-ranging study of this sort has been performed in inadequately controlled Black 
asthmatics of any age. As indicated previously, more evidence is needed to establish 
guidelines for therapy for Black adults and children with asthma who are not acceptably 
controlled on low dose ICS. We will therefore enroll sufficient numbers of both Black 
adults/adolescents and children to provide adequate numbers of participants to address 
the research hypotheses. It is likely that some of the performance sites may need to 
recruit larger numbers of Black participants than others due to the relative availability of 
participants in their immediate recruitment areas (See Recruitment Section XXV). 
However, all attempts will be made to recruit proportionately among sites as much as 
possible.  Methods for accounting for potential asymmetric recruitment are discussed in 
the section on Statistics.   
B. Definition of “Black” for this study:  
 
For this study, we define “Black” as individuals who self-report Black ancestry, with at 
least 1 Black grandparent. Self-identified race is a concept that may be easily 
translatable to the community. Additionally, all the data we have cited that demonstrated 
differential responses by race utilized self-identified Black identification. 
   
We will, however, also estimate degree of both overall, and gene-specific, Black 
ancestry based on genetic variants identified based on genetic ancestry as discussed 
below in our section on Genetics. We will use this data to determine whether degree of 
Black ancestry is associated with a differential response to pharmacotherapy. 
 
C. Genetic Analysis of Responses 
 
While self-identification as Black is the clinical phenotype that has been associated with 
differences in response to medications, this phenotype has a complex genetic makeup.  
As was pointed out in our Background and Significance section, genetic markers which 
allow estimation of genetic ancestry, may actually permit greater precision in detecting 
and understanding the phenotype (Kumar 2010).  Therefore, an important part of this 
proposal relates to determining the potential association of Black ancestry, first, at a 
genome-wide level, and, as explained below, in an exploratory manner within a specific 
gene or gene cluster, to the observed variation in response to medications.   
 
In specific we propose the following: 
 
Our primary hypothesis is that in asthmatics who self-report Black ancestry, those with a 
better response to LABAs will have a lower overall proportion of African ancestry.  As a 


 22 
corollary, we hypothesize that those with a better response to ICS will have a higher 
overall proportion of African ancestry. 
 
On an exploratory basis, we hypothesize that that the variability in response to the 
treatments will be related to degree of African ancestry at specific genetic loci.   
 
In addition to the information we reviewed in the Background and Significance section 
regarding global African ancestry, below we review techniques using GWAS and 
admixture mapping that have been used to identify specific areas of the genome  that 
may contribute to the observed differences between groups and that we expect to use 
to carry out our exploratory aims.     
 
 
 
Specific Loci and Ancestry at Specific Loci and Rare Variant Analyses. 
 
In addition to global estimates of ancestry, ancestry markers and genome-wide studies 
can be used to identify areas of the genome that may yield specific loci that differentiate 
differences in response to therapy.  Tantisira and coworkers performed a GWAS in 118 
probands from the Childhood Asthma Management Program (CAMP) and 935 
asthmatics from 4 replication cohorts (primarily consisting of non-Hispanic Whites) that 
revealed a single nucleotide polymorphism (SNP) in the promoter region of the 
glucocorticoid-induced transcript 1 gene (GLCCl1), rs37972, that was associated with 
lung function responses to inhaled glucocorticoids, specifically that the less common 
allele was associated with diminished response (Tantisira 2011). Although this SNP was 
polymorphic in this population of asthmatics of European descent, (minor allele 
frequency= 45% in whites of European descent), this variant is less common in an 
African population (minor allele frequency=14%).  
 
More recently, a GWAS performed by Himes and coworkers consisting of 1,644 non-
Hispanic whites for 6 clinical trials demonstrated that SNP’s adjacent to SPATS2L (gene 
that determines β2-adrenergic receptor expression), rs295137 and rs295114, were 
associated with lung function response to short-acting β2-adrenergic receptor agonists 
(SABA). The minor or less common alleles of these SNP’s were associated with a 
greater bronchodilator response (Himes 2012).  The SNP with the most significant 
association, rs295137, is polymorphic in those of European descent, (minor allele 
frequency= 42% among Utah residents) but its minor allele is more common in an 
African population (minor allele frequency=59% among Yorubans).   The disparate 
allele frequency of this SNP, hypothetically, contributes to a greater frequency of 
treatment failures or other adverse responses to LABA treatment observed among 
Blacks when compared to non-Hispanic Whites (Lemanske 2010, Nelson 2006, 
Wechsler 2011).  
 
In addition, since African-Americans are an admixed population, there is an increased 
frequency of rare variants. In the gene encoding for the pharmacogenetic target for 
LABA therapy, the β2 adrenergic receptor gene (ADRβ2), we found four rare coding 
variants plus a 25 base-pair insertion-deletion for a total allele frequency of 8% in 
African-American asthmatics while in non-Hispanic White asthmatics, only the Thr164Ile 


 23 
variant was found at a 2% frequency (Genetics Table 1 below).
 
A significant relationship was observed between rare variants and loss of asthma 
control in individuals treated with a LABA. In 581 asthmatics on LABA therapy (with 
adjusting for age, sex and race), the 35 individuals with a rare variant had increased risk 
of hospitalization for asthma in the last year (42%) versus 22% in those without a rare 
variant (OR=2.2, p=0.04, Genetics Figure 2 below) (Ortega 2009, 2010).   
 
 
 
 
 
 
 


 24 
Unfortunately, data were only available on 179 African-Americans. No difference was 
observed in the 412 asthmatics not being treated with a LABA (which may be expected 
since many of these subjects probably have mild asthma). 
 
Mapping by Admixture Linkage Disequilibrium? 
 
Mapping by admixture linkage (admixture mapping) is a genome-wide approach that 
utilizes a subset of SNP’s to determine genetic ancestry at given loci in the genome 
(Genetics Figure 3 below). Admixture mapping determines local or regional estimates 
of genetic ancestry rather than global ancestry and has greater statistical power 
than classic Genome-Wide Association Studies (GWAS) because it requires a 
substantially smaller number of genetic markers (approximately 1,300 single nucleotide 
polymorphisms or SNP’s) (Smith 2004, Zhu 2008). In addition, it provides better 
coverage of rare variants that vary in frequency between populations with different 
ancestries (Gravel 2011, Mckeigue 2005). 
 
Admixture mapping is based on the fundamental principle that a proportion of genetic 
variants vary in frequency between populations of different ancestries. Recent 
generations of mixing between different genetically heterogeneous populations results 
in admixed populations that inherit chromosomal regions unique to an individual 
ancestry (Smith 2005). Through admixture mapping, these regions can be identified 
with genetic markers that show marked differences in allele frequencies between 
ancestral populations--ancestry informative markers. Genomic regions where ancestry 
has a statistically significant effect on a pre-specified phenotype are represented by 
admixture mapping peaks. The optimal setting for the use of admixture mapping is in an 
admixed population where there are marked racial disparities in disease phenotype not 


 25 
attributed to environmental factors, such as responses to asthma therapies between 
Blacks and non-Hispanic White asthmatics (Patterson 2004, Smith 2004).  
 
Examples of Admixture mapping in Genetic Studies 
Colleagues of our investigators at Wake Forest have extensive expertise in using 
admixture approaches in type 2 diabetes in African-Americans who have an increased 
burden of chronic kidney and end-stage kidney diseases as complications of diabetes 
mellitus type 2. In a genetic study using admixture mapping scanning with only 1,272 
SNP’s, variants in MYH9 were associated with idiopathic and HIV-associated focal 
segmental glomerulosclerosis in a small population of 190 Black cases and 222 controls 
(Kopp 2008). In addition, these investigators participated in another analysis that used a 
similar approach with 1,354 genetic markers to identify variants in MYH9 associated 
with progression to end-stage renal disease in Blacks (Kao 2008). They found that 
genetic variation in MYH9 substantially explains the increased burden of these 
complications in African-Americans. 
 
In asthma, the Wake Forest genomics group has collaborated with other investigators 
from the NIH NHLBI Severe Asthma Research Program and the NIH NHLBI 
Collaborative Study on the Genetics of Asthma in using high-density admixture mapping 
in 355 African-American asthma cases and 444 controls using 1,026,072 SNP’s to 
identify a novel asthma susceptibility locus in chromosome 6q14.1 (Torgerson 2012). 
Admixture-based approaches have also been used by Genetics of Asthma in Latinos 
(GALA) investigators to identify an asthma susceptibility locus in chromosome 5q23 in 
96 Puerto Rican asthma subjects and 88 controls. Puerto Ricans are a population with a 
significant proportion of sub-Saharan African Ancestry in which the use of admixture 
mapping provided a statistical advantage for the analysis of such a small population 
(Choudhry 2008). Based on the observed differences in response to LABA or ICS 
therapy in Black asthmatics when compared to non-Hispanic Whites, admixture 


 26 
mapping can be used to identify novel loci that predict responses to ICS and LABA 
therapy.  
 
To summarize, we propose to use global ancestry analysis and analysis of admixture in 
the BARD trial in two ways: 
- First, in our primary aim, to determine the role of global African ancestry 
on the preferential response to inhaled corticosteroid (ICS) or long-acting beta 
agonist (LABA) therapy.  
- Second, in our exploratory aims, to determine the role of genetic variation 
on the preferential response to ICS or LABA therapy using candidate gene 
analyses and unbiased genome-wide admixture mapping scanning to identify 
novel loci that determine therapeutic responses. 
 
IX. 
SPECIAL CONSIDERATIONS INVOLVING THE STUDY POPULATION 
AND STUDY MEDICATIONS  
 
The drugs that will be used in this study include ICS (low to high dose fluticasone 
propionate) and the long-acting beta agonist (LABA) salmeterol. Blinded drugs will be 
made available for this study by GlaxoSmithKline. Both ICS and LABA therapy have 
been used in previous ACRN (adult) and CARE (pediatric) trials without the occurrence 
of any significant side effect or adverse event attributable to either form of therapy. 
Salmeterol is currently approved for use in children down to at least 5 years of age. The 
FDA has reviewed the protocol and exempted AsthmaNet from holding an IND for the 
BARD trial. 
 
A. Justification of inclusion of participants who are symptomatic on low 
doses of ICS or ICS/LABA: 
 
Participants who are symptomatic at baseline on low doses of ICS or ICS/LABA will be 
allowed to participate in the trial and enter the run-in period. It has been the practice in 
NHLBI trials to allow such patients to participate in trials because entering a trial, being 
in a monitored setting, and gaining a better understanding of one’s asthma, all may be 
particularly beneficial for such a patient.  For instance, there may be confounding 
factors contributing to the poor control (e.g. technique, adherence) that could be 
addressed in greater detail in a trial. Alternatively, such a patient may never be exposed 
to various step up options after treatment for an exacerbation, as asthma is highly 
episodic and clinical practices do not automatically recommend step-up with a single 
exacerbation. Furthermore, if it is demonstrated that such a patient is poorly controlled, 
a study participant may benefit from the alternative dosing strategies to be offered in 
this trial (e.g. 5xICS BID). In addition, safety algorithms are in place (see below), and 
with the study’s close monitoring, participants will be assigned treatment failure status if 
the poor control persists. If in the run-in, they will either be randomized or treated for an 
exacerbation if needed. If post-randomization, they will also be treated as needed. 
 
 


 27 
B. Escalation of ICS dose: 
 
Escalation of ICS Dose:  In this study, we will increase ICS monotherapy dose from low 
dose in the run-in to medium- or high-dose monotherapy ICS during the treatment 
period, utilizing dosing that may abrogate exacerbations in individuals with asthma. 
Several adult studies including TALC and OPTIMA (O’Byrne 2001) suggest that 2xICS 
may not be adequate, and others e.g. Pauwels (FACET 1997) and Kelly (2011) have 
suggested that 4-5xICS offers potential to reduce exacerbations. As participants with 
asthma may benefit from alternative dosing strategies to be offered in this trial (like 
5xICS BID), we are thus examining an escalation to 5x dosing because these prior 
studies have shown that 2x dosing is not always sufficient to attain control.  However, 
we will be examining ICS dose response, both with and without LABA, to assess 
whether or not lower doses are effective in these Black populations. Depending on 
which ICS is acquired for this study, escalation from low to medium dose may range 
from 2x to 5x the initial dose (at least a quadrupling).  In order to assess safety, we will 
monitor for steroid side effects such as adrenal suppression (with overnight urine 
cortisol) (see Safety Monitoring section XXII), and thus plan to ascertain whether there 
is a differential clinical effect of different ICS dosing in Blacks. 
 
C. Assessment of Black adults/adolescents vs. children, rationale for 
breakdown of age groups into age 5-11 years and 12 and older, and dosing 
issues: 
 
It is important to perform the BARD protocol in both adults and adolescents 12 to 18 
years of age, as well as in children in the age range of 5 to 11 years. To date, there is no 
cross-age, dose-ranging study of any ICS to determine the appropriate dose in these 
age groups. Indeed, the “boxed” labeling for LABA’s was in part due to effects of LABA in 
children in the 5-11 year old age group. This cross-age study is particularly important 
since the FDA currently recognizes asthma as the same disease in children and adults 
and thus designs regulatory studies with this assumption in mind. We also have the 
opportunity in BARD to compare the effects of these therapies on different outcome 
measures in this population, and also to utilize a variety of baseline parameters, 
including genotype as well as phenotypic characteristics (e.g. bronchodilator 
responsiveness, methacholine responsiveness) to assess predictors of responsiveness 
to the different therapies across the ages.   
D. Steroid dose response in Blacks in relation to age: 
 
To date, there is no information available on specific dosing of ICS in the Black 
population, regardless of age, and there has not been an across-age, ICS dose ranging 
study in Blacks. BARD with its current dosing strategy can address the question of best 
step up therapy in Black children 5 to 11 years of age and in Black individuals aged 12 
or greater  and determine whether consideration for dosing recommendations should be 
changed in Blacks of different ages. Information on this topic is urgently needed since it 
is well known that the Black population, including children and adults, has a higher 
proportion of asthma mortality and urgent care utilization as compared to other 
races/ethnicity in the United States (Szefler 2011). There is also concern that the Black 
population may have a higher risk for steroid insensitivity (Chan 1998) and/or reduced 
cellular sensitivity to corticosteroids (Federico 2005). Therefore, BARD offers the unique 


 28 
opportunity to define the dose-response relationship of ICS as well as the additive effect 
of long-acting ß-adrenergic agonists in a cross-age manner in a patient population at 
high risk for asthma mortality and morbidity. We are thus trying to characterize dose 
response in this patient population, and we hypothesize that Blacks may require a 
higher dose of ICS to attain control.  Therefore, both the adult/adolescent and the 
pediatric aspects of this study will include evaluation of the dose response to inhaled 
corticosteroids, but lower doses of ICS will be used in the pediatric age group to 
minimize risks of higher doses of inhaled corticosteroids. We seek to assess what the 
inhaled steroid dose response is in this population, when inadequately responsive to 
low dose inhaled corticosteroid, a dose defined by 100 mcg fluticasone twice daily in 
individuals aged 12 or greater or 50 mcg fluticasone twice daily in children <12 years 
old. These doses are considered low in adolescents and adults as well as in children 5 
to 11 years of age (NAEPP guidelines tables 4-8b and 4-4b). This strategy will still allow 
us to evaluate whether this population requires higher doses of ICS due to steroid 
insensitivity (Chan 1998, Federico 2005, Szefler 2011). 
 
In individuals aged 12 or greater, the second dose of fluticasone propionate (the first 
step up dose) will be 250 mcg twice daily as this is the next higher available step up 
dose that is used in these ages. While this dose is at the upper limit of medium dose in 
adolescents and adults, it exceeds the designated medium dose of fluticasone 
propionate by 100 mcg per day (maximum range designated as 400 mcg per day) in 
children, so we are stepping up to 100 mcg BID of fluticasone in children <12 years old.  
The third dose to be studied in individuals aged 12 or greater is 500 mcg twice per day 
or 1,000 mcg per day. This dose is in the approved labeling for adolescents and adults 
but is greater than the limit of the high dose for children 5-11 years so in the younger 
subjects, we will use 250 mcg BID as the second step up.  
 
E. Combining adults and adolescents aged 12 and greater to develop data to 
inform guideline and treatment recommendations: 
 
While it might be argued that 13 year olds differ from adults, this strategy is consistent 
with both FDA and NAEPP guidelines.  Utilizing these cutoffs will increase the likelihood 
that our findings will be incorporated into ongoing guidelines and recommendations.   
While studies by Visser et al with a comparable ICS (fluticasone propionate) dosing 
strategy in an adolescent population with a comparable delivery device (Visser 2001, 
2004) did note that HPA suppression and growth were suppressed with the 500 and 
1,000 mcg per day dose given over a time frame similar to our study design, 3 months, 
these effects were reversible through the course of the study. 
 
F. HPA Axis Suppression: 
 
Due to the absence of data, we are not certain whether the reports of steroid 
insensitivity in the Black population are limited to the anti-inflammatory effect of steroid 
therapy or if they are also extended to the systemic effects of steroid therapy on growth 
and HPA axis suppression. To address this question, we will obtain measures of growth 
throughout the study and we will measure HPA suppression (utilizing overnight urine 
cortisol). 
 


 29 
We feel that this comprehensive study of a range of inhaled corticosteroid dosing will 
help define medication recommendations for managing asthma in the Black population 
that will be informative across ages and will define the advantages and limitations of 
each treatment strategy.  
 
G. Symmetry between adult/adolescent and pediatric studies:  
 
We are attempting to answer many of the same research questions in the pediatric and 
non-pediatric population. However, due to real differences between these groups, the 
study designs are not identical.  
 
Dose of ICS.  Both studies utilize an ICS dose escalation, but the pediatric population 
starts at half the dose and escalates to a maximum that is half the dose of the non-
pediatric population. This decision was made to approximate dose exposure based on 
size and also due to safety concerns related to use of high dose ICS (500 mcg FP BID) 
in children <12 years old).  Additionally, due to specific ICS dose availability, the step up 
in the 5-11 age group is a 2 fold increase in ICS (from 1xICS, 50 mcg BID, to 2xICS, 
100 BID), whereas in the older age group, the first step up is a 2.5 fold increase (from 
1xICS, 100 mcg BID, to 2.5xICS, 250 mcg BID). Nonetheless, there remains symmetry 
between the studies in those less than and greater than age 12, as both cohorts will get 
increasing doses of ICS with and without LABA.  
“Closest” Dose Step Up.  In the 12 year old and older study, the next “closest” 
randomized step up is from run-in ICS 100 mcg BID to addition of a LABA (ICS 100 mcg 
BID + LABA BID). In those less than 12 years old the next “closest” step up is from run-
in ICS 50 mcg BID to ICS 100 mcg BID and the LABA does not get “added-on” to the 
lowest dose of ICS but rather to the next dose of ICS. See section XIII.C Statistical 
Design and Analyses, Statistical Analysis Plan Statistical Analysis Plan for the 
Primary and Secondary Outcomes, first two paragraphs, for a listing that allows one to 
appreciate this difference. Due to lack of a placebo inhaler (and potential concerns of 
utilizing two separate inhalers in children), we are unable to move up to ICS 50 mcg 
+LABA BID.  We could not start the children at 100 mcg BID during the run-in because 
this would result in a maximum dose of 500 mcg BID which is not acceptable due to 
safety concerns as referenced in the previous paragraph. While this creates some 
differences in the degree to which we can answer all questions, we can still answer the 
primary and secondary research questions in both age groups (see section XIII 
Statistical Analysis Plan below).  
 
 


 30
X. 
PROTOCOL DETAIL AND VISIT STRUCTURES 
 
 
Table 6.  Visit Schedule in Tabular Form 
Study Procedure 
 
 
 
Rolling Run-In 
Open-Label 1xICS 
(Adherence, Safety, & 
Eligibility Assessment) 
Randomization 
Visit 
Double-Blind Treatment Phase 
 
During each period participants receive one of 4 blinded treatments 
with order determined randomly: 
≥12 y.o.: 2.5xICS, 1xICS/LABA, 5xICS, 2.5xICS/LABA 
5-11 y.o.: 2xICS, 2xICS/LABA, 5xICS, 5xICS/LABA  
 
 
Period 1 
Period 2 
Period 3 
Period 4 
Visit 
Sa 
 
Sa13 
Sb 
Sc 
Sd 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Week 
-10 
 
-10 
-8 
-4 
-0 
0 
2 
8 
14 
16 
22 
28 
30 
36 
42 
44 
50 
56 
Window (regular / 
extended) 
-- 
 
+3d/ 
+5d 
+3d/ 
+5d 
±3d/ 
±5d 
±3d/ 
±5d 
 
+3d/ 
±3d/ 
±3d/ 
+3d/ 
±3d/ 
±3d/ 
+3d/ 
±3d/ 
±3d/ 
+3d/ 
±3d/ 
±3d/ 
-- 
+5d 
±5d 
±5d 
+5d 
±5d 
±5d 
+5d 
±5d 
±5d 
+5d 
±5d 
±5d 
Informed Consent 
+ 
 
 
 
 
 
 
 
ICS Step-down 
assessment 
 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genotyping 
 
 
 
 
 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
CBC w/ differential4 
 
 
 
 
 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
Serum total IgE 
 
 
 
 
 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
ImmunoCAP 
 
 
 
 
 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Cotinine 
 
 
 
 
 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
                                            
3 Screen Visit A1 is required only for participants in the 2-step step-down group.  This visit occurs 2 weeks after Screen Visit A to assess participants for the 
ability to step down to 1xICS. 
4 CBC = Total blood count/total eosinophil count 


 31
Study Procedure 
 
 
 
Rolling Run-In 
Open-Label 1xICS 
(Adherence, Safety, & 
Eligibility Assessment) 
Randomization 
Visit 
Double-Blind Treatment Phase 
 
During each period participants receive one of 4 blinded treatments 
with order determined randomly: 
≥12 y.o.: 2.5xICS, 1xICS/LABA, 5xICS, 2.5xICS/LABA 
5-11 y.o.: 2xICS, 2xICS/LABA, 5xICS, 5xICS/LABA  
 
 
Period 1 
Period 2 
Period 3 
Period 4 
Visit 
Sa 
 
Sa13 
Sb 
Sc 
Sd 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Week 
-10 
 
-10 
-8 
-4 
-0 
0 
2 
8 
14 
16 
22 
28 
30 
36 
42 
44 
50 
56 
Window (regular / 
extended) 
-- 
 
+3d/ 
+5d 
+3d/ 
+5d 
±3d/ 
±5d 
±3d/ 
±5d 
 
+3d/ 
±3d/ 
±3d/ 
+3d/ 
±3d/ 
±3d/ 
+3d/ 
±3d/ 
±3d/ 
+3d/ 
±3d/ 
±3d/ 
-- 
+5d 
±5d 
±5d 
+5d 
±5d 
±5d 
+5d 
±5d 
±5d 
+5d 
±5d 
±5d 
Dispense overnight urine 
collection materials and 
instructions 
 
 
+ 
 
 
 
 
+ 
 
 
+ 
 
 
+ 
 
 
+ 
 
Overnight Urine Cortisol 
Creatinine (OUCC) 
 
 
 
+ 
+ 
+5 
 
 
+ 
 
 
+ 
 
 
+ 
 
 
+ 
Urine Pregnancy Test 
 
 
+ 
 
 
+ 
 
 
+ 
 
 
+ 
 
 
+ 
 
 
+ 
Medical History 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete Physical Exam 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
+ 
Brief Physical Exam  
 
 
 
 
 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
Height measurement 
(age<21) 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Body measurements (ht, 
wt, waist, hip, neck) (age 
≥18) 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
+ 
Spirometry 
+ 
+ 
+ 
 
 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Bronchodilator 
Reversibility (4 puffs) 
+ 
 
 
 
 
+6 
 
 
+ 
 
 
+ 
 
 
+ 
 
 
+ 
Methacholine Challenge 
 
 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                            
5 The baseline OUCC sample should be collected and returned to the clinic at any visit following Sb, up to and including Visit 1. 
6 Reversibility testing will be done in those ≥12 years of age to qualify for sputum induction 


 32
Study Procedure 
 
 
 
Rolling Run-In 
Open-Label 1xICS 
(Adherence, Safety, & 
Eligibility Assessment) 
Randomization 
Visit 
Double-Blind Treatment Phase 
 
During each period participants receive one of 4 blinded treatments 
with order determined randomly: 
≥12 y.o.: 2.5xICS, 1xICS/LABA, 5xICS, 2.5xICS/LABA 
5-11 y.o.: 2xICS, 2xICS/LABA, 5xICS, 5xICS/LABA  
 
 
Period 1 
Period 2 
Period 3 
Period 4 
Visit 
Sa 
 
Sa13 
Sb 
Sc 
Sd 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Week 
-10 
 
-10 
-8 
-4 
-0 
0 
2 
8 
14 
16 
22 
28 
30 
36 
42 
44 
50 
56 
Window (regular / 
extended) 
-- 
 
+3d/ 
+5d 
+3d/ 
+5d 
±3d/ 
±5d 
±3d/ 
±5d 
 
+3d/ 
±3d/ 
±3d/ 
+3d/ 
±3d/ 
±3d/ 
+3d/ 
±3d/ 
±3d/ 
+3d/ 
±3d/ 
±3d/ 
-- 
+5d 
±5d 
±5d 
+5d 
±5d 
±5d 
+5d 
±5d 
±5d 
+5d 
±5d 
±5d 
Sputum Induction 
(age≥12)7 
 
 
 
 
 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
Home Environment 
Questionnaire 
 
 
 
 
 
 
+ 
 
 
 
 
 
 
 
 
 
 
 
Household Socio-
Economic Info 
Questionnaire 
 
 
 
 
 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
Asthma QOL (RAND-
IAQL-12, AQLQ or 
PedsQL)8 
+ 
 
 
 
 
+ 
 
 
+ 
 
 
+ 
 
 
+ 
 
 
+ 
Asthma Control Test 
(ACT, c-ACT) 
+ 
 
+ 
 
 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Asthma Control 
Questionnaire (ACQ) 
 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                            
7 Sputum induction will be performed only at a subset of BARD sites that have sputum induction equipment, training, and certification.  
8 The Juniper AQLQ+12 (Juniper 2005) and RAND-IAQL-12 (Stucky currently under review, Eberhart currently under review) will be used for participants ages 12 and up. 
The Juniper pediatric AQLQ(S) (Juniper 1996) will be used for participants ages 7-11. The PedsQL(Varni 2001) will be used for participants ages 5-6 (this is a general 
quality of life tool, not asthma-specific, in this age group)  


 33
Study Procedure 
 
 
 
Rolling Run-In 
Open-Label 1xICS 
(Adherence, Safety, & 
Eligibility Assessment) 
Randomization 
Visit 
Double-Blind Treatment Phase 
 
During each period participants receive one of 4 blinded treatments 
with order determined randomly: 
≥12 y.o.: 2.5xICS, 1xICS/LABA, 5xICS, 2.5xICS/LABA 
5-11 y.o.: 2xICS, 2xICS/LABA, 5xICS, 5xICS/LABA  
 
 
Period 1 
Period 2 
Period 3 
Period 4 
Visit 
Sa 
 
Sa13 
Sb 
Sc 
Sd 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Week 
-10 
 
-10 
-8 
-4 
-0 
0 
2 
8 
14 
16 
22 
28 
30 
36 
42 
44 
50 
56 
Window (regular / 
extended) 
-- 
 
+3d/ 
+5d 
+3d/ 
+5d 
±3d/ 
±5d 
±3d/ 
±5d 
 
+3d/ 
±3d/ 
±3d/ 
+3d/ 
±3d/ 
±3d/ 
+3d/ 
±3d/ 
±3d/ 
+3d/ 
±3d/ 
±3d/ 
-- 
+5d 
±5d 
±5d 
+5d 
±5d 
±5d 
+5d 
±5d 
±5d 
+5d 
±5d 
±5d 
Asthma-Specific Work 
Productivity and Activities 
Impairment 
Questionnaire 
(WPAI:Asthma)9 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acute Asthma 
Assessment 
Questionnaire (AAAQ) 10 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Perceived Stress Scale 
(PSS-10)11 
 
 
 
 
 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense asthma 
exacerbation 
characterization kit12 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense e-diary/PEF 
meter 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                            
9 This questionnaire will be administered to participants ages 12 and older only; it will be administered at Screen Visit A, as well as in an asthma exacerbation kit that is 
completed at the time prednisone treatment is initiated for an exacerbation.  Additional questionnaires will be administered at visits immediately following an 
exacerbation (see Section XX.F). 
10 This questionnaire will be administered to participants ages 12 and older only; it will be administered at Screen Visit A, as well as in an asthma exacerbation kit that is 
completed at the time prednisone treatment is initiated for an exacerbation.  Additional questionnaires will be administered at visits immediately following an 
exacerbation (see Section XX.F). 
11 For participants ages 12 and older. 
12 For participants ages 12 and older.  Consists of  WPAI:Asthma and Acute Asthma Assessment Questionnaire. See Section XX.F.  


 34
Study Procedure 
 
 
 
Rolling Run-In 
Open-Label 1xICS 
(Adherence, Safety, & 
Eligibility Assessment) 
Randomization 
Visit 
Double-Blind Treatment Phase 
 
During each period participants receive one of 4 blinded treatments 
with order determined randomly: 
≥12 y.o.: 2.5xICS, 1xICS/LABA, 5xICS, 2.5xICS/LABA 
5-11 y.o.: 2xICS, 2xICS/LABA, 5xICS, 5xICS/LABA  
 
 
Period 1 
Period 2 
Period 3 
Period 4 
Visit 
Sa 
 
Sa13 
Sb 
Sc 
Sd 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Week 
-10 
 
-10 
-8 
-4 
-0 
0 
2 
8 
14 
16 
22 
28 
30 
36 
42 
44 
50 
56 
Window (regular / 
extended) 
-- 
 
+3d/ 
+5d 
+3d/ 
+5d 
±3d/ 
±5d 
±3d/ 
±5d 
 
+3d/ 
±3d/ 
±3d/ 
+3d/ 
±3d/ 
±3d/ 
+3d/ 
±3d/ 
±3d/ 
+3d/ 
±3d/ 
±3d/ 
-- 
+5d 
±5d 
±5d 
+5d 
±5d 
±5d 
+5d 
±5d 
±5d 
+5d 
±5d 
±5d 
Review/evaluate PEF 
technique and diary 
procedures 
+ 
+ 
+ 
+ 
+ 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
Collect e-diary/PEF 
meter 
 
 
 
 
+13 
 
 
 
 
 
 
 
 
 
 
 
 
+ 
Review/evaluate inhaler 
technique 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
 
Dispense run-in open-
label ICS 
+ 
+ 
+ 
+ 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect run-in open-label 
ICS 
 
+ 
+ 
+ 
+ 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense/collect rescue 
albuterol 
+ 
 
 
 
 
+ 
 
 
+ 
 
 
+ 
 
 
+ 
 
 
+ 
Dispense rescue 
prednisone supply 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense randomized 
medications (double-
blind Diskus) 
 
 
 
 
 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
 
Collect randomized 
medications 
 
 
 
 
 
 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Review diaries/PEF 
 
 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
                                            
13 For those ineligible at the end of the run-in. 


 35
Study Procedure 
 
 
 
Rolling Run-In 
Open-Label 1xICS 
(Adherence, Safety, & 
Eligibility Assessment) 
Randomization 
Visit 
Double-Blind Treatment Phase 
 
During each period participants receive one of 4 blinded treatments 
with order determined randomly: 
≥12 y.o.: 2.5xICS, 1xICS/LABA, 5xICS, 2.5xICS/LABA 
5-11 y.o.: 2xICS, 2xICS/LABA, 5xICS, 5xICS/LABA  
 
 
Period 1 
Period 2 
Period 3 
Period 4 
Visit 
Sa 
 
Sa13 
Sb 
Sc 
Sd 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Week 
-10 
 
-10 
-8 
-4 
-0 
0 
2 
8 
14 
16 
22 
28 
30 
36 
42 
44 
50 
56 
Window (regular / 
extended) 
-- 
 
+3d/ 
+5d 
+3d/ 
+5d 
±3d/ 
±5d 
±3d/ 
±5d 
 
+3d/ 
±3d/ 
±3d/ 
+3d/ 
±3d/ 
±3d/ 
+3d/ 
±3d/ 
±3d/ 
+3d/ 
±3d/ 
±3d/ 
-- 
+5d 
±5d 
±5d 
+5d 
±5d 
±5d 
+5d 
±5d 
±5d 
+5d 
±5d 
±5d 
Set/review/update PEF 
reference value14 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
 
Review medication use 
 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Distribute AsthmaNet 
Satisfaction 
Questionnaire 
 
 
 
 
+15 
 
 
 
 
 
 
 
 
 
 
 
 
+ 
Telephone Contacts  
 
 
Weeks -6 & -2 
 
Weeks 5 & 11 
Weeks 19 & 25 
Weeks 33 & 39 
Weeks 47 & 53 
                                            
14 PEF reference values will not change after randomization for individuals aged 21 and older at enrollment. Reference values may change beyond randomization for 
individuals aged 5-20 as a result of changing predicted PEF values due to increases in height and age over the course of the study. 
15 For those ineligible at the end of the run-in.  Any individual formally enrolled in BARD at Screen Visit A who terminates from the trial at any point will be given a 
Satisfaction Questionnaire to complete at home and send to the DCC in an addressed, postage-paid envelope. 


 36 
A. Study visits and telephone contacts 
 
1. Week -10, Screen Visit A (Sa) 
The purpose of this visit is to screen participants for the trial and assess eligibility 
based on review of history, physical exam, and bronchodilator responsiveness.  
a. Informed consent (participant’s consent if ≥18 years and parent’s consent 
if participant is <18 years; child’s assent based on age and local IRB 
guidelines) 
b. Asthma questionnaire administration (ACT/c-ACT, AQLQ/PedsQL, RAND-
IAQL-12, WPAI:Asthma) 
c. Acute Asthma Assessment Questionnaire (AAAQ) 
d. Review of inclusion and exclusion criteria 
e. Physical examination (including vitals, height, and weight) and body 
measurements (waist, hip, neck circumference) in adults  
f. Complete medical history, including cold history 
g. Pulmonary function assessment 
i. Baseline spirometry 
ii. Bronchodilator reversibility assessment (4 puffs)  
h. Electronic peak flow meter/e-diary (Spirotel®) dispensed and appropriate 
PEF technique and understanding of diary instructions assured 
i. Run-in PEF reference value determined and action plan and medications 
provided for management/treatment of asthma exacerbations 
j. Inhaler technique (MDI, Diskus®) reviewed  
k. Instructions provided for study medications  
l. Study medications (low dose ICS (1xICS), rescue albuterol, rescue 
prednisone) dispensed 
  
As noted in Exclusion Criteria, children 5-11 taking a dose of FP greater 
than 500 mcg per day are ineligible.  As noted in Randomization Inclusion 
Criteria, so as to ensure participants’ safety, individuals taking more than 
2-2.5xICS monotherapy equivalent/day or ≥2-2.5xICS/LABA will be 
stepped down initially to 2-2.5xICS BID and then reassessed in 2 weeks at 
Screen Visit A1 to assure stability to taper down to the baseline of 1xICS 
BID. If not inadequately controlled (i.e., the participant has not 
exacerbated and does not have an ACQ score ≥1.5), then the ICS dose 
will be stepped down to 1xICS BID for the remainder of the run-in and the 
participant will be scheduled for Screen Visit B in 2 weeks. If individuals 
are inadequately controlled on 2-2.5xICS BID (i.e., they have an ACQ 
score ≥1.5 and/or experience an asthma exacerbation), then they will be 
terminated from further study participation. 
 
2. Week -10, Screen Visit A1 (Sa1) 
The purpose of this visit is to evaluate participants who require 2-step step-down 
procedures to determine if they are eligible to taper to the 1xICS dose. This visit 
is only required for those in the 2-step step-down group. 
a. Asthma Control Questionnaire (ACQ) 
b. Height measurement for those <21 years 
c. Pulmonary function assessment 
i. Spirometry 


 37 
d. Assess eligibility for step-down to 1xICS 
e. Review PEF technique and have participant perform 3 technically 
acceptable maneuvers on Spirotel®. Review diary instructions to ensure 
they are understood. 
f. Update run-in PEF reference value if the Sa1 pre-bronchodilator PEF 
value or any PEF collected during the first two weeks at home is higher 
than the PEF reference value determined at Sa.  
g. Review diary information and PEFs in Spirotel® 
h. Evaluate and reinforce adherence to medication schedule and diary 
completion 
i. Collect/distribute run-in medications 
 
3. Week -8, Screen Visit B (Sb) 
The purpose of this visit is to assess for airway hyperresponsiveness for 
evaluation of eligibility criteria and to characterize/phenotype study participants. 
Diary data is uploaded and reviewed to evaluate participants for lack of 
acceptable control criteria and to determine if a participant is eligible for early 
randomization. 
a. Asthma questionnaire administration (ACT, c-ACT) 
b. Height measurement for those <21 years 
c. Pulmonary function assessment 
i. Spirometry 
d. Urine Sample for pregnancy test for female participants who have reached 
menarche 
e. Methacholine challenge  
This test will be performed before randomization for two reasons. First, if 
the participant did not previously qualify for study entry based on 
reversibility criteria at Visit Sa or documentation from two spirometry 
sessions over the course of a year, the participant may qualify for entry 
based on a methacholine PC20 value of ≤ 16 mg/ml. Second, the 
methacholine bronchoprovocation is performed at this visit to establish a 
reference baseline for characterization purposes. If the methacholine 
bronchoprovocation cannot be performed at this visit because the FEV1 is 
< 55% predicted or 1.0 liters (adults) or <70% predicted (<18 years of 
age), one additional attempt to perform the test may be made prior to 
randomization if the participant is clinically stable. 
f. Review PEF technique and have participant perform 3 technically 
acceptable maneuvers on Spirotel®. Review diary instructions to ensure 
they are understood. 
g. Update run-in PEF reference value if the Sb pre-bronchodilator PEF value 
or any PEF collected during the first two weeks at home is higher than the 
PEF reference value determined at Sa/Sa1.  
h. Review diary information and PEFs in Spirotel® 
i. Evaluate and reinforce adherence to medication schedule and diary 
completion 
j. Assess eligibility; if participant is eligible for randomization, Visit 1 will be 
scheduled as soon as possible (+5 day/+14 day window) 
k. Collect/distribute run-in medications 
l. Distribute overnight urine collection materials and instructions 


 38 
 
4. Weeks -4,-0 Screen Visits C & D (Sc, Sd) 
a. Height measurement for those <21 years 
b. Review PEF technique and have participant perform 3 technically 
acceptable maneuvers on Spirotel®. Review diary instructions to ensure 
they are understood. 
c. Review diary information and PEFs in Spirotel® 
d. Update run-in PEF reference value if the Sc or Sd pre-bronchodilator PEF 
value or any PEF collected at home between screening visits is higher 
than the participant’s current PEF reference value  
e. Evaluate and reinforce adherence to medication schedule and diary 
completion 
f. Assess eligibility; if participant is eligible for randomization, Visit 1 can be 
completed on the same day or scheduled as soon as possible (+5 day/+14 
day window) 
g. Collect/distribute run-in medications, as needed 
h. Collect baseline overnight urine sample if participant provided one (once 
sample is collected, processed and stored, no additional samples are 
needed) 
 
 
5. Week -6, -2 Telephone Contacts 
Participants and/or their families will be contacted by telephone every 2 weeks 
between scheduled visits during the rolling run-in period.  Participants/parents 
will be asked about the participant’s symptoms, peak flows, nighttime 
awakenings, and rescue use during the past 2 weeks to determine if criteria for 
randomization may have been met. If the participant appears to meet 
randomization criteria, Visit 1 will be scheduled as soon as possible (+5 day/+14 
day window). Eligibility criteria will be confirmed via data uploaded from the 
Spirotel® before proceeding with the tests and evaluations required at Visit 1.   
 
6. Randomization: Week 0, Visit 1 
The purpose of this visit is to perform a final assessment of eligibility for 
randomization and to phenotype eligible participants with allergy testing, induced 
sputum (≥12 years of age), and blood tests. Blood will be drawn for genotyping 
and the overnight urine sample for baseline urine cortisol will be collected if not 
previously submitted at a screen visit. Randomized, double-blind medications will 
be dispensed. 
a. Administer asthma questionnaires (ACT/c-ACT, AQLQ/PedsQL, RAND-
IAQL-12) 
b. Administer Perceived Stress Scale (Cohen 1983) for participants ≥12 
years (PSS-10) 
c. Review diary information and PEFs in Spirotel® 
d. Review PEF technique and have participant perform 3 technically 
acceptable maneuvers with Spirotel®. Review diary instructions to ensure 
they are understood. 
e. Determine post-randomization PEF reference value as the highest of the 
run-in PEF reference value, the PEFs obtained at home during the run-in, 
or the PEF measurement obtained at the randomization visit 


 39 
f. Evaluate and reinforce adherence to medication schedule and diary 
completion 
g. Confirm  eligibility to continue with Visit 1 
h. Brief physical examination 
i. Height measurement for those <21 years 
j. Assess pulmonary function 
i. Spirometry 
k. Assess bronchodilator reversibility (4 puffs) (for those ≥12 years to qualify 
for sputum induction) 
l. Administer Household Socioeconomic Info questionnaire 
(HOUSEHOLD_SEI)  
m. Collect overnight Urine Sample16 for: 
i. 
Baseline assessment of overnight urine cortisol 
ii. 
Pregnancy test for female participants who have reached menarche 
iii. 
Storage for future analyses of biomarkers to be determined  
n. Collect blood samples for: 
i. Complete blood count with total eosinophil count 
ii. Serum total IgE 
iii. Serum cotinine 
iv. Allergen-specific IgE (ImmunoCAP as per Asthmanet MOP) 
v. Genotyping 
vi. Serum storage for future analyses of biomarkers 
o. Collect sputum sample for eosinophilia  and future analysis of biomarkers 
(in those 12 and older)17 
p. Randomization 
q. Provide instructions for study medications 
r. Collect run-in medications  
s. Dispense double-blind study medications 
 
7. Week 2, Visit 2 and 
Week 8, Visit 3 
The purpose of these visits is to monitor participant stability and adherence 
during the treatment period and to collect longitudinal lung function data. 
 
a. Administer asthma questionnaire (ACT/c-ACT) 
b. Administer Home Environment Questionnaire (HEQ) (Visit 2 only) 
c. Height measurement for those <21 years 
d. Pulmonary function assessment 
i. Spirometry 
e. Review e-diary information and PEFs in Spirotel® 
f. Evaluate and reinforce adherence to medication schedule and diary 
completion 
g. Collect/dispense study medications 
h. Distribute overnight urine collection materials and instructions (Visit 3 only) 
                                            
16 The baseline overnight urine sample can be collected and stored during screen visits prior to Visit 1. If a sample 
was stored previously, then female participants of child-bearing potential must supply a fresh sample for 
pregnancy testing at the time of Visit 1. 
17 Sputum induction procedures will be carried out only at a subset of BARD sites that have sputum induction 
equipment, training and certification. 


 40 
 
8. Week 14, Visit 4 (cross over visit) 
The purpose of this visit is to monitor participant stability and adherence during 
the treatment period and collect data at the end of treatment period 1 as the 
participant crosses over to the randomized period 2 treatment regimen. 
a. Administer asthma questionnaires (ACT/c-ACT, AQLQ/PedsQL, RAND-
IAQL-12) 
b. Collection of overnight urine sample for: 
i. 
Assessment of overnight urine cortisol 
ii. 
Pregnancy test for female participants who have reached menarche 
c. Height measurement for those <21 years 
d. Pulmonary function assessment 
i. Spirometry 
ii. Bronchodilator reversibility assessment (4 puffs)  
e. Review e-diary information and PEFs in Spirotel® 
f. Evaluate and reinforce adherence to medication schedule and diary 
completion 
g. Collect/dispense study medications 
 
 
 
 
9. Week 16, Visit 5 
Week 22, Visit 6 
The purpose of these visits is to monitor participant stability and adherence 
during the treatment period and collect longitudinal lung function data. 
 
a. Administer asthma questionnaire (ACT/c-ACT) 
b. Height measurement for those <21 years 
c. Pulmonary function assessment 
i. Spirometry 
d. Review e-diary information and PEFs in Spirotel® 
e. Evaluate and reinforce adherence to medication schedule and diary 
completion 
f. Collect/dispense study medications 
g. Distribute overnight urine collection materials and instructions (Visit 6 only) 
 
10. Week 28, Visit 7 (cross over visit) 
The purpose of this visit is to monitor participant stability and adherence during 
the treatment period and collect data at the end of treatment period 2 as the 
participant crosses over to the randomized period 3 treatment regimen. 
a. Administer asthma questionnaires (ACT/c-ACT, AQLQ/PedsQL, RAND-
IAQL-12) 
b. Collection of overnight urine sample for: 
i. 
Assessment of overnight urine cortisol 
ii. 
Pregnancy test for female participants who have reached menarche 
c. Height measurement for those <21 years 
d. Pulmonary function assessment 
i. Spirometry 


 41 
ii. Bronchodilator reversibility assessment (4 puffs)  
e. Review e-diary information and PEFs in Spirotel® 
f. Evaluate and reinforce adherence to medication schedule and diary 
completion 
g. Collect/dispense study medications 
 
11. Week 30, Visit 8 
Week 36, Visit 9 
The purpose of these visits is to monitor participant stability and adherence 
during the treatment period and to collect longitudinal lung function data. 
 
a. Administer asthma questionnaire (ACT/c-ACT) 
b. Height measurement for those <21 years 
c. Pulmonary function assessment 
i. Spirometry 
d. Review e-diary information and PEFs in Spirotel® 
e. Evaluate and reinforce adherence to medication schedule and diary 
completion 
f. Collect/dispense study medications 
g. Distribute overnight urine collection materials and instructions (Visit 9 only) 
 
 
 
12. Week 42, Visit 10 (cross over visit) 
The purpose of this visit is to monitor participant stability and adherence during 
the treatment period and collect data at the end of treatment period 3 as the 
participant crosses over to the randomized period 4 treatment regimen. 
a. Administer asthma questionnaires (ACT/c-ACT, AQLQ/PedsQL, RAND-
IAQL-12 ) 
b. Collection of overnight urine sample for: 
i. 
Assessment of overnight urine cortisol 
ii. 
Pregnancy test for female participants who have reached menarche 
c. Height measurement for those <21 years 
d. Pulmonary function assessment 
i. Spirometry 
ii. Bronchodilator reversibility assessment (4 puffs)  
e. Review e-diary information and PEFs in Spirotel® 
f. Evaluate and reinforce adherence to medication schedule and diary 
completion 
g. Collect/dispense study medications 
 
 
13. Week 44, Visit 11 
Week 50, Visit 12 
 
The purpose of these visits is to monitor participant stability and adherence 
during the treatment period and to collect longitudinal lung function data. 
 
a. Administer asthma questionnaire (ACT/c-ACT) 


 42 
b. Height measurement for those <21 years 
c. Pulmonary function assessment 
i. Spirometry 
d. Review e-diary information and PEFs in Spirotel® 
e. Evaluate and reinforce adherence to medication schedule and diary 
completion 
f. Collect/dispense study medications 
g. Distribute overnight urine collection materials and instructions (Visit 12 
only) 
 
14. Week 56, Visit 13 (final visit) 
The purpose of this visit is to monitor participant stability and adherence during 
the treatment period and to collect data at the end of treatment period 4. Study 
drugs and the Spirotel® are collected and study termination procedures are 
completed. 
a. Administer asthma questionnaires (ACT/c-ACT, AQLQ/PedsQL, RAND-
IAQL-12) 
b. Complete physical examination (including vitals, height, weight) and body 
measurements (waist, hip, neck circumference) in adults 
c. Collection of overnight urine sample for: 
i. 
Assessment of overnight urine cortisol 
ii. 
Pregnancy test for female participants who have reached menarche 
d. Pulmonary function assessment 
i. Spirometry 
ii. Bronchodilator reversibility with 4 puffs albuterol 
e. Review e-diary and PEF information from Spirotel® 
f. Collect drugs and Spirotel® 
g. Evaluate adherence to medication schedule and diary completion 
h. Dispense Satisfaction Questionnaire and postage-paid envelope 
 
 
15. Week 5, 11, 19, 25, 33, 39, 47, 53 Telephone Contacts (±5 day window) 
Participants and/or their families will be contacted by telephone every 3 weeks 
between scheduled visits during the double-blind treatment periods.  
Participants/parents will be asked about the participant’s symptoms, peak flows, 
nighttime awakenings, and rescue use during the past 3 weeks, as well as the 
occurrence of any hospitalizations or urgent care visits, to determine if the 
participant has met criteria for treatment failure or drop-out status. If the 
participant appears to have met criteria for treatment failure or drop-out status or 
is experiencing symptoms indicative of an asthma exacerbation, he or she will be 
seen for an unscheduled visit at the performance site as soon as possible. 
 
 
 


 43 
XI. 
OUTCOMES 
 
Primary Outcome: The primary outcome is a hierarchical asthma measure that 
uses exacerbations, asthma control days (ACDs) during the last 12 of 14 weeks of 
a treatment regimen, and the %predicted FEV1 at the end of the 14-week treatment 
regimen. This composite outcome, used in BADGER (the pediatric trial comparing 
LABA, increased ICS, and LTRA in subjects inadequately controlled on low dose ICS 
(Lemanske 2010)), uses a hierarchical method to ascertain differences in asthma 
control. Treatments are first compared to see if they differ in terms of exacerbations. If 
one treatment produces one or more exacerbations less than the alternate treatment, 
then it is classified as the superior treatment. If none of the treatments for a specific 
participant is superior, then his or her responses are compared by asthma control days 
(ACDs- see definition below). If one treatment differs by at least 31 annualized ACDs 
from the other, then the participant is now assigned to treatment superiority for that 
treatment. If treatment superiority still cannot be assigned by ACDs, then a participant’s 
responses to treatments are compared by the %predicted FEV1 at the end of the 14-
week treatment regimen (a difference of 5% or more between treatments being 
necessary to assign superiority). If no treatment superiority can be assigned based on 
FEV1, then participants are classified as having “no preference”.   
At the end of the study, each participant will be identified as either a differential or non-
differential treatment responder. A differential responder is someone who exhibits 
significantly better outcomes on one treatment than on another. Treatment response is 
based on asthma exacerbations, ACD, and the %predicted FEV1 at the end of the 14-
week treatment regimen.  A participant will be identified as a differential responder if he 
or she responds differentially with respect to asthma exacerbations, ACD, or the 
%predicted FEV1. 
This trial is not a typical clinical trial comparison of treatments. A typical trial employs 
either a parallel or cross-over design to compare treatments with respect to population 
averages of a given outcome. Such trials are able to demonstrate that one treatment is 
superior to another in the sense that the average treatment response across a 
population of individuals is better. However, some individuals in that population may not 
respond better to the superior treatment. Conversely, such trials might demonstrate that 
two treatments are not different with respect to the population average.  In this case, it is 
possible that the lack of average difference occurs because some individuals respond 
markedly better to one treatment while others respond markedly better to the other.  
Sub-group analyses of such trials are often used to predict treatment response 
according to a set of phenotypic and/or genotypic characteristics. The purpose of these 
analyses is to identify sub-groups of the population that are more homogeneous with 
respect to treatment response. However, inference based on these analyses is still at 
the level of population averages. 
 
Secondary Outcome(s): 
 Asthma control days 
An Asthma Control Day (ACD) will be defined as a day without:  
 
1. 
Albuterol rescue use (pre-exercise treatment permitted) 
 


 44 
2. 
Use of non-study asthma medications including oral steroids. In addition, 
the 7 days immediately following the end of a course of oral steroids will 
be considered non-ACDs. 
 
3. 
Daytime 
or 
nighttime 
asthma 
symptoms 
(wheezing, 
coughing, 
phlegm/mucus, chest tightness, or shortness of breath) 
 
4. 
Unscheduled health care provider visits for asthma, emergency room visit 
or hospital admission for asthma, or missed work or school due to asthma 
 
5. 
AM or PM peak flow less than 90% of the analysis PEF reference value 
defined as: Average AM PEF from the run-in week (7 days) most proximal 
to randomization Visit 1 that met the definition as a ‘lack of acceptable 
asthma control’ week on the basis of rescue use, asthma symptoms, or 
PEF as defined in section VII.A. If the participant qualified for 
randomization on the basis of nighttime awakenings alone, then the 
reference will be the average AM PEF from the week (7 days) prior to the 
awakening that occurred most proximal to Visit 1. In the unlikely event that 
the participant qualified for randomization on the basis of having had an 
asthma exacerbation during the run-in, and he or she did not experience 
an uncontrolled week or meet the nighttime awakenings definition of ‘lack 
of control’, then the reference PEF will be the average AM PEF from the 
week (7 days) prior to the first dose of prednisone used to treat the 
exacerbation. If an individual experienced two exacerbations prior to 
randomization, then the reference will be the average AM PEF from the 
week (7 days) prior to the first dose of prednisone used to treat the first 
exacerbation. 
 
Days without asthma will be calculated from daily e-diary entries. Other secondary 
outcomes of asthma control collected from e-diary include percentage of: rescue-
free days, albuterol-free days and episode-free days. A rescue-free day is defined as 
no albuterol rescue use (pre-exercise treatment permitted), no use of oral steroids 
for asthma, no use of non-study asthma medications, no unscheduled primary care 
provider visits for asthma, and no emergency room visits or hospital admissions for 
asthma. An albuterol-free day is defined as no albuterol use for rescue or for pre-
exercise treatment. An episode-free day is defined in the same way as a day without 
asthma with the additional requirement that morning and evening peak flow are 
greater than 80% of personal best (Sorkness 2007). 
 
 Lung Function (pre and post bronchodilator FEV1 including albuterol) 
 Airway Hyperresponsiveness at baseline as a predictor of responsiveness to each 
therapy 
 Asthma Control: well-controlled week, or ACT (or c-ACT) 
 Asthma Quality of Life Measures: AQLQ+12 (Juniper 2005) and RAND-IAQL-12 
(Stucky currently under review, Eberhart currently under review) (ages 12 and older) 
or pediatric AQLQ (Juniper 1996) (ages 7-11)  or PedsQL (general quality of life, not 
asthma-specific) (Varni 2001) (ages 5-6) 
  
Exploratory Outcomes:  


 45 
 Number of Asthma exacerbations (ATS criteria i.e. requiring prednisone) and 
characterization of asthma exacerbations (see section XX). 
XII. 
GENOTYPING METHODS 
 
Individuals in the BARD trial will be genotyped using Illumina OmniExpress and Human 
Exome beadchips, according to manufacturer’s protocol (Illumina, Inc., San Diego, CA). 
These platforms have whole exome coverage that includes 742,000 common and rare 
genetic variants for detailed regional admixture-based methods. Briefly, genotyping 
quality control will consist of the following procedures within BeadStudio:  1) initial 
clustering with Illumina-defined clusters; 2) removal of samples with call rates less than 
90%; 3) removal of SNPs with call rates less than 90%; 4) re-calculation of call rates 
and removal of samples with call rates less than 95%; 5) re-clustering of remaining 
samples; and 6) removal of SNPs with poor clustering (GenTrain < 0.75 and ClusterSep 
< 0.3). Additional quality control measures including calculation of genotyping efficiency 
and Hardy-Weinberg equilibrium will be performed using the publically available 
software Plink v1.07 and Haploview v4.1. Although it is more cost effective to utilize a 
GWAS chip, a small subset consisting of approximately 1,536 variants that are ancestry 
informative are sufficient to determine genome-wide or global ancestry based on data 
sets from Smith et al, Hinds et al, and the Phase International Haplotype Map.(Smith 
2004, HapMap 2003, Hinds 2005). However, by having GWAS data, we will have the 
ability to interrogate specific genes of interest such as ADBR2 without having to perform 
additional genotyping. 
XIII. 
STATISTICAL DESIGN AND ANALYSES 
A. Randomization 
The target sample size for the BARD trial is 291 Black adults/adolescents (ages 12 and 
older) and 284 Black children (ages 5-11). Each participant’s age group will be defined 
at his/her enrollment visit, Screen Visit A. Individuals who are ages 5-11 at enrollment 
will be placed in the child track for data purposes and will continue to be treated 
according to the procedures for children for the duration of their trial participation. 
This study incorporates a design in which each participant will receive each of four 
treatment regimens over four 14-week periods (known as a four-way crossover design). 
For adults/adolescents, if we denote the four treatment regimens as A, B, C, and D, 
then each BARD adolescent/adult will be randomized to one of the following four 
treatment sequences: 
ABCD, BDAC, CADB, DCBA 
For children, if we denote the four treatment regimens as E, F, G, and H, then each 
BARD child will be randomized to one of the following four treatment sequences: 
EFGH, FHEG, GEHF, HGFE 
Because BARD invokes a four-way crossover design, a stratified randomization based 
on prognostic factors is not critical. Instead, we only will invoke clinical center 
partnership within age group at enrollment (adults/adolescents, children) as a stratifying 


 46 
variable with permuted blocks of size four (one complete cycle of the four treatment 
sequences). When a participant at a particular performance site is deemed eligible for 
the study at Visit 1, the Clinic Coordinator will access the AsthmaNet server and 
indicate to the system that a participant requires randomization. After entering the 
pertinent information with respect to clinical center partnership and eligibility criteria, the 
Clinic Coordinator will be asked to verify that all of the entered information is correct.  If 
so, the Clinic Coordinator will be given the number of a blinded Diskus to dispense to 
the participant. At all post-randomization visits the coordinator will access the 
randomization module to generate the number of a new Diskus that contains the 
regimen consistent with the participant’s randomized drug sequence. Some visit 
intervals are long enough in duration to require the dispensation of two Diskuses, each 
with its own unique number. In order to maintain security of the randomization 
schedules, DCC data management and coordination staff will receive automatically a 
notice from the AsthmaNet server that a participant has been randomized and/or had a 
new Diskus number generated. 
B. Masking 
To minimize the bias due to possible knowledge of the sequence assignment, the study 
will be double-blinded. Thus, the investigators and the participants will not know which 
treatments are being administered during the treatment periods. Further, key personnel 
at the DCC will also remain blinded through study implementation and analysis phases.  
This includes the data managers, scientific coordinators, and statisticians. Only the 
project coordinator and a database programmer will have access to the unblinding 
documentation while the trial is being implemented and the data are being analyzed for 
the primary publication. 
C. Statistical Analysis Plan 
 
Statistical Analysis Plan for the Run-in Period 
The run-in period is considered the baseline evaluation period. The initial statistical 
analysis will focus on summarizing the baseline characteristics of the study participants.  
We will calculate descriptive statistics (means and standard deviations, or medians and 
inter-quartile ranges) for continuous baseline measures such as current age, age at first 
asthma 
diagnosis, 
pulmonary 
function 
parameters 
including 
methacholine 
hyperresponsiveness, and asthma symptom severity.  We will generate frequency 
tables for categorical baseline measures such as gender, prior medication history, 
atopic status, and genotype. 
Statistical Analysis Plan for the Primary and Secondary Outcomes 
The BARD trial invokes a four-way crossover design. For convenience, the four 
treatment regimens A,B,C, and D are designated as follows for adolescents/adults: 
Run In 1.0xICS 
A = 1.0×ICS/LABA 
B = 2.5×ICS 
C = 2.5×ICS/LABA 
D = 5.0×ICS 
where 1.0×ICS is equivalent to 100 mcg fluticasone propionate BID. 


 47 
 
The four treatment regimens E,F,G, and H are designated as follows for children: 
 
Run In 1.0xICS 
E = 2.0×ICS 
F = 2.0×ICS/LABA 
G = 5.0×ICS 
H = 5.0×ICS/LABA 
where 2.0×ICS is equivalent to 100 mcg fluticasone propionate BID. 
 
Each of the four treatment periods endures for 14 weeks, but the data from the first two 
weeks of each treatment period are not used in the statistical analyses because of the 
lack of wash-out periods in the crossover design. These four sequences yield a 
crossover design that is uniform within periods, uniform within sequences, and balanced 
with respect to first-order carryover effects. 
The primary outcome in the BARD trial is adapted from the CARE Network BADGER 
trial and represents superiority of one treatment regimen compared to another treatment 
regimen using a variable based on a hierarchical determination from three asthma 
outcomes – asthma exacerbations, asthma control days (ACDs), and FEV1. For each 
BARD participant, we will compare any two treatment regimens based on the data from 
the latter 12 weeks of his/her respective treatment periods. The process is described as 
follows for the generic comparison of any two treatment regimens: 
1. If the BARD participant experiences fewer asthma exacerbations on one 
treatment regimen relative to another treatment regimen, then the treatment 
regimen that yields the fewer asthma exacerbations is deemed to be superior to 
the other treatment regimen and the process is terminated. If not, then continue 
to the next step.  
2. If the BARD participant experiences at least 31 fewer annualized ACDs on one 
treatment regimen relative to another treatment regimen, then the treatment 
regimen that yields at least 31 more annualized ACDs is deemed to be superior 
to the other treatment regimen and the process is terminated. If not, then 
continue to the next step. 
3. If the BARD participant displays at least 5 percentage points higher in the 
%predicted FEV1 at the end of the 14-week treatment regimen relative to another 
treatment regimen, then the treatment regimen that yields the higher %predicted 
FEV1 is deemed to be superior to the other treatment regimen. If not, then the 
two treatment regimens are deemed to be “equivalent” or “tied” for that BARD 
participant. 
 
This outcome allows pairwise comparisons of treatment regimens. The following table 
displays the pairwise comparisons of interest for the primary and secondary hypotheses 
in the BARD trial: 
 
 


 48 
 
 
Hypothesis 
 
Age Group 
 
Treatment Regimen Comparison(s) 
 
Primary #1 
 
 
Adolescents/Adults 
 
A versus B; C versus D  
 
Primary #1 
 
 
Children 
 
F versus G 
 
 
 
 
Secondary #1 
 
 
Adolescents/Adults; Children 
 
(A versus B) versus (F versus G); 
(C versus D) versus (F versus G) 
 
 
 
 
Secondary #2 
 
Adolescents/Adults 
 
A versus C; A versus D; B versus C; 
B versus D 
 
Secondary #2 
 
Children 
 
E versus F; E versus G; F versus H;  
G versus H 
 
Secondary #2 
 
Adolescents/Adults; Children 
 
(A versus C) versus (F versus H); 
(B versus D) versus (E versus G) 
 
 
 
 
Exploratory 
 
Adolescents/Adults 
 
characteristics and biomarkers affecting  
A versus B; C versus D 
 
Exploratory 
 
Children 
 
characteristics and biomarkers affecting  
F versus G 
 
Each BARD participant within the ith age group, i = 1 (adolescents/adults) or 2 (children), 
generates a trinary random variable for each pairwise comparison identified in the table 
above. We illustrate this for the jth participant within the adolescents/adults group, in 
which there are six pairwise comparisons of interest (two primary and four secondary): 
 
Y1j,AB = –1, if B is superior to A for the jth participant 
 
 
    0, if A and B are equivalent for the jth participant 
 
 
  +1, if A is superior to B for the jth participant 
 
Y1j,CD = –1, if D is superior to C for the jth participant 
 
 
    0, if C and D are equivalent for the jth participant 
 
 
  +1, if C is superior to D for the jth participant 
 
Y1j,AC = –1, if C is superior to A for the jth participant 
 
 
    0, if A and C are equivalent for the jth participant 
 
 
  +1, if A is superior to C for the jth participant 


 49 
 
Y1j,AD = –1, if D is superior to A for the jth participant 
 
 
    0, if A and D are equivalent for the jth participant 
 
  +1, if A is superior to D for the jth participant 
 
Y1j,BC = –1, if C is superior to B for the jth participant 
 
 
    0, if B and C are equivalent for the jth participant 
 
  +1, if B is superior to C for the jth participant 
 
Y1j,BD = –1, if D is superior to B for the jth participant 
 
 
    0, if B and D are equivalent for the jth participant 
 
 
  +1, if B is superior to D for the jth participant 
 
For the jth participant within the adolescents/adults group, we collect these six trinary 
random variables into a 6 × 1 random vector: 
 
Y1j = [Y1j,AB Y1j,CD Y1j,AC Y1j,AD Y1j,BC Y1j,BD]T 
 
In order to construct the 6 × 1 expectation vector, E(Y1j) = µ1, and the 6 × 6 variance-
covariance matrix Var(Y1j) = Σ1 for the adolescents/adults group, we define the following 
marginal univariate probabilities and marginal bivariate probabilities: 
 
p1,A<B = Pr[Y1j,AB = –1] and p1,A>B = Pr[Y1j,AB = +1] 
with Pr[Y1j,AB = 0] = 1 – p1,A<B – p1,A>B 
 
p1,C<D = Pr[Y1j,CD = –1] and p1,C>D = Pr[Y1j,CD = +1] 
with Pr[Y1j,CD = 0] = 1 – p1,C<D – p1,C>D 
 
p1,A<C = Pr[Y1j,AC = –1] and p1,A>C = Pr[Y1j,AC = +1] 
with Pr[Y1j,AC = 0] = 1 – p1,A<C – p1,A>C 
 
p1,A<D = Pr[Y1j,AD = –1] and p1,A>D = Pr[Y1j,AD = +1] 
with Pr[Y1j,AD = 0] = 1 – p1,A<D – p1,A>D 
 
p1,B<C = Pr[Y1j,BC = –1] and p1,B>C = Pr[Y1j,BC = +1] 
with Pr[Y1j,BC = 0] = 1 – p1,B<C – p1,B>C 
 
p1,B<D = Pr[Y1j,BD = –1] and p1,B>D = Pr[Y1j,BD = +1] 
with Pr[Y1j,BD = 0] = 1 – p1,B<D – p1,B>D 
 
p1,A<B,C<D = Pr[Y1j,AB = –1, Y1j,CD = –1], p1,A<B,C>D = Pr[Y1j,AB = –1, Y1j,CD = +1], 
p1,A>B,C<D = Pr[Y1j,AB = +1, Y1j,CD = –1], p1,A>B,C>D = Pr[Y1j,AB = +1, Y1j,CD = +1] 
 
 
p1,A<B,A<C = Pr[Y1j,AB = –1, Y1j,AC = –1], p1,A<B,A>C = Pr[Y1j,AB = –1, Y1j,AC = +1], 
p1,A>B,A<C = Pr[Y1j,AB = +1, Y1j,AC = –1], p1,A>B,A>C = Pr[Y1j,AB = +1, Y1j,AC = +1] 
 
p1,A<B,A<D = Pr[Y1j,AB = –1, Y1j,AD = –1], p1,A<B,A>D = Pr[Y1j,AB = –1, Y1j,AD = +1], 
p1,A>B,A<D = Pr[Y1j,AB = +1, Y1j,AD = –1], p1,A>B,A>D = Pr[Y1j,AB = +1, Y1j,AD = +1] 
 


 50 
p1,A<B,B<C = Pr[Y1j,AB = –1, Y1j,BC = –1], p1,A<B,B>C = Pr[Y1j,AB = –1, Y1j,BC = +1], 
p1,A>B,B<C = Pr[Y1j,AB = +1, Y1j,BC = –1], p1,A>B,B>C = Pr[Y1j,AB = +1, Y1j,BC = +1] 
 
p1,A<B,B<D = Pr[Y1j,AB = –1, Y1j,BD = –1], p1,A<B,B>D = Pr[Y1j,AB = –1, Y1j,BD = +1], 
p1,A>B,B<D = Pr[Y1j,AB = +1, Y1j,BD = –1], p1,A>B,B>D = Pr[Y1j,AB = +1, Y1j,BD = +1] 
 
 
p1,C<D,A<C = Pr[Y1j,CD = –1, Y1j,AC = –1], p1,C<D,A>C = Pr[Y1j,CD = –1, Y1j,AC = +1], 
p1,C>D,A<C = Pr[Y1j,CD = +1, Y1j,AC = –1], p1,C>D,A>C = Pr[Y1j,CD = +1, Y1j,AC = +1] 
 
p1,C<D,A<D = Pr[Y1j,CD = –1, Y1j,AD = –1], p1,C<D,A>D = Pr[Y1j,CD = –1, Y1j,AD = +1], 
p1,C>D,A<D = Pr[Y1j,CD = +1, Y1j,AD = –1], p1,C>D,A>D = Pr[Y1j,CD = +1, Y1j,AD = +1] 
 
p1,C<D,B<C = Pr[Y1j,CD = –1, Y1j,BC = –1], p1,C<D,B>C = Pr[Y1j,CD = –1, Y1j,BC = +1], 
p1,C>D,B<C = Pr[Y1j,CD = +1, Y1j,BC = –1], p1,C>D,B>C = Pr[Y1j,CD = +1, Y1j,BC = +1] 
 
p1,C<D,B<D = Pr[Y1j,CD = –1, Y1j,BD = –1], p1,C<D,B>D = Pr[Y1j,CD = –1, Y1j,BD = +1], 
p1,C>D,B<D = Pr[Y1j,CD = +1, Y1j,BD = –1], p1,C>D,B>D = Pr[Y1j,CD = +1, Y1j,BD = +1] 
 
p1,A<C,A<D = Pr[Y1j,AC = –1, Y1j,AD = –1], p1,A<C,A>D = Pr[Y1j,AC = –1, Y1j,AD = +1], 
p1,A>C,A<D = Pr[Y1j,AC = +1, Y1j,AD = –1], p1,A>C,A>D = Pr[Y1j,AC = +1, Y1j,AD = +1] 
 
p1,A<C,B<C = Pr[Y1j,AC = –1, Y1j,BC = –1], p1,A<C,B>C = Pr[Y1j,AC = –1, Y1j,BC = +1], 
p1,A>C,B<C = Pr[Y1j,AC = +1, Y1j,BC = –1], p1,A>C,B>C = Pr[Y1j,AC = +1, Y1j,BC = +1] 
 
p1,A<C,B<D = Pr[Y1j,AC = –1, Y1j,BD = –1], p1,A<C,B>D = Pr[Y1j,AC = –1, Y1j,BD = +1], 
p1,A>C,B<D = Pr[Y1j,AC = +1, Y1j,BD = –1], p1,A>C,B>D = Pr[Y1j,AC = +1, Y1j,BD = +1] 
 
p1,A<D,B<C = Pr[Y1j,AD = –1, Y1j,BC = –1], p1,A<D,B>C = Pr[Y1j,AD = –1, Y1j,BC = +1], 
p1,A>D,B<C = Pr[Y1j,AD = +1, Y1j,BC = –1], p1,A>D,B>C = Pr[Y1j,AD = +1, Y1j,BC = +1] 
 
p1,A<D,B<D = Pr[Y1j,AD = –1, Y1j,BD = –1], p1,A<D,B>D = Pr[Y1j,AD = –1, Y1j,BD = +1], 
p1,A>D,B<D = Pr[Y1j,AD = +1, Y1j,BD = –1], p1,A>D,B>D = Pr[Y1j,AD = +1, Y1j,BD = +1] 
 
p1,B<C,B<D = Pr[Y1j,BC = –1, Y1j,BD = –1], p1,B<C,B>D = Pr[Y1j,BC = –1, Y1j,BD = +1], 
p1,B>C,B<D = Pr[Y1j,BC = +1, Y1j,BD = –1], p1,B>C,B>D = Pr[Y1j,BC = +1, Y1j,BD = +1] 
 
Then for the adolescents/adults group, 
 




















=


















=
BD
BD,
1,
BD
BC,
1,
BD
AD,
1,
BD
AC,
1,
BD
CD,
1,
BD
AB,
1,
BD
BC,
1,
BC
BC,
1,
BC
AD,
1,
BC
AC,
1,
BC
CD,
1,
BC
AB,
1,
BD
AD,
1,
BC
AD,
1,
AD
AD,
1,
AD
AC,
1,
AD
CD,
1,
AD
AB,
1,
BD
AC,
1,
BC
AC,
1,
AD
AC,
1,
AC
AC,
1,
AC
CD,
1,
AC
AB,
1,
BD
CD,
1,
BC
CD,
1,
AD
CD,
1,
AC
CD,
1,
CD
CD,
1,
CD
AB,
1,
BD
AB,
1,
BC
AB,
1,
AD
AB,
1,
AC
AB,
1,
CD
AB,
1,
AB
AB,
1,
1
BD
1,
BC
1,
AD
1,
AC
1,
CD
1,
AB
1,
1
 
and
 
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
Σ
μ
μ
μ
μ
μ
μ
μ
 
 
where 
 
µ1,AB = p1,A>B – p1,A<B 


 51 
µ1,CD = p1,C>D – p1,C<D 
µ1,AC = p1,A>C – p1,A<C 
µ1,AD = p1,A>D – p1,A<D 
µ1,BC = p1,B>C – p1,B<C 
µ1,BD = p1,B>D – p1,A<B 
 
σ1,AB,AB = p1,A>B(1 – p1,A>B) + p1,A<B(1 – p1,A<B) + 2p1,A>Bp1,A<B 
σ1,CD,CD = p1,C>D(1 – p1,C>D) + p1,C<D(1 – p1,C<D) + 2p1,C>Dp1,C<D 
σ1,AC,AC = p1,A>C(1 – p1,A>C) + p1,A<C(1 – p1,A<C) + 2p1,A>Cp1,A<C 
σ1,AD,AD = p1,A>D(1 – p1,A>D) + p1,A<D(1 – p1,A<D) + 2p1,A>Dp1,A<D 
σ1,BC,BC = p1,B>C(1 – p1,B>C) + p1,B<C(1 – p1,B<C) + 2p1,B>Cp1,B<C 
σ1,BD,BD = p1,B>D(1 – p1,B>D) + p1,B<D(1 – p1,B<D) + 2p1,B>Dp1,B<D 
 
σ1,AB,CD = (p1,A>B,C>D – p1,A>Bp1,C>D) – (p1,A>B,C<D – p1,A>Bp1,C<D) 
 
 
  – (p1,A<B,C>D – p1,A<Bp1,C>D) + (p1,A<B,C<D – p1,A<Bp1,C<D) 
σ1,AB,AC = (p1,A>B,A>C – p1,A>Bp1,A>C) – (p1,A>B,A<C – p1,A>Bp1,A<C) 
 
 
  – (p1,A<B,A>C – p1,A<Bp1,A>C) + (p1,A<B,A<C – p1,A<Bp1,A<C) 
σ1,AB,AD = (p1,A>B,A>D – p1,A>Bp1,A>D) – (p1,A>B,A<D – p1,A>Bp1,A<D) 
 
  – (p1,A<B,A>D – p1,A<Bp1,A>D) + (p1,A<B,A<D – p1,A<Bp1,A<D) 
σ1,AB,BC = (p1,A>B,B>C – p1,A>Bp1,B>C) – (p1,A>B,B<C – p1,A>Bp1,B<C) 
 
  – (p1,A<B,B>C – p1,A<Bp1,B>C) + (p1,A<B,B<C – p1,A<Bp1,B<C) 
σ1,AB,BD = (p1,A>B,B>D – p1,A>Bp1,B>D) – (p1,A>B,B<D – p1,A>Bp1,B<D) 
 
 
  – (p1,A<B,B>D – p1,A<Bp1,B>D) + (p1,A<B,B<D – p1,A<Bp1,B<D) 
σ1,CD,AC = (p1,C>D,A>C – p1,C>Dp1,A>C) – (p1,C>D,A<C – p1,C>Dp1,A<C) 
 
 
  – (p1,C<D,A>C – p1,C<Dp1,A>C) + (p1,C<D,A<C – p1,C<Dp1,A<C) 
σ1,CD,AD = (p1,C>D,A>D – p1,C>Dp1,A>D) – (p1,C>D,A<D – p1,C>Dp1,A<D) 
 
  – (p1,C<D,A>D – p1,C<Dp1,A>D) + (p1,C<D,A<D – p1,C<Dp1,A<D) 
σ1,CD,BC = (p1,C>D,B>C – p1,C>Dp1,B>C) – (p1,C>D,B<C – p1,C>Dp1,B<C) 
 
  – (p1,C<D,B>C – p1,C<Dp1,B>C) + (p1,C<D,B<C – p1,C<Dp1,B<C) 
σ1,CD,BD = (p1,C>D,B>D – p1,C>Dp1,B>D) – (p1,C>D,B<D – p1,C>Dp1,B<D) 
 
 
  – (p1,C<D,B>D – p1,C<Dp1,B>D) + (p1,C<D,B<D – p1,C<Dp1,B<D) 
σ1,AC,AD = (p1,A>C,A>D – p1,A>Cp1,A>D) – (p1,A>C,A<D – p1,A>Cp1,A<D) 
 
  – (p1,A<C,A>D – p1,A<Cp1,A>D) + (p1,A<C,A<D – p1,A<Cp1,A<D) 
σ1,AC,BC = (p1,A>C,B>C – p1,A>Cp1,B>C) – (p1,A>C,B<C – p1,A>Cp1,B<C) 
 
  – (p1,A<C,B>C – p1,A<Cp1,B>C) + (p1,A<C,B<C – p1,A<Cp1,B<C) 
σ1,AC,BD = (p1,A>C,B>D – p1,A>Cp1,B>D) – (p1,A>C,B<D – p1,A>Cp1,B<D) 
 
 
  – (p1,A<C,B>D – p1,A<Cp1,B>D) + (p1,A<C,B<D – p1,A<Cp1,B<D) 
σ1,AD,BC = (p1,A>D,B>C – p1,A>Dp1,B>C) – (p1,A>D,B<C – p1,A>Dp1,B<C) 
 
 
  – (p1,A<D,B>C – p1,A<Dp1,B>C) + (p1,A<D,B<C – p1,A<Dp1,B<C) 
σ1,AD,BD = (p1,A>D,B>D – p1,A>Dp1,B>D) – (p1,A>D,B<D – p1,A>Dp1,B<D) 
 
 
  – (p1,A<D,B>D – p1,A<Dp1,B>D) + (p1,A<D,B<D – p1,A<Dp1,B<D) 
σ1,BC,BD = (p1,B>C,B>D – p1,B>Cp1,B>D) – (p1,B>C,B<D – p1,B>Cp1,B<D) 
 
 
  – (p1,B<C,B>D – p1,B<Cp1,B>D) + (p1,B<C,B<D – p1,B<Cp1,B<D) 
 
For the children group, we construct a similar set of marginal univariate probabilities and 
marginal bivariate probabilities, although there only are three pairwise comparisons of 
interest listed in the table above. The five pairwise comparisons of interest for the 
children group are F versus G (primary), E versus F (secondary), E versus G 


 52 
(secondary), F versus H (secondary), and G versus H (secondary). This leads to a 5 × 1 
expectation vector, E(Y2j) = µ2, and a 5 × 5 variance-covariance matrix Var(Y2j) = Σ2 for 
the children group.  These are described below. 
 
For the jth participant within the children group, the five pairwise comparisons of interest 
are as follows: 
 
Y2j,FG = –1, if G is superior to F for the jth participant 
 
 
    0, if F and G are equivalent for the jth participant 
 
 
  +1, if F is superior to G for the jth participant 
 
Y2j,EF = –1, if E is superior to F for the jth participant 
 
 
    0, if E and F are equivalent for the jth participant 
 
 
  +1, if E is superior to F for the jth participant 
 
Y2j,EG = –1, if E is superior to G for the jth participant 
 
 
    0, if E and G are equivalent for the jth participant 
 
 
  +1, if E is superior to G for the jth participant 
 
Y2j,FH = –1, if H is superior to F for the jth participant 
 
 
    0, if F and H are equivalent for the jth participant 
 
 
  +1, if F is superior to H for the jth participant 
 
Y2j,GH = –1, if G is superior to H for the jth participant 
 
 
    0, if G and H are equivalent for the jth participant 
 
 
  +1, if G is superior to H for the jth participant 
 
For the jth participant within the children group, we collect these five trinary random 
variables into a 5 × 1 random vector: 
 
Y2j = [Y2j,FG Y2j,EF Y2j,EG Y2j,FH Y2j,GH]T 
 
In order to construct the 5 × 1 expectation vector, E(Y2j) = µ2, and the 5 × 5 variance-
covariance matrix Var(Y2j) = Σ2 for the adolescents/adults group, we define the following 
marginal univariate probabilities and marginal bivariate probabilities: 
 
p2,F<G = Pr[Y2j,FG = –1] and p2,F>G = Pr[Y2j,FG = +1] 
with Pr[Y2j,FG = 0] = 1 – p2,F<G – p2,F>G 
 
p2,E<F = Pr[Y2j,EF = –1] and p2,E>F = Pr[Y2j,EF = +1] 
with Pr[Y2j,EF = 0] = 1 – p2,E<F – p2,E>F 
 
p2,E<G = Pr[Y2j,EG = –1] and p2,E>G = Pr[Y2j,EG = +1] 
with Pr[Y2j,EG = 0] = 1 – p2,E<G – p2,E>G 
 
p2,F<H = Pr[Y2j,FH = –1] and p2,F>H = Pr[Y2j,FH = +1] 
with Pr[Y2j,FH = 0] = 1 – p2,F<H – p2,F>H 
 
p2,G<H = Pr[Y2j,GH = –1] and p2,G>H = Pr[Y2j,GH = +1] 


 53 
with Pr[Y2j,GH = 0] = 1 – p2,G<H – p1,G>H 
 
p2,F<G,E<F = Pr[Y2j,FG = –1, Y2j,EF = –1], p2,F<G,E>F = Pr[Y2j,FG = –1, Y2j,EF = +1], 
p2,F>G,E<F = Pr[Y2j,FG = +1, Y2j,EF = –1], p2,F>G,E>F = Pr[Y2j,FG = +1, Y2j,EF = +1] 
 
p2,F<G,E<G = Pr[Y2j,FG = –1, Y2j,EG = –1], p2,F<G,E>G = Pr[Y2j,FG = –1, Y2j,EG = +1], 
p2,F>G,E<G = Pr[Y2j,FG = +1, Y2j,EG = –1], p2,F>G,E>G = Pr[Y2j,FG = +1, Y2j,EG = +1] 
 
p2,F<G,F<H = Pr[Y2j,FG = –1, Y2j,FH = –1], p2,F<G,F>H = Pr[Y2j,FG = –1, Y2j,FH = +1], 
p2,F>G,F<H = Pr[Y2j,FG = +1, Y2j,FH = –1], p2,F>G,F>H = Pr[Y2j,FG = +1, Y2j,FH = +1] 
 
 
p2,F<G,G<H = Pr[Y2j,FG = –1, Y2j,GH = –1], p2,F<G,G>H = Pr[Y2j,FG = –1, Y2j,GH = +1], 
p2,F>G,G<H = Pr[Y2j,FG = +1, Y2j,GH = –1], p2,F>G,G>H = Pr[Y2j,FG = +1, Y2j,GH = +1] 
 
p2,E<F,E<G = Pr[Y2j,EF = –1, Y2j,EG = –1], p2,E<F,E>G = Pr[Y2j,EF = –1, Y2j,EG = +1], 
p2,E>F,E<G = Pr[Y2j,EF = +1, Y2j,EG = –1], p2,E>F,E>G = Pr[Y2j,EF = +1, Y2j,EG = +1] 
 
p2,E<F,F<H = Pr[Y2j,EF = –1, Y2j,FH = –1], p2,E<F,F>H = Pr[Y2j,EF = –1, Y2j,FH = +1], 
p2,E>F,F<H = Pr[Y2j,EF = +1, Y2j,FH = –1], p2,E>F,F>H = Pr[Y2j,EF = +1, Y2j,FH = +1] 
 
p2,E<F,G<H = Pr[Y2j,EF = –1, Y2j,GH = –1], p2,E<F,G>H = Pr[Y2j,EF = –1, Y2j,GH = +1], 
p2,E>F,G<H = Pr[Y2j,EF = +1, Y2j,GH = –1], p2,E>F,G>H = Pr[Y2j,EF = +1, Y2j,GH = +1] 
 
p2,E<G,F<H = Pr[Y2j,EG = –1, Y2j,FH = –1], p2,E<G,F>H = Pr[Y2j,EG = –1, Y2j,FH = +1], 
p2,E>G,F<H = Pr[Y2j,EG = +1, Y2j,FH = –1], p2,E>G,F>H = Pr[Y2j,EG = +1, Y2j,FH = +1] 
 
p2,E<G,G<H = Pr[Y2j,EG = –1, Y2j,GH = –1], p2,E<G,G>H = Pr[Y2j,EG = –1, Y2j,GH = +1], 
p2,E>G,G<H = Pr[Y2j,EG = +1, Y2j,GH = –1], p2,E>G,G>H = Pr[Y2j,EG = +1, Y2j,GH = +1] 
 
p2,F<H,G<H = Pr[Y2j,FH = –1, Y2j,GH = –1], p2,F<H,G>H = Pr[Y2j,FH = –1, Y2j,GH = +1], 
p2,F>H,G<H = Pr[Y2j,FH = +1, Y2j,GH = –1], p2,F>H,G>H = Pr[Y2j,FH = +1, Y2j,GH = +1] 
 
 
Then for the children group, 
 
















=
















=
GH
GH,
2,
GH
FH,
2,
GH
EG,
2,
GH
EF,
2,
GH
FG,
2,
GH
FH,
2,
FH
FH,
2,
FH
EG,
2,
FH
EF,
2,
FH
FG,
2,
GH
EG,
2,
FH
EG,
2,
EG
EG,
2,
EG
EF,
2,
EG
FG,
2,
GH
EF,
2,
FH
EF,
2,
EG
EF,
2,
EF
EF,
2,
EF
FG,
2,
GH
FG,
2,
FH
FG,
2,
EG
FG,
2,
EF
FG,
2,
FG
FG,
2,
2
GH
2,
FH
2,
EG
2,
EF
2,
FG
2,
2
 
and
 
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
Σ
μ
μ
μ
μ
μ
μ
 
 
where 
 
µ2,FG = p2,F>G – p2,F<G 
µ2,EF = p2,E>F – p2,E<F 
µ2,EG = p2,E>G – p2,E<G 
µ2,FH = p2,F>H – p2,F<H 
µ2,GH = p2,G>H – p2,G<H 
 


 54 
σ2,FG,FG = p2,F>G(1 – p2,F>G) + p2,F<G(1 – p2,F<G) + 2p2,F>Gp2,F<G 
σ2,EF,EF = p2,E>F(1 – p2,E>F) + p2,E<F(1 – p2,E<F) + 2p2,E>Fp2,E<F 
σ2,EG,EG = p2,E>G(1 – p2,E>G) + p2,E<G(1 – p2,E<G) + 2p2,E>Gp2,E<G 
σ2,FH,FH = p2,F>H(1 – p2,F>H) + p2,F<H(1 – p2,F<H) + 2p2,F>Hp2,F<H 
σ2,GH,GH = p2,G>H(1 – p2,G>H) + p2,G<H(1 – p2,G<H) + 2p2,G>Hp2,G<H 
 
σ2,FG,EF = (p2,F>G,E>F – p2,F>Gp2,E>F) – (p2,F>G,E<F – p2,F>Gp2,E<F) 
 
  – (p2,F<G,E>F – p2,F<Gp2,E>F) + (p2,F<G,E<F – p2,F<Gp2,E<F) 
σ2,FG,EG = (p2,F>G,E>G – p2,F>Gp2,E>G) – (p2,F>G,E<G – p2,F>Gp2,E<G) 
 
  – (p2,F<G,E>G – p2,F<Gp2,E>G) + (p2,F<G,E<G – p2,F<Gp2,E<G) 
σ2,FG,FH = (p2,F>G,F>H – p2,F>Gp2,F>H) – (p2,F>G,F<H – p2,F>Gp2,F<H) 
 
 
  – (p2,F<G,F>H – p2,F<Gp2,F>H) + (p2,F<G,F<H – p2,F<Gp2,F<H) 
σ2,FG,GH = (p2,F>G,G>H – p2,F>Gp2,G>H) – (p2,F>G,G<H – p2,F>Gp2,G<H) 
 
 
  – (p2,F<G,G>H – p2,F<Gp2,G>H) + (p2,F<G,G<H – p2,F<Gp2,G<H) 
σ2,EF,EG = (p2,E>F,E>G – p2,E>Fp2,E>G) – (p2,E>F,E<G – p2,E>Fp2,E<G) 
 
  – (p2,E<F,E>G – p2,E<Fp2,E>G) + (p2,E<F,E<G – p2,E<Fp2,E<G) 
σ2,EF,FH = (p2,E>F,F>H – p2,E>Fp2,F>H) – (p2,E>F,F<H – p2,E>Fp2,F<H) 
 
  – (p2,E<F,F>H – p2,E<Fp2,F>H) + (p2,E<F,F<H – p2,E<Fp2,F<H) 
σ2,EF,GH = (p2,E>F,G>H – p2,E>Fp2,G>H) – (p2,E>F,G<H – p2,E>Fp2,G<H) 
 
  – (p2,E<F,G>H – p2,E<Fp2,G>H) + (p2,E<F,G<H – p2,E<Fp2,G<H) 
σ2,EG,FH = (p2,E>G,F>H – p2,E>Gp2,F>H) – (p2,E>G,F<H – p2,E>Gp2,F<H) 
 
  – (p2,E<G,F>H – p2,E<Gp2,F>H) + (p2,E<G,F<H – p2,E<Gp2,F<H) 
σ2,EG,GH = (p2,E>G,G>H – p2,E>Gp2,G>H) – (p2,E>G,G<H – p2,E>Gp2,G<H) 
 
  – (p2,E<G,G>H – p2,E<Gp2,G>H) + (p2,E<G,G<H – p2,E<Gp2,G<H) 
σ2,FH,GH = (p2,F>H,G>H – p2,F>Hp2,G>H) – (p2,F>H,G<H – p2,F>Hp2,G<H) 
 
 
  – (p2,F<H,G>H – p2,F<Hp2,G>H) + (p2,F<H,G<H – p2,F<Hp2,G<H) 
 
 
We will apply maximum likelihood (ML) estimation to arrive at estimates for all of the 
marginal univariate probabilities and marginal bivariate probabilities. If n1 and n2 denote 
the total sample sizes for the adolescents/adults and children, respectively, and if I(x) 
denotes the indicator function (equal to one if the event x is true and zero otherwise), 
then the ML estimates of the marginal univariate probabilities and marginal bivariate 
probabilities for the adolescents/adults groups are of the form 
1)
 Y
1,
(Y
n
1
j
I
n
1
p
 
and
 
1)
(Y
n
1
j
I
n
1
p
CD
1i,
AB
1,
1
1
D
C
B,
A
1,
AB
1,
1
1
B
A
1,
=
=
∑
=
=
=
∑
=
=
>
>
>
ˆ
ˆ
 
Within the adolescents/adults group, there is a one-to-one correspondence between the 
27 marginal univariate and bivariate probabilities and the 27 parameters in the 
expectations, variances, and covariances (µ1 and Σ1). Within the children group, there is 
a one-to-one correspondence between the 20 marginal univariate and bivariate 
probabilities and the 20 parameters in the expectations, variances, and covariances (µ2 
and Σ2). Therefore, the ML estimates for the marginal univariate probabilities and the 
marginal bivariate probabilities lead to ML estimates for the expectation vectors µ1 and 
µ2 and the variance-covariance matrices Σ1 and Σ2, denoted as 
,
Σˆ
Σˆ
μˆ
μˆ
2
1
2
1
,
,
 ,
respectively, by substituting the ML estimates of the probabilities into the expressions 
for the expectation vectors and variance-covariance matrices above. 
 


 55 
The null hypotheses corresponding to the composite outcome are of the form 
 
H0: (C1µ1 + C2µ2) = 0 
 
where C1 is a known c × 6 matrix and C2 is a known c × 5 matrix. The test statistic for 
such a null hypothesis is 
2
c
2
2
1
1
1
T
2
2
2
2
T
1
1
1
1
T
2
2
1
1
2
 ~
 
asymp
 
C
C
C
C
n
1
C
C
n
1
C
C
Q
χ
)
μˆ
μˆ
(
ˆ
ˆ
)
μˆ
μˆ
(
+






Σ
+
Σ
+
=
−
 
although a better distributional approximation is 
ddf
c,
2
F
 ~
/c 
Q
 to account for smaller 
sample sizes, where ddf = (n1 – 6) + (n2 – 5) if both C1 and C2 are nonnull matrices, ddf 
= (n1 – 6) if only C1 is a nonnull matrix, and ddf = (n2 – 5) if only C2 is a nonnull matrix. 
 
For example, the C1 and C2 matrices for primary hypothesis #1 with respect to 
adolescents/adults (see the Table above) are 
 








=
=
0
0
0
0
0
0
0
0
0
0
C
 ,
0
0
0
0
1
0
0
0
0
0
0
1
C
primary1
2,1,
primary1
1,1,
 
 
and we will apply the Q2 statistic at the 0.05 significance level, in which approximately
6
−
1
n
2,
2
F ~
 
/2
Q
. The C1 and C2 matrices for primary hypothesis #1 with respect to children 
(see the Table above) are 
 
 
[
]
[
]
0
0
1
C
 ,
0
0
0
0
C
primary1
2,2,
primary1
1,2,
=
=
 
 
and we will apply the Q2 statistic at the 0.05 significance level, in which approximately
.
3
n
1,
2
2
F ~ 
Q
− 
 
Statistical Analysis Plan for Additional Secondary and Exploratory Hypotheses   
 
We will analyze separately each of three components of the composite outcome as 
secondary outcomes. We will apply a Weibull hazards regression analysis for the time 
to first asthma exacerbation and linear mixed-effects models for the longitudinal data on 
ACDs and FEV1. The linear mixed-effects models will include 
1. fixed effects for treatment regimen, sequence, period, and season of enrollment 
(spring, summer, fall, winter) nested within each of the age groups 
2. a random effect for clinical center partnership within each of the age groups 
3. a 12 × 12 unstructured variance-covariance matrix for the 12 measurements per 
participant within each of the age groups 
The Weibull hazards regression model will include the same set of fixed terms and 
random effects as the linear mixed-effects models, as well as a random effect (frailty) 
for the BARD participant to account for the correlations within the BARD participant (Liu 
2008). 
 
We will apply a similar statistical approach with the linear mixed-effects model for the 
other secondary outcomes that are measured on a continuum, such as diary peak flow 
values and quality-of-life scores. 


 56 
 
Secondary hypothesis #1 and secondary hypothesis #3 both involve comparisons of 
adolescents/adults to children. As indicated in the table above, these comparisons are 
based on (step 1) within-age comparisons of the treatment regimens and then (step 2) 
comparisons of the results from step 1. Such two-step comparisons are constructed via 
the Q2 statistic described above. 
 
With respect to secondary hypothesis #2 (genetic marker effects), we will include the 
genetic markers as regressors in the linear mixed-effects models and a Weibull hazards 
regression model (in addition, see Genetics Analysis below).  With respect to the 
exploratory hypothesis (characteristics and biomarker effects), we will include the 
patient characteristics (atopy, pulmonary function, and methacholine responsiveness) 
and selected biomarkers (sputum eosinophils) as regressors in the linear mixed-effects 
models and the proportional hazards regression model. 
 
Accounting for Family Members 
 
It is very likely that some randomized participants will be members of the same family. 
We anticipate that this clustering could comprise 5-10% of the sample. To account for 
this clustering effect, we will expand the statistical models for the primary and 
secondary outcomes described above. In particular, we will incorporate (1) an additional 
random effect for family membership into the linear mixed-effects models for continuous 
outcomes, (2) a random effect for family membership into a nonlinear mixed-effects 
model for continuous outcomes, and (3) a random effect for family membership into a 
nonlinear mixed-effects Weibull hazards model for time-to-event outcome variables. 
Intention-to-treat analyses 
All of the analyses described above will follow the intention-to-treat paradigm whereby 
all available data from randomized participants are included in the analyses regardless 
of information about deviations from study protocol. 
 
Sensitivity Analyses 
With respect to the composite preference outcome, there may be period effects due to 
the crossover design and there may be seasonal effects due to the staggered entry over 
time for participant enrollment. For example, an exacerbation is more likely to occur 
during the winter months than the summer months for a participant, regardless of the 
respective treatments administered to the participant during the summer and winter 
months. Similar scenarios can be envisioned for asthma symptom and pulmonary 
function outcomes. In this context, expression of the participant’s asthma may not 
remain stable over the seasons even though the underlying disease may not change 
measurably. The permuted blocks within the randomization scheme will alleviate this 
concern to a modest extent, but will not resolve it completely. 
Therefore, as a sensitivity analysis, we will adjust the ACD and FEV1 measurements of 
the composite preference scores for each BARD participant by subtracting off the 
estimates of the fixed effects (sequence, period, and season of enrollment nested within 
each of the age groups) in the linear mixed-effects models described above. We will 
conduct additional sensitivity analyses by constructing the composite preference scores 
using only ACD and FEV1 measurements. 


 57 
There could be some disparity in recruitment numbers across clinical center 
partnerships due to the fact that only Blacks are eligible for BARD. Therefore, we will 
apply sensitivity analyses in the form of meta-analyses across all the clinical center 
partnerships. We will invoke the proportional hazards regression models and the linear 
mixed-effects models described above, except that the random effects for clinical center 
partnerships will be excluded. Instead, we will analyze the data within each clinical 
center partnership separately, and then combine the results across partnership via a 
random-effects meta-analysis model. We will supplement these meta-analyses with 
statistical diagnostics by re-performing the meta-analyses on selected subgroups of 
clinical center partnerships (those with high Black recruitment and those with low Black 
recruitment). 
 
Missing Data 
 
Because of the possibility of drop-outs and other missed visits, there will be some 
missing data. The statistical models and analyses that are planned for the primary and 
secondary outcomes assume that the data are missing-at-random (MAR). Because we 
are applying likelihood-based methods for the data adjustment with the primary 
outcome and for all of the secondary outcomes, MAR data still yield valid estimates. 
Although not expected, if it appears that the MAR assumption is not reasonable, then 
we will invoke shared parameter models to simultaneously model the time to drop-out 
and the individual secondary outcome (Vonesh 2006). 
 
Interim Analyses 
There will be no formal interim analysis of efficacy in this trial. Nevertheless, interim 
statistical analyses to evaluate the safety of the four treatment regimens will be 
presented to the AsthmaNet Data and Safety Monitoring Board (DSMB) semi-annually 
for review. Based on the results of these interim analyses, the DSMB will recommend to 
the NHLBI the continuation or discontinuation of the trial. In addition, the DSMB will be 
monitoring all of the safety data throughout the course of the trial and will be notified 
within 72 hours of any serious adverse event (SAE) that is deemed both unexpected 
and related to the study. All SAEs will be reviewed at each 6-month review.  
D. Statistical Analysis Plan for Genetics 
 
Our primary hypothesis is that in Black asthmatics, those with a better response to 
LABAs will have a lower overall proportion of African ancestry.  As a corollary, we 
hypothesize that those with a better response to ICS will have a higher overall 
proportion of African ancestry. 
 
On an exploratory basis, we hypothesize that the variability in response to the 
treatments will be related to a degree of African ancestry at specific pharmacogenetic 
loci.  
 
Per the clinical protocol, the primary outcome for BARD is a hierarchical asthma 
measure based on exacerbations, asthma control days (ACDs), and FEV1. Based on 
the clinical protocol, for the genetic analysis, the percentage of African ancestry will 
serve as a continuous regressor for the trinary outcome variables, described in Section 
VII.C above, via a trinary logistic regression. Analysis will be similar to Lemanske et al., 


 58 
in which a priori predictors (such as PC20 and FeNO) were tested for association with 
the probability of best response to a particular therapy (Lemanske 2010). 
 
Approach to Determining Genetic Ancestry 
 
Global estimates of African ancestry will be obtained with 1,536 ancestry-informative 
markers to infer population structure within our sample and assign individuals to 
ancestral populations using the program STRUCTURE (Pritchard 2000, Smith 2004, 
HapMap 2003, Hinds 2005). Global estimates of African ancestry will be compared 
between preferential treatment response groups.  
 
We will identify whether whole-genome or global African ancestry is associated with 
preferential responses to LABA and secondarily associated with a preferential response 
to ICS.  To make those determinations we will examine response pairs in which the only 
difference between groups is the drug of interest.  We will use response data from both 
those <12 and >12 year of age.  In each age group we will examine the treatment pairs 
that vary with the drug of interest (e.g. in <12 y.o. for LABA-- 2x ICS vs. 2x ICS + LABA 
or for ICS—2x ICS vs. 5x ICS).  If more than one potential comparison for an age group 
exists we will choose the one in which the greatest preference for that drug is seen. In 
each case, those who “preferred” the treatment of interest will be compared to those 
who preferred the alternative plus those who showed no preference. 
 
Approach to Secondary and Exploratory Genetic Analyses:   
 
We will assess the role of genetic variation on the preferential response to ICS or LABA 
therapy using an analysis of global genetic ancestry, candidate gene analyses, and 
unbiased genome-wide admixture mapping scanning to identify novel loci that 
determine therapeutic responses. 
 
We will perform a candidate gene and an unbiased genome-wide approach using 
admixture mapping scanning throughout the genome to identify specific genomic 
regions or loci where ancestry is associated with treatment response. The approach 
outlined (admixture mapping) is focused on local or regional estimates of ancestry 
rather than global ancestry. In contrast to an analysis of global African genetic ancestry, 
admixture mapping scanning has the potential to identify novel loci with rare or common 
variants that determine treatment response.  
 
We will also assess differential response based on a case/control admixture mapping 
analysis. For this analysis, we define cases as those who respond best to ICS (versus 
those who do not) and those that respond best to LABA combination therapy (versus 
those who do not). We will use admixture mapping to identify chromosomal regions that 
may harbor common and rare genetic predictors of treatment response which will be 
represented by admixture mapping peaks (Figure 4). We will then investigate individual 
genes and variants within these regions. 
 
Next, we will try to identify genomic areas associated with preferential responses to 
LABA and secondarily those associated with a preferential response to ICS.  To make 
those determinations we will also examine response pairs in which the only difference 
between groups is the drug of interest.  We will use response data from both those <12 


 59 
and >12 year of age.  In each age group we will examine the treatment pairs that vary 
with the drug of interest (e.g. in <12 yo for LABA-- 2x ICS vs. 2x ICS + LABA or for 
ICS—2x ICS vs. 5x ICS).  If more than one potential comparison for an age group exists 
we will choose the one in which the greatest preference for that drug is seen. In each 
case, those who “preferred” the treatment of interest will be compared to those who 
preferred the alternative plus those who showed no preference. 
 
The statistical analyses required for admixture-based genetic approaches are primarily 
based on a Markov Chain Carlo-based methodology which can be performed with 
different programs or methods, including the STRUCTURE program, Local Ancestry in 
adMixed Populations 
(LAMP) method, the 
ADMIXTURE program, 
and ANCESTRYMAP 
(Pritchard 2000, 
Patterson 2004, 
Alexander 2009, 
Sankararaman 2008). 
Based on the Wake 
Forest site’s established 
experience in admixture 
mapping studies, 
STRUCTURE will be 
the program primarily 
used to determine both 
global estimates of 
ancestry and 
ANCESTRYMAP will be 
used to determine local 
estimates of ancestry in the BARD cohort. 
 
Since we plan to use the OmniExpress Beadchip platform, we will have whole exome 
coverage that includes 742,000 common and rare genetic variants for detailed regional 
admixture-based methods. Genotyping data from this platform will be used for classic 
case-control candidate gene analyses of loci identified with admixture mapping 
scanning or pre-selected candidate genes of interest.  
 
SNP’s from our exome sequencing project consisting of 191 Blacks in the NHLBI 
Severe Asthma Research Program (SARP) and the NHLBI exome sequencing project 
will complement data from admixture mapping scanning and the OmniExpress 
Beadchip platform. The use of this additional sequencing data is crucial because 
important variants identified with admixture mapping might be in linkage disequilibrium 
with other potentially causative common or rare variants. 
 
Local or regional estimates of ancestry will be obtained with 1,536 ancestry-informative 
markers sufficient for genome-wide coverage based on data sets of ancestry 
informative SNP’s using ANCESTRYMAP (Smith 2004, HapMap 2003, Hinds 2005).   
Genomic regions where ancestry has a statistically significant effect on preferential 
treatment response will be represented by admixture mapping peaks where an 


 60 
increased number of SNP’s from the OmniExpress Beadchip genotyping platform will be 
analyzed for more detailed admixture mapping to identify rare and common variants in 
novel candidate genes (Figure 4). Statistical significance will be set at a 2-tailed p-value 
of < 10-5 based on a conservative Bonferroni correction for multiple comparisons. 
Although we will use a small subset of ancestry-informative markers to minimize the 
number of comparisons in the analysis, this platform does provide the option of 
performing more detailed genome-wide admixture mapping (Torgerson 2012)  
 
Exploratory Analyses:  In the case of our investigation of effect of genetic ancestry on 
specific genomic regions, in order to decrease the issue of multiple testing, we will 
analyze pre-selected candidate genes specific to corticosteroid and beta agonist 
response based on prior studies and those that encode for the glucocorticoid and β2 
adrenergic receptor pathway.  They include ADRβ2, adenyl cyclase type 9 (ADCY9), 
corticotropin-releasing hormone (CRHR1), heat shock organizing protein (STIP1), and 
glucocorticoid-induced transcript 1 (GLCCI1). (Tantisira 2004, 2005, 2011; Israel 2004, 
Hawkins 2009). Genotyping data from these genes will be used to estimate local or 
regional Sub-Saharan African and European ancestry with ANCESTRYMAP. Classic 
candidate gene analyses will also be performed for all of these genes using global and 
regional ancestry as a covariate. Statistical significance will be set at a 2-tailed p-value 
of < 0.05 after correcting for multiple comparisons using a conservative Bonferroni 
correction. 
 
 
Further Exploratory Analyses: 
 
In an exploratory part of this aim, we will test for associations between estimated global 
African ancestry and each individual component of the composite endpoint based on 
treatment responses on measures of exacerbation frequency, asthma control days, and 
FEV1 during each individual arm of the BARD trial. 
 
Also as exploratory, association tests for rare variants (MAF< 5%) will also be 
performed using statistical methods developed for handling of these variants, including 
Fisher’s exact test and collapsing variants within a gene. 
 
E. Power Calculations 
The initial target sample size for the BARD trial was 494 participants (236 Black 
adults/adolescents, 258 Black children).  It was revised to 544 participants (260 Black 
adults/adolescent, 284 Black children) when preliminary estimates of the post-
randomization drop-out rate exceeded 20%.  Details are provided below for the January 
2015 amendment (increase) made to the adult/adolescent sample size and the April 
2015 amendment (increase) made to the pediatric sample size. 
In September 2015, after accruing a significant amount of follow-up data for the 
adult/adolescent group, it appeared that the drop-out rate was in danger of exceeding 
30%. The target sample size for this group was increased further to 291, bringing the 
total sample size for the study to 575. 
 


 61 
The AsthmaNet Steering Committee considers a 20% absolute difference (0.2) in the 
composite preference outcome between any two treatment regimens (that seen in the 
CARE Network BADGER trial and in the ACRN TALC trial) as evidence that one 
treatment regimen is superior to the other treatment regimen and thus to be 
recommended. 
 
With respect to primary hypothesis #1 for adolescents/adults (N=236), a two-sided, 0.05 
significance level test that allows for as much as a 20% withdrawal rate, yields 98% 
statistical power if the difference between treatment regimen A and treatment regimen B 
with respect to the composite outcome of preference is 0.2 and the difference between 
treatment regimen C and treatment regimen D also is 0.2 (µ1,AB = 0.20 and µ1,CD = 0.20). 
There is 81% statistical power in the worst case scenario, which occurs if the difference 
between treatment regimen A and treatment regime B is 0.2 but the difference between 
treatment regimen C and treatment regimen D is 0 (µ1,AB = 0.20 and µ1,CD = 0) within the 
adolescents/adults group. There is 90% statistical power in the anticipated scenario, 
which occurs if the difference between treatment regimen A and treatment regimen B is 
0.2 and the difference between treatment regimen C and treatment regimen D is 0.10 
(µ1,AB = 0.20 and µ1,CD = 0.10) within the adolescents/adults group. The following power 
curve illustrates the range of the statistical power as µ1,AB is fixed at 0.20 and µ1,CD 
ranges from –0.20 to +0.20.  
 
 
With respect to primary hypothesis #1 for children (N=258), a two-sided, 0.05 
significance level test that allows for as much as a 20% withdrawal rate, yields 90% 
statistical power if the difference between treatment regimen F and treatment regimen G 
with respect to the composite outcome of preference is 0.2 (µ2,FG = 0.20). 
 
January 2015 Amendment to Adolescent/Adult Sample Size 


 62 
 
The original target sample size was 236 Black adolescent/adults per the sample size 
calculations with assumptions described above. In January 2015 we became concerned 
that we may be underpowered for our primary analysis in the adolescent/adult group, 
given a higher than expected number of drop-outs early in the follow-up period. At that 
time, 12% of participants (17/142) had dropped out during period 1. Of the participants 
who made it to period 2, 6% (5/82) had dropped out. Assuming slightly lower drop-out 
rates for periods 3 and 4, which could not be projected at that time, we estimated that 
the overall drop-out rate in this age group could be as high as 25%. Original sample 
size calculations were based on a withdrawal rate of 20%.  To ensure that the primary 
analysis will have evaluable data from at least 189 participants to yield adequate power 
for the comparisons of interest, the AsthmaNet Steering Committee requested an 
increase in the adult sample size to 260 randomized participants (an increase of 10% or 
24 participants).  The AsthmaNet DSMB approved this request during their meeting on 
January 23, 2015. 
 
September 2015 Amendment to Adolescent/Adult Sample Size 
 
In September 2015, after monitoring the BARD drop-out rate over several months and 
accruing a significant amount of follow-up data, we became concerned that the actual 
drop-out rate in the older age group could exceed 30%. This was based on estimates of 
completion rates for periods one through four calculated at the time as: 0.88, 0.91 (of 
those who completed period 1), 0.92 (of those who completed period 2), and 0.93 (of 
those who completed period 3), respectively.  These estimates yielded an overall drop-
out rate estimate of 32%. To protect the power of the primary analysis, the AsthmaNet 
Steering Committee requested an increase in the adult sample size to 291 randomized 
participants (a net increase of 22 participants over the 269 that were randomized at the 
time). A sample size of 291 will allow for up to 35% drop out without compromising 
statistical power. We felt that we needed to commit to over-recruiting at that time, in 
conjunction with implementing new approaches to increase retention, in order to bring in 
new participants while the recruitment window remained open within the study and 
Network timelines.  The AsthmaNet DSMB approved our request during their meeting 
on September 10, 2015. 
 
April 2015 Amendment to Pediatric (Age 5-11) Sample Size 
 
The original target sample size was 258 Black children per the sample size calculations 
with assumptions described above. After observing a similar drop-out rate to that of the 
adolescent/adult group and becoming aware of additional participants who appeared to 
be lost to follow-up, we requested an increase in the pediatric sample size to 284 
randomized participants (an increase of 10% or 26 participants).  This request was 
made in conjunction with planning timelines and resources to complete the AsthmaNet 
grant funding period.  Although recruitment in the pediatric group was slower than in the 
adolescent/adult group and it was difficult to estimate the proportion of participants who 
would complete the trial based on available data at the time, we wanted to ensure that 
we had earmarked sufficient resources to complete the study successfully. The 
AsthmaNet DSMB approved this request during their meeting on April 10, 2015. 
 
Sample Size for Genetics Analysis 


 63 
 
Our primary hypothesis is that in Black asthmatics those with a better response to 
LABAs will have a lower overall proportion of African ancestry. 
Secondarily, we hypothesize that those with a better response to ICS will have a higher 
overall proportion of African ancestry. 
On an exploratory basis, we hypothesize that the variability in response to the 
treatments will be related to a degree of African ancestry at specific genetic loci.  
Power Calculation: For our primary question, a sample size of 140 African Americans 
provides 90% statistical power with a 2-sided, 0.05 significance level test, to detect a 
difference of 0.2 in the response at the mean value of the regressor (the percentage of 
Black ancestry) vs. the mean + one standard deviation value of the regressor (response 
to ICS or LABA as described above).   
 
As fewer genetic variants are required for admixture mapping than a typical genome-
wide scan (~1,300 single nucleotide polymorphisms), P<10-5 is accepted as “genome-
wide significant” instead of P<10-8. For this study of 494 African-Americans, assuming 
50% of the trial participants are ICS-superior vs. 50% non-ICS superior, we have 90% 
power to detect a relative of risk of 2.0 at the two-sided 10-5 significance level. 
Based on the Bailey et al. 2008 article (Bailey 2008),which studied the response to 
LABA in patients on ICS,  in which the primary outcome exacerbation rate was 0.45 per 
year for African-Americans treated with combination ICS and LABA and 0.53 per year 
for individuals treated with ICS alone (p=0.169; not significantly different), we estimate 
that approximately 50% of the trial participants will be ICS-superior vs. 50% non-ICS 
superior, according to the hierarchical preference system we are utilizing.   
 
As an example of our specific “allelic” genetic analysis, the GLCCI1 steroid 
pharmacogenetic variant (rs37972) is expected to have the following minor allele 
frequencies (from hapmap.org): 45% in non-Hispanic whites and 14% in Africans with 
29% in African-Americans. For an additive genetic model with a minor allele frequency 
of 20% and a sample size of 494, we have 90% power to detect a relative risk of 1.5 
and with a minor allele frequency of 30%, we have 90% power to detect a relative risk of 
1.4 for a two-sided test with a type I error rate of 0.05. 
 
 
 


 64 
F. Timeline 
We will randomize 575 total Black subjects, 291 adults/adolescents, and 284 children 
(age 5-11). All 18 AsthmaNet centers, both adult and pediatric (5 years and older), will 
be recruiting approximately 32 Black subjects each.  
It is expected to take 24 months to randomize 291 adults/adolescents (32.3 participants 
for each of the nine AsthmaNet adult centers or 1.35 randomized participants per center 
per month).  It is expected to take 24 months to randomize 284 children (32 participants 
for each of the nine pediatric AsthmaNet centers or 1.31 participants per center per 
month).  
Recognizing that some centers are underrepresented by Blacks and others have 
greater access to this population, no restrictions will be set on the maximum number of 
subjects that can be randomized at a particular center. The total time from study 
initiation to last subject completed will include 2 years of recruitment and 1.3 years for 
study participation for a total of 3.3 years. 
G. Anticipated Results 
 
Anticipated Results and Impact in Adults/Adolescents: Based on the published literature 
in self-identified Blacks and data presented above, we expect that we will not be able to 
demonstrate that LABA added to lower dose ICS (1x) will be more effective than 
increased ICS dose (2.5x)(Comparison 1 - Treatment Regimen A versus Treatment 
Regimen B). As a reminder the regimens are as follows:  
Run In= 1.0xICS 
A = 1.0×ICS/LABA 
B = 2.5×ICS 
C = 2.5×ICS/LABA 
D = 5.0×ICS 
In contrast, we anticipate that LABA added to higher dose ICS (2.5x ICS) may be 
superior to further increasing the ICS dose (5x) (Comparison 2 - Treatment Regimen C 
versus Treatment Regimen D).  
There are three main major patterns of outcome that are possible and/or likely:  
# 1) That we cannot demonstrate ICS/LABA superiority in Comparison 1 but we 
can in Comparison 2;  
#2) That we cannot demonstrate superiority in Comparison 1 and 2;  
#3) That we demonstrate superiority in Comparison 1 and 2.   
We discuss the implications of each as follows:  #1)  If we show that adding 
LABA at lower dose ICS is not more effective than increasing the dose of ICS but is 
superior at the higher dose of ICS, our results will have suggested that contrary to 
current guidelines, in Blacks, ICS should be increased before addition of a LABA.  They 
would suggest that once this has been done, adding a LABA would provide additional 
clinical benefit for the outcomes we measure. It would also suggest that Blacks require 
higher doses of ICS for LABA to be effective. Our in vitro studies regarding CS 
sensitivity will be informative in this regard.  #2) If adding LABA to ICS at either dose of 


 65 
ICS is not superior to increased ICS, we will have suggested that Blacks differ from the 
known results in Caucasians at both lower and higher doses of ICS and that the 
difference in response to LABA as compared to Caucasians is not due to a requirement 
for more ICS before LABAs can be effective in Blacks. #3) We will have disproved our 
hypothesis and laid to rest the issue of whether Blacks experience less benefit than 
Caucasians when treated with LABA.    
Outcomes #1 and #2 in Blacks will weigh heavily on reconsideration of the national 
treatment recommendations for Blacks. This is important in view of the disproportionate 
asthma burden borne by Blacks and, in the case of LABAs, the continued concern 
about the potential risk to Blacks from regimens containing a LABA.  
Anticipated Results and Impact in Pediatric Population:  In the pediatric population, we 
will not be able to conduct the same analysis as the adult study except for the 
comparisons of ICS treatment arms. As a reminder the treatment regimens are shown 
as follows: 
Run In:  1.0xICS 
E = 2.0×ICS 
F = 2.0×ICS/LABA 
G = 5.0×ICS 
H = 5.0×ICS/LABA. 
 
Due to previous reports of steroid insensitivity in the Black population reported by 
Federico et al (2005), we anticipate that there will be an incremental increase in 
response with increasing dose of ICS.  Therefore, we should see a higher differential 
response with Treatment G as compared to Treatment E. This may not be the case if 
the maximal response is achieved with Treatment E.  
Based on analysis of the entire population of the BADGER study (Lemanske 2010), one 
might anticipate that the response to ICS/LABA step-up would be greater than to 
increased ICS. However, in the Black subpopulation, the differential response in the 
composite outcome for these two treatments was comparable and greater than low 
dose ICS step-up therapy. 
We have two opportunities to determine whether LABA when added to ICS increases 
the likelihood of a more favorable response when combined with medium and high 
doses of ICS.  Therefore, we will look to compare differential response in Treatment F 
over Treatment E and Treatment H over Treatment G. 
In addition, we can examine the direct comparison of increasing the dose of ICS vs. 
adding the LABA by analyzing Treatments F vs. G.  Based on the studies by Wechsler 
et al, (2011) derived from the Asthma Clinical Research Network and the BADGER 
data, we anticipate that adding LABA to ICS in this population will not be shown to be 
favored by more Black children than increasing the dose of ICS.  Such a result would 
suggest that the treatment guidelines for Blacks need to be modified to focus on 
increased ICS over adding LABA therapy.  This will be especially true, if our data 
concerning HPA axis suppression shows only a minority of subjects experience such an 
effect.   
Unfortunately, we will not be able to compare the results of adding LABA to low dose 


 66 
ICS compared to medium dose ICS as conducted in the adult study due to availability of 
the required formulations. Our study drug provider, GlaxoSmithKline, and many 
investigators in the AsthmaNet Pediatric Investigator group, are reticent to support a 
treatment arm that would utilize ICS and LABA in two separate devices since this would 
be contrary to FDA guidance on the use of these two medications. The FDA guidance 
strongly recommends the combination of ICS/LABA in a single delivery device.  Despite 
this compromise in study design, we still feel that the questions regarding ICS dose-
response and the impact of LABA when added to ICS therapy will be answered and 
provide important information for the national asthma guidelines in managing asthma in 
Black children between the ages of 5 to 11 years.  
Anticipated Results- Pediatric vs. Non- Pediatric Population:  We expect to see similar 
results in children and adolescents/adults.  We will have 98% power to detect whether a 
0.2 preference difference within each comparison between adults and children is 
significant.  We will have significant power to detect differences between 
adolescent/adults and children in their responses to each treatment. This will be one of 
the first times such a comparison can be made and will allow us to understand whether 
the drugs differ in their effectiveness as measured by our outcome between these age 
groups.  
Anticipated Results- Genetic Analysis: Our analysis regarding genetic ancestry will 
allow us to examine whether degrees of genetic African ancestry affect the response to 
LABA or ICS. If, as we suspect, the degree of genetic African ancestry is associated 
with the preference for one treatment escalation over the other, we anticipate that such 
testing would eventually be used to identify and guide treatment decision for individual 
patients.  Since, as we note, genetic admixture is increasing and self-reported labeling 
may become less accurate, the importance of such a tool will increase.    Since the cost 
of such genetic profiling is falling rapidly, if confirmed, such profiling would be used to 
guide treatment escalation in such populations.   
Global ancestry and loci-specific admixture approaches complement each other. Since 
genetic association studies have already shown pharmacogenetic effects for both 
steroids and B2 agonists, we expect our exploratory efforts to identify specific loci that 
associate with differential pharmacologic responses to bear fruit.  This is especially true 
given the increase in power from using admixture–based analytical approaches. Thus, 
there are several outcomes that may be observed. First, a significant effect may be 
observed for only global ancestry which would indicate that there are multiple genes 
involved, each with a small effect. Second, global ancestry analysis may not be 
significant but through admixture mapping, we may identify gene(s) due to local 
ancestry with a stronger effect demonstrating that there are a limited number of 
important genes affecting drug response. Therefore, we expect to identify genes that 
regulate response to corticosteroids or B2 agonists that are differentially important in 
those with more or less African ancestry. This is an important step in personalized 
medicine and individualized therapies in moderate to severe asthma for individuals of 
mixed African/White ancestry. 
It is possible that neither the global ancestry nor the locus specific approaches 
associate with differential pharmacologic responses.  This would suggest that DNA 
sequence modifications may not be the source of this variation and that other post-
sequence event, such as epigenetic modifications, may be determinative.   
 


 67 
H. Exploratory Analyses 
 
Below we outline additional exploratory analyses we wish to undertake.   
 
a) Analyses of baseline phenotype as a predictor of treatment response in Blacks: 
This trial offers a unique opportunity to assess biomarkers that may serve as 
predictors of response to each treatment in Black individuals with asthma across the 
ages. Indeed, there is evidence that there are differences in biomarkers of asthma 
severity among Blacks (Gamble 2011). We will thus take advantage of this study’s large 
patient population of Black adults/adolescents and children to take the opportunity to  
collect blood and sputum samples (in those 12 and older). We are planning to perform 
the following studies that will allow us to do predictive biomarker analyses: i) Induced 
sputum for differential and supernatant (in those 12 years of age and older) ii) CBC with 
differential iii) Blood for future exploratory cytokine/biomarker and genetic analyses (as 
above) iv) IgE and in vitro allergy testing. These samples will be collected and 
processed (or stored for future analysis) to assess whether any may predict 
responsiveness to a given therapy. (See also: XVII.  Phenotyping and special study 
techniques section below.) 
 
While some blood/serum will be stored for study of biomarkers in the future (e.g. 
IL-5 levels and periostin levels and others to be determined in the future as our 
knowledge base expands), blood and sputum eosinophil count will be measured, and 
analyzed in an exploratory manner, to examine the relationship between potential 
biomarkers in the blood and sputum and the differential response to drugs in Blacks 
across the ages.  In particular, the AsthmaNet is interested in the ability of sputum 
eosinophils to predict those who would respond preferentially to ICS vs. a beta-
agonist.  This interest stems from data compiled from ACRN studies (Deykin, 2005) that 
suggested that sputum eosinophils counts could accurately identify those patients that 
require ICS for continued control of their asthma.  A recent unpublished analysis of 
sputum eosinophils across the ACRN studies suggests that sputum eosinophils (in 
patients not on ICS) could identify those patients that have a response to ICS in groups 
of patients who have similar responses to beta-agonists.  Since our group will be on 
ICS, in an exploratory manner, we will investigate whether sputum eosinophil counts in 
patients 
currently 
receiving 
ICS 
therapy 
also 
associate 
with 
corticosteroid 
responsiveness across the ages in Blacks.  Of note, due to concerns about the ability of 
younger children to effectively perform sputum induction, this procedure will only be 
done in those aged 12 and older. 
 
b)  Analyses of multidimensional clinical phenotypes as predictors of treatment, 
by race (cluster analysis):  
 
Clinical phenotypes based on multidimensional composites of clinical characteristics 
and lung function parameters have recently been described in the Severe Asthma 
Research Program (SARP) cohort (Moore 2010). This cohort includes asthma subjects 
of all disease severity and thus, is ideal to explore novel disease phenotypes. Using an 
unsupervised hierarchal agglomerative cluster analysis of subjects >=12 years of age, 
five clinical phenotypes were identified that ranged from milder to more severe asthma. 
The majority of mild to moderate asthma subjects were present in two clusters (1 and 
2). These clusters include 60% of the SARP cohort and are racially diverse (30% self-


 68 
identified Blacks) with elevated measures of atopy and preserved lung function. 40% of 
the subjects in these clusters reported current use of low to medium doses of inhaled 
corticosteroids and 40% report concurrent use of LABAs, yet 30% had sought urgent 
evaluation for an asthma exacerbation in the past year (ED visit, unscheduled MD visit, 
need for oral steroids) indicative of poor asthma control. Thus, these subjects would be 
representative of the subjects to be studied in the proposed protocol.  
 
Preliminary analysis of differences between White and Black subjects within clusters 1 
or 2 (unpublished data, Moore) shows more atopy, lower quality of life scores (by 
Juniper AQLQ) and more health care utilization in the self- identified Black subjects 
despite similar baseline lung function. The frequency of reported LABA use was lower in 
Blacks subjects in cluster 1, while Blacks and Whites in cluster 2 had similar LABA use. 
Comparison of Black and White subjects in the more severe clusters (4, 5) show less 
disparity between these racial groups, suggesting that self-identified race may be more 
important in mild-moderate asthma than more severe disease. The disparity in reported 
LABA use in Blacks as compared to Whites, particularly in cluster 1, raises the question 
of a possible racial difference in drug efficacy, drug adverse effect, pharmacogenetic or 
pharmacoeconomic interactions. 
 
 
The SARP algorithm by which one assigns subjects to clinical cluster phenotypes has 
been refined to include a smaller group of variables identified as most important by 
discriminant analysis. These variables include age of onset, asthma duration, sex, BMI, 
race, baseline and maximal lung function and medication use (steroid dose, other 
controllers). For the proposed exploratory analysis, study subjects would be assigned to 
a cluster phenotype using the refined algorithm; this would require no additional testing 
other than what is in the current protocol. This approach will allow assessment of the 
ability of a multidimensional, MD-friendly composite clinical phenotype to predict 
response to treatments in general, in this Black asthmatic population. 
Participants will also be extensively phenotyped during screening and during post-
randomization visits to assess predictors of response to each treatment; this will be one 
of the largest phenotypic assessments in Black asthmatics.  Phenotyping includes, but 
is not limited to, spirometry, airway hyperresponsiveness if FEV1 > 50% predicted, 
maximum bronchodilator response after 4 puffs albuterol, IgE and presence of atopy; 
extensive questionnaires to capture full patient history, medication history, family 
history, smoking history, exposures, atopic status, presence of co-morbid conditions, 
and number and severity of exacerbations. Sputum supernatant, serum, plasma and 
DNA will also be collected and stored for future predictor analysis as detailed above). 
 
c) Analyses of predictors of responsiveness to different therapies by race based 
on environmental characterization:  
In all subjects, we will characterize the subjects’ home environment to assess whether 
any environmental parameters can predict a differential responsiveness across 
individuals of all ages. For example we will examine the following: smoking exposure 
(by history and through cotinine levels), allergen exposure, perceived stress (Cohen 
1983) and socioeconomic status. These parameters all reflect a subject’s home 
environment and smoking exposure and may relate to responsiveness to a specific 
therapy. An ancillary protocol based on Geographic Information Systems analysis 
(GIS)-based information is also planned. 
 


 69 
d) Pharmacoeconomic analyses 
We will do pharmacoeconomic analyses similar to what we performed for the PACT 
study, conducted by the CARE Network (Wang 2011).  
 
Cost effectiveness analysis (CEA) compares the effectiveness of different treatments 
relative to their costs. For example, suppose that increased ICS add-on has better 
effectiveness than LABA add-on; if it also has lower cost than LABA add-on, then ICS 
add-on is said to dominate LABA add-on. However, if treatment with ICS add-on is not 
the dominant strategy, e.g., ICS add-on has better effectiveness and higher cost than 
LABA add-on, then the choice decision can be made by comparing a decision maker’s 
willingness to pay (WTP) for one unit of effect using the incremental cost-effectiveness 
ratio (ICER). ICER measures the additional cost for one additional unit of effect, i.e., 
ICER=Δcost/Δeffect, where Δ stands for difference between the two candidate 
therapies. The units for the ‘effect’ term reflect the outcome of interest, for example, 
ACD or number of exacerbations.  If WTP is greater than ICER, then one is willing to 
pay the additional cost of LABA add-on in order to gain its additional effect, and LABA 
add-on is cost-effective.   
 
Both direct costs from a third-party payer’s perspective and societal costs from a 
societal perspective will be assessed. Payer costs will be standardized across sites 
using 
microcosting 
methods 
including 
unit 
costs 
for 
rescue 
medications, 
hospitalizations, emergency department visits and unscheduled visit physician 
costs.  Societal costs will be the value of lost productivity from missed school or work 
estimated by the Human Capital approach. The drug costs will be calculated as the 
average wholesale prices from the Drug Topics Red Book.   Deterministic models will 
be used to estimate the ICER for the various treatment comparison and effectiveness 
outcome combinations.  A probabilistic approach to account for sampling uncertainty will 
be conducted by nonparametric bootstrap. The 95% confidence interval for an estimate 
of the ICER will be defined by the 2.5% percentile through the 97.5% percentile of the 
corresponding values from all bootstrapped samples.  
 
 
 


 70 
XIV. 
DRUG SUPPLIES  
During the run-in phase, participants will be given low dose inhaled corticosteroids 
(1xICS). Medications will consist of open-label inhaled corticosteroid fluticasone 
propionate 100 mcg BID (i.e., Flovent Diskus, GlaxoSmithKline) for individuals 12 
years old and above and fluticasone propionate 50 mcg BID (Flovent Diskus®, 
GlaxoSmithKline) for children age 5-11.  
Individuals requiring a 2 step step-down process to achieve the low dose will be put on 
2-2.5xICS for the first 2 weeks of the run-in order to assure that their asthma is stable 
prior to stepping them down to 1xICS. Individuals 12 years old and above who require 2 
step step-down therapy will be given open-label fluticasone propionate 250 mcg BID 
(2.5xICS) (Flovent Diskus®, GlaxoSmithKline). Children aged 5-11 who require 2 step 
step-down therapy will be given open-label fluticasone propionate 100 mcg BID (2xICS) 
(Flovent Diskus®, GlaxoSmithKline).  
During the treatment periods, in adults and adolescents, we will use masked, double-
blind Diskus® preparations of fluticasone propionate ICS monotherapy (Flovent Diskus® 
250, 500 mcg) and fluticasone/salmeterol ICS/LABA combination medications (Advair 
Diskus® 100/50, 250/50 mcg). During the treatment periods, in children age 5-11, we 
will use masked, double-blind Diskus® preparations of fluticasone propionate ICS 
monotherapy (Flovent Diskus® 100, 250 mcg) and fluticasone/salmeterol ICS/LABA 
combination medications (Advair Diskus® 100/50, 250/50 mcg). All run-in and treatment 
period ICS and ICS/LABA medications will be supplied by GlaxoSmithKline. 
Individuals who experience an exacerbation near the end of a treatment period or who 
qualify as having had a treatment failure during a treatment period (see Section XX.A) 
will receive open-label 5xICS for 2-3 weeks following their last dose of oral or parenteral 
corticosteroids, prior to starting the next double-blind treatment period. For individuals 
12 years old and above, treatment will be open-label fluticasone propionate 500 mcg 
BID. For children aged 5-11, treatment will be open-label fluticasone propionate 250 
mcg BID. 
We will use albuterol MDI and prednisone (5 day course, see Section XX.E) for rescue.  
The following table lists the allocation of the drug supplies during the run-in phase 
(1xICS) and each of the four treatment periods. 
 
 
Age 12 and 
above 
Open-
Label  
Run-In 
Phase 
 
Double-Blind Treatment Phase 
 
2.5x 
ICS 
1x ICS + 
LABA 
5x ICS 
2.5x ICS + 
LABA 
AM (1 puff) 
Diskus® 
Fluticasone 
100 mcg  
Diskus® 
Fluticasone 
250 mcg 
Advair 
Diskus® 
100/50 mcg 
Diskus® 
Fluticasone 
500 mcg 
Advair Diskus® 
250/50 mcg 
PM (1 puff) 
Diskus® 
Fluticasone 
100 mcg  
Diskus® 
Fluticasone 
250 mcg  
Advair 
Diskus® 
100/50 mcg 
Diskus® 
Fluticasone 
500 mcg 
Advair Diskus® 
250/50 mcg 
 
 


 71 
 
Age 5-11 
Open-
Label 
Run-In 
Phase 
Double-Blind Treatment Phase 
 
2x 
ICS 
2x ICS + 
LABA 
5x ICS 
5x ICS + 
LABA 
AM  (1 puff) 
Diskus® 
Fluticasone 
50 mcg  
Diskus®  
Fluticasone 
100 mcg   
Advair 
Diskus® 
100/50 mcg 
Diskus®  
Fluticasone 
250 mcg   
Advair Diskus® 
250/50 mcg 
PM (1 puff) 
Diskus® 
Fluticasone 
50 mcg   
Diskus®  
Fluticasone 
100 mcg   
Advair 
Diskus® 
100/50 mcg 
Diskus®  
Fluticasone 
250 mcg   
Advair Diskus® 
250/50 mcg 
 
 
XV. 
ADHERENCE AND MONITORING  
The following mechanisms will be employed to determine adherence and measure 
outcomes: 
1. The Spirotel® electronic peak flow meter/e-diary device will be used to measure 
peak expiratory flows (PEF) and will serve as a general adherence check (date 
and time are electronically recorded). Electronic measurements will be 
downloaded at each study visit and a compliance report will be reviewed with the 
participants. AsthmaNet coordinators will provide positive feedback to 
participants who demonstrate good adherence, and ongoing encouragement 
when warranted. 
2.  Medications: The AsthmaNet Network has explored various published methods of 
assessing adherence to asthma treatment, including pharmacy records, canister 
weights, self-report, and electronic devices attached to metered dose inhalers.  
No single adherence measure is currently deemed to provide complete accuracy.  
Self-report accuracy is enhanced if the participant or parent is asked to report on 
medication use in the daily e-diary within the previous 24-hour period, rather than 
asked to provide a global characterization of adherence. This approach will be 
employed in BARD. In addition, Diskus® counter information will be recorded 
from visit to visit. 
XVI. 
INHALATION TECHNIQUES  
To minimize the variability in the dose of both the ICS and LABA delivered to the lungs, 
the participant’s inhalation technique will be reviewed at each study visit. Objective 
feedback 
will 
be 
given 
to 
each 
participant 
to 
improve 
performance.  
 
XVII. 
PHENOTYPING AND SPECIAL STUDY TECHNIQUES  
Participants will be extensively phenotyped during screening and during the post-
randomization visits to assess predictors of response to each treatment. Phenotyping 
includes, but is not limited to, spirometry, airway hyperresponsiveness (if participant 


 72 
meets safety requirements for methacholine challenge), bronchodilator response after 4 
puffs albuterol, extensive questionnaires to capture full participant history, medication 
history, family history, smoking history, exposures, atopic status, presence of co-morbid 
conditions, and number and severity of exacerbations. Urine, sputum supernatant, 
serum, plasma and DNA will also be collected and will be stored for future predictor 
analysis (see above analyses). 
1. Bronchodilator reversibility – The bronchodilator reversibility procedure is 
detailed in the AsthmaNet Spirometry Manual of Operations and will include 4 
puffs of albuterol. 
 
2. Methacholine bronchoprovocation – The methacholine bronchoprovocation 
procedure is detailed in the AsthmaNet Methacholine Challenge Manual of 
Operations. 
 
3. ImmunoCAP – ImmunoCAP testing of standard allergens will be performed at 
Visit 1 including at a minimum: rat, grass mix, tree mix, weed mix, mite mix, 
cockroach mix, mouse, penicillium/alternaria/aspergillus/cladosporium (mold 
mix), cat, dog.  
 4. Genetics analysis (See Section XIII.D)– Blood will be obtained at the study site 
from the participant and shipped to the AsthmaNet Genetics Lab in Tucson, AZ 
for DNA extraction and storage according to AsthmaNet procedures. DNA will be 
prepared and shipped the laboratory of Dr. Eugene Bleecker at the Wake Forest 
site for study analysis. This will be limited to genetics analysis related to drug 
response, drug metabolism, allergy, asthma and inflammation. In addition, we will 
use genetic ancestry to conduct secondary analyses of participant responses to 
medications based on genetic ancestry.  Although ancestry may be estimated 
using Ancestry Informative Markers (AIMs), it is becoming more effective to 
perform a GWAS and use the SNP data for calculating % African versus % 
European Caucasian.  
Thus, using GWAS data and/or AIMs, analyses will be performed in three areas: 
1) Percent predicted lung function will be recalculated using estimates of 
individual geographical ancestry (Kumar et al, NEJM 2010) and lung function 
analyses (that are already specified) will be repeated, 2) Individual estimates of 
geographical ancestry will be calculated for use as a covariate in analyses of the 
clinical endpoints, 3) local ancestry for the chromosomal region on 5q 
surrounding ADRB2 will be calculated for use as a covariate in analyses of the 
clinical endpoints. With GWAS data available on this African-American cohort, 
we will examine quantitative as well as qualitative response parameters. Specific 
biologic pathways related to pharmacogenetics of the two therapies (beta 
agonists, and corticosteroids) will be evaluated to determine whether 
pharmacologic responses in this protocol are associated with genetic variation. 
These results can be compared to the GWAS analyses being performed in the 
ACRN TALC and BASALT studies to determine differences form non-Hispanic 
whites in an exploratory manner. Finally, specific phenotypes (clusters) and 
genetic subgroups will be identified to determine their interaction with therapeutic 
responses in African-Americans. 
 
5. Blood, urine, and sputum samples – Blood (including serum), urine, and sputum 
will be collected and stored for future analyses of biomarkers in these specimens 


 73 
that are considered directly relevant to asthma and allergies.  This will also 
provide a means to assess whether certain asthma and allergy genes have the 
potential of increasing or decreasing proteins in these compartments to gain new 
insights into pathophysiologic mechanisms underlying these diseases. For 
example, sputum eosinophils in those 12 and above will be measured, as these 
have been shown to predict asthma control in the context of inhaled 
corticosteroid use (Deykin 2005). Cotinine levels will also be measured to assess 
smoking exposure.  
 
Sputum induction. Sputum induction is a relatively simple, repeatable and 
noninvasive method of collecting airway secretions. Cellular and biochemical 
analyses of induced sputum samples collected from asthmatic and non-asthmatic 
subjects have revealed differences in markers of eosinophilic inflammation and 
bronchovascular permeability in an asthmatic population. Induced sputum will be 
collected at Visit 1 following inhalation of hypertonic saline according to the 
AsthmaNet Sputum Induction MOP. Sputum total and differential cell counts will 
be counted by a central reader at the San Francisco adult site. Cell free 
supernatant and cell pellets will be frozen and stored for future analysis. Sputum 
induction for asthma is increasingly used as a way to predict response to therapy 
and define individuals as eosinophilic/noneosinophilic. This is particularly 
important in this population. Each participant will perform one sputum induction at 
baseline to assess whether sputum indices can predict response in Blacks. Of 
note, as sputum induction cannot be done reliably in children down to age 5-6, 
this procedure will be performed only in individuals at least 12 years of age. 
 
 
XVIII. 
SAFETY ASSESSMENTS  
 
Assessment of systemic exposure/activity to inhaled corticosteroids (ICSs) 
Due to the escalating doses of ICS to be used in this trial, along with limited data 
available on the dose-response relationship between escalating ICS dosing and HPA 
axis function in children and adults, and the use of high doses of ICS as defined by the 
NAEPP Guidelines, we will assess the potential for systemic effects on HPA axis 
function. We have chosen overnight urinary cortisol/creatinine (OUCC) as the measure 
of systemic exposure in all participants, along with linear growth by stadiometry in 
children 5-17 years of age. This choice resulted from extensive review of the literature 
and consultation with David Allen MD, an endocrinologist at the University of Wisconsin 
who has written extensively about systemic effects of ICSs (Allen 2003, Allen 2004, 
Allen 2005, Allen 2007, Bernstein and Allen 2007), as well as being a consultant to the 
Food and Drug Administration (FDA). We feel the OUCC provides minimal 
invasiveness, particularly in children, and sufficient sensitivity for detecting systemic 
activity in adults and children. It is also more convenient than the 24 hour urine 
collection or overnight plasma cortisol sampling. 
Choice of OUCC for HPA-axis effect. Available measures of the hypothalamic-
pituitary-adrenal (HPA) axis include the insulin tolerance test, metyrapone test, standard 
and low-dose cosyntropin stimulation, and measures of basal cortisol secretion 


 74 
including morning cortisol concentration, 24-hour plasma area under the curve (AUC) 
cortisol concentration, 24-hour urinary free cortisol (UFC), OUCC, and salivary cortisol 
concentrations.  
The pros and cons of each of these tests for assessing systemic activity of ICSs have 
been extensively reviewed (Bernstein and Allen 2007, Kelly 2003, Krasner 1999, 
Oelkers 1996, Zollner 2007) but will be briefly discussed here to establish our selection 
rationale. While the insulin tolerance test and metyrapone test are considered the “gold 
standards” for assessing clinically relevant adrenal insufficiency as they test the entire 
HPA axis, they require hospitalization and can cause significant adverse effects 
(Oelkers 1996, Krasner). Thus, the high dose (250 mcg) cosyntropin stimulation test 
has been used as the standard stimulation test for assessing HPA axis function 
secondary to systemic corticosteroid and ICS exposure by the FDA and the medical 
community. Due to the supraphysiologic dose delivered, this test produces some false 
negatives and has been criticized for missing adrenal suppression (Oelkers 1996, Allen 
2007).  
Therefore, the low-dose (0.5 mcg/m2 or 1 mcg) cosyntropin test has been developed. 
The low dose test has been shown to be a sensitive test for detecting low levels of 
adrenal suppression and correlates well with the insulin tolerance test, but it is not clear 
whether the increased sensitivity is picking up clinically relevant suppression that 
predicts adrenal insufficiency (Allen 2007, Kelly 2003, Zollner 2007). In addition, there 
are no normative data in children for this test and it requires careful dilution for 
preparing and intravenous access. 
The standard test for basal cortisol excretion (morning cortisol) has been shown to be 
insensitive to low levels of adrenal suppression with high variability due to the diurnal 
variation of cortisol secretion (Krasner 1999, Oelkers 1996). Thus, the 24-hr AUC and 
24-hr UFC were developed to obviate the diurnal variation problem. The 24-hr UFC has 
demonstrated consistency with the low dose cosyntropin test for detecting low levels of 
adrenal function (Broide 1995). Both of these tests are highly sensitive to systemic 
corticosteroid exposure and allow dose-response comparisons within an ICS molecule 
as well as direct comparisons between various delivery devices and/or ICS molecules 
(Martin 2002, Nielsen 2000). They have been recommended as a means of comparing 
relative bioavailability/systemic activity between various ICS preparations and the FDA 
accepts 24-hour UFC for this purpose (Allen 2007, Zollner 2007). However, both 24-hr 
collections require overnight hospitalizations to permit observed collections and would, 
therefore, increase the expense and patient burden in large clinical trials. Also, they do 
not project clinical risk for meaningful adverse effects on bone density, linear growth 
and cataracts. 
Choice of OUCC for systemic activity. Two studies suggest that OUCC is as 
sensitive as 24-hr AUC and 24-hr UFC (McIntyre 1995, Wilson and Lipworth 
1999;54:20). The initial study compared OUCC to 24-hr UFC and AM serum cortisol in 
12 healthy volunteers given 800 and 2000 mcg/day of BDP by MDI; however, there was 
a lot of scatter to both measures. Wilson and Lipworth then looked at 12 moderately 
severe asthmatics in a crossover study comparing 24-hr AUC to OUCC and 24-hr UFC 
for triamcinolone acetonide 1600 mcg/day and FP 1760 mcg/day by CFC-MDI. Although 
the 24-UFC looked a little more sensitive, it actually had a wider confidence interval. 
The ACRN used this data to perform 24-hr AUC, 24-hr UFC and OUCC with about 23-


 75 
25 patients/drug tested in a parallel escalating dose-response and only found consistent 
dose-response with the 24-hr AUC and more inconsistent results with 24-UFC and 
OUCC due to the lesser variability of the former (Martin 2002). However, others have 
found it sufficiently sensitive to detect dose-response differences between 1000 and 
2000 mcg/day of FP by DPI (Fardon 2004).  Raissy and colleagues (2006) 
demonstrated that correcting UFC for creatinine provided an index that is independent 
of age and weight in healthy children (N=64) and children with mild asthma (N=36) 6-16 
years old. The clinical pharmacology group from the University of Dundee has used 
OUCC in excess of 20 trials over the past 12 years that have compared different ICS 
molecules and delivery devices and have demonstrated the ability of OUCC to 
differentiate between potency and devices when the ICSs are delivered in high doses 
(Lipworth 1999, Lipworth 2001). 
Expected findings: As we are proposing to use FP and the combination by dry-powder 
inhalers (DPIs) in maximum doses of 1000 mcg/day in adolescents and adults and 500 
mcg/day in children, 5 to 11 years, we expect to see that some patients (approximately 
20-30%) will have mild HPA-axis suppression, on the average of a 5-20% decrease in 
OUCC. The ACRN study with FP-DPI (via Diskhaler) showed only 10% suppression of 
24 hr cortisol AUC at 800 mcg/day with a median dose and 95% confidence interval of 
445 mcg/day (0-918 mcg/day) (Martin 2002). The GOAL study (Bateman 2004) using 
FP-DPI up to 1000 mcg/day for as little as 12 weeks and as much as 40 weeks found 
no significant suppression of OUCC in 166 patients in the high dose range. At the end 
of the study there were 15 patients who had values below the lower limit of normal, but 
there were also 12 patients who had values below the normal range at baseline who 
corrected to normal after receiving FP.  
In a randomized parallel trial comparing the therapeutic index of budesonide and FP 
DPIs at medium to high doses in 66 patients with asthma, 1000 mcg/day for 2 weeks of 
FP produced a 4% decline in 24-hr UFC compared to baseline and a 30% decline at 
2000 mcg/day for 2 weeks (Nielsen and Dahl 2000).  In 21 adult patients comparing 
mometasone furoate and FP by DPIs, 1000 mcg/day for 2 weeks FP produced a 28% 
reduction in OUCC compared to a 45% reduction for 2000 mcg/day for 2 weeks (Fardon 
2004).   
In children, a study of fifty-five 6-10 year-olds with asthma treated with FP-DPI 500 and 
1000 mcg/day for 2 months each demonstrated a 11% reduction of 24-hr UFC with the 
500 mcg/day dose and 24% reduction with 1000 mcg/day (Visser 2004). Kannisto 
(2000) reported that only 5 of 30 5-14 year olds had mild suppression by low dose 
cosyntropin stimulation receiving a dose of FP-DPI 500 mcg/day. Verona (2003), in an 
open label 52 week study of 528 4-11 year olds given FP-DPI at doses of 200 and 400 
mcg/day, reported unchanged to slightly increased OUCC at 16 and 52 weeks at the 
400 mcg/day dose.  
Finally, GSK is performing the FDA mandated LABA safety studies (available at 
clinicaltrials.gov) with doses of FP up to 500 mcg/day in 6000 5-11 year old children and 
dose up to 1000 mcg/day in 11,000 adult subjects (the FDA has reviewed the studies). 
Interestingly, function of the HPA axis is not being measured in these trials due to the 
fact that FDA review of the existing data was not compelling enough for this safety data 
to be mandated in the trials. 


 76 
As a result of both our review and FDA opinion of these data, we feel there is sufficient 
data to support that the proposed low doses of ICS during the run-in period for both 
children and adults will not produce any clinically significant effects on HPA axis 
function and, moreover, that these doses will not interfere with our ability to detect 
significant effects with the high-dose regimens that will be used following randomization 
(Martin 2002, Fardon 2004, Kannisto 2000, Lipworth 2001, Nielsen 2000, Masoli 2004, 
Verona 2003, Visser 2004). 
Linear growth will be used in children 5-17 as an additional measure of systemic activity 
as it is provides additional insight regarding systemic effects of ICS that may not be 
seen with an evaluation of the HPA axis alone and occurs at lower doses of ICSs than 
those required to produce HPA-axis suppression (Ferguson 2007, Kelly 2003, CAMP 
2000, Visser 2004). As with the HPA-axis suppression data, there exists ample 
evidence that the 100 mcg/day run-in dose in children 5 to 11 years, and 200 mcg/day 
in adolescents, will not have an effect on growth velocity (Allen 1998, Ferguson 2007, 
Price 1997, Visser 2004).     
 
XIX. 
RISK/BENEFITS IN ADULTS/CHILDREN  
Although both adults and children enrolled into this protocol will need to demonstrate 
lack of control at the time of randomization, all will receive some form of adjunctive 
therapy once they enter the treatment phase of the trial (i.e. no participant will receive 
either placebo or experimental therapy that has not yet been proven to be efficacious in 
asthma) and all participants will be closely monitored throughout.  
In a previously published BADGER trial (Lemanske), both increasing the dose of ICS 
and keeping the dose the same and adding LABA were found to produce a differential 
treatment response in favor of that form of step-up in children. LABA step-up was found 
to be significantly more frequent as being the best choice. Thus, in at least two of the 
four treatment phases of this trial, children are likely to receive a form of therapy that will 
produce the best differential treatment response using a similar composite outcome 
measure to the one that was used in the BADGER trial.  
In adults, all four add-on options have shown some efficacy. Increasing dose of ICS is 
currently the FDA’s recommended add-on therapy. However, as outlined in the 
background, increasing ICS dose appears to be less effective than adding LABA (TALC, 
Peters 2010). Nonetheless, there are potential risks of these therapies as well, and it 
has been advocated that quadrupling corticosteroid dose is more effective than doubling 
ICS dosing in maintaining asthma control (Pauwels 1997, Oborne 2009). Whether these 
therapies are equally effective in Blacks remains unclear and remains one of the major 
goals of this study. In either circumstance, individuals who participate in this trial will be 
closely monitored and will be treated for worsening asthma should that occur.  
 
 
 
 
 


 77 
A. Medication Risks: 
 
a.) LABA Risks 
The proposed study is a comparison of the effect of adding a long-acting beta-agonist 
(LABA) to the effect of increasing the dose of ICS in patients with asthma. There 
remains some controversy surrounding the use of LABA in the treatment of asthma. The 
SMART study suggested that there may be a risk of life threatening events in patients 
treated with salmeterol, particularly in Blacks (Nelson, 2006). Nonetheless, treatment 
with a LABA and an inhaled corticosteroid continues to be an accepted part of treatment 
for asthma of moderate severity. Newly revised national asthma treatment guidelines 
continue to approve and advocate for this treatment in patients not well controlled on 
single agent therapy (NAEPP, 2007). For the majority of patients, the decision to use a 
LABA for treatment will have already been made by the treating physician and thus 
participation will not result in patient exposure to a LABA for the sake of the study. In 
addition, the SMART study suggested that the risk of LABA treatment might be 
diminished by the concomitant use of inhaled corticosteroids. All patients in this study 
will be receiving concomitant inhaled corticosteroids and we will reinforce the 
importance of the use of both agents. 
 
The SMART study (Nelson 2006) further suggested that using the LABA, salmeterol, 
was associated with a small increase in the risk of fatal and severe life-threatening 
asthma attacks (1 in 10,000). Although the SMART study did not find a statistically 
significant increase in the risk of these severe attacks when salmeterol and inhaled 
corticosteroids were used together, the study results could not exclude the possibility 
that an increase in severe attacks may occur even when salmeterol is used with an 
inhaled corticosteroid. No LABA will ever be taken alone in this study; it will be taken 
with an inhaled corticosteroid. Furthermore, in the SMART study, the patients did not do 
any home monitoring and did not have any return visits to the clinic. In this study, 
asthma symptoms will be monitored daily in the e-diary, by visits to the clinic, as well as 
by calls to the performance site as needed should safety concerns arise. Medications 
and instructions will be given by study physicians or the patient’s primary care 
physicians in case of asthma worsening, so that any attack may be treated promptly. 
 
Other side effects of long-acting beta-agonists (LABA) include tremors, nervousness, 
rapid heart rate, headaches, dizziness, lightheadedness, sweating, nausea, and less 
frequently, insomnia, chest pain, and irregular heartbeat. This study hopes to find out if 
taking this class of medication makes some people’s asthma worse because of race or 
because of one’s genetic makeup. In this study, the LABA is used in combination with 
an inhaled corticosteroid, a controller medication. LABAs have also been used alone to 
treat asthma. Studies that we have performed, as well as those performed by others, 
suggest that LABAs should not be used without a controller medication, because, when 
used alone, they do not protect well against asthma attacks (Lazarus 2001; Lemanske 
2001). 
 
b.) Inhaled Corticosteroids Risks 
All participants will have been on inhaled corticosteroids prior to enrollment in the study. 
Corticosteroid dosing will be increased in most treatment regimens for this study. 
Nonetheless, participants will be informed that when taken at high doses for extended 
periods, inhaled corticosteroids can produce hoarseness, sore throat, and thrush, as 
well as cause adrenal gland suppression, weight gain, bruising of the skin, and 


 78 
diabetes. These side effects are not anticipated in our studies because of the doses we 
propose using and the duration of the study. Inhaled corticosteroids have also been 
associated with reduced growth velocity in children; height will be monitored throughout 
the clinical trial, as will urine cortisol. 
 
B. Risks and Benefits of Study Procedures: 
 
a) Venipuncture 
Blood samples will be obtained by venipuncture of an antecubital vein to determine 
blood counts, total and specific IgE, cotinine levels, and for DNA extraction for future 
genotyping studies and ancestry characterization. 
 
Risks: The risks of venipuncture are minimal. The possible risks include bruising and/or 
infection at the site of the venipuncture and vasovagal episodes experienced by the 
blood donors. Pressure will be applied to the venipuncture site to prevent bruising. 
Aseptic technique will be used to prevent infection. Blood will be obtained while the 
donors are in a seated position and medical and nursing personnel will be available at 
the study sites to treat and manage vasovagal episodes. 
 
Benefits: The DNA isolated for future genotyping studies will provide important insight 
into potential genetic modifiers of responses to each of the studied therapies. 
Measurement of IgE, allergen-specific IgE (ImmunoCAP®) and blood counts will allow 
for better participant characterization and an assessment of whether these factors can 
predict responsiveness to a given therapy. 
 
The potential benefits justify the potential risks. 
 
a) Pulmonary Function Testing (spirometry) 
Spirometry will be performed to determine the participants’ pulmonary function.  
 
Risks: The risks of spirometry are minimal. The possible risks include precipitation of 
bronchospasm and light-headedness from repeated blowing attempts. Medical and 
nursing personnel and medications will be available at the study sites to treat and 
manage bronchospasm. Inhalation of a short-acting beta-2 adrenergic agonist (such as 
albuterol) will be used to assess reversibility at some visits. The possible risks of inhaled 
beta-2 adrenergic agonists include tachycardia and hand tremors. These side effects 
are non-life threatening and are short-lived. 
 
Benefits: Spirometry with assessment of reversibility to a short-acting beta-2 adrenergic 
agonist will be used to determine if the participants meet the inclusion criteria for this 
study; it will also serve as a secondary outcome for the study, as will FEV1 measured 
longitudinally. FEV1 measured through spirometry also provides part of the primary 
composite outcome variable. 
 
The potential benefits justify the potential risks. 
 
b) Methacholine Inhalation Challenge 
Methacholine challenge will be used to assess airway hyper-responsiveness. 


 79 
 
Risks: The major risk of methacholine challenge is the induction of severe 
bronchoconstriction. As a precaution, participants will not undergo methacholine 
challenge if their FEV1 is less than 55% of predicted or 1.0 liter (adults) or 70% of 
predicted (children under 18 years). Medical and nursing personnel, medications and 
equipment will be available at the study sites to treat and manage any 
bronchoconstriction episodes.  
 
Benefits: There are no direct benefits to the participant. This procedure is considered 
necessary for the protocol due to the following reasons: First, for the participants who 
do not demonstrate a 12% improvement in FEV1, a positive methacholine challenge 
would allow them to meet one of the inclusion criteria for this study. Second, the 
assessment at baseline will allow for participant characterization and an assessment of 
whether airway hyperresponsiveness can predict responsiveness to a given therapy. 
 
The potential benefits justify the potential risks. 
 
c) Induced Sputum 
Sputum will be induced with hypertonic saline to collect an airway sample and to assess 
for airway inflammation. As not all children younger than 12 years old can reliably 
perform induced sputum induction, this procedure will not be performed in individuals 
younger than 12 years of age. 
 
Risks: Like any bronchoprovocation challenge, sputum induction can provoke 
bronchospasm and warrants close supervision during its performance. 
 
Benefits: There are no direct benefits to the participant. This procedure will allow us to 
characterize baseline airway inflammatory status to help assess predictors of 
responsiveness to each of the therapies.  
 
The potential benefits justify the potential risks. 
 
d) Urine collection  
Urine will be collected to assess overnight urine cortisol, to perform pregnancy tests at 
specified visits, and for future exploratory assessments of urine biomarkers. 
 
Risks: There are no risks associated with urine collection. 
 
Benefits: This test will be for cortisol measurement, pregnancy testing, and for 
assessment of urinary biomarkers that may help predict responsiveness to these 
therapies in different participants.  
 
The potential benefits justify the potential risks. 
 
 


 80 
XX. 
TREATMENT FAILURE, DROP-OUT STATUS AND ASTHMA 
EXACERBATIONS 
 
A. Criteria for assigning treatment arm failure during any one of the four 
treatment periods 
 
1. Participant hospitalized due to asthma 
2. Participant requires 10 or more days of treatment with prednisone for asthma 
exacerbation(s) 
3. Participant experiences two distinct asthma exacerbations 
 
If the participant experiences two distinct asthma exacerbations, or requires 10 or 
more days of treatment with prednisone for asthma exacerbation(s), or is 
hospitalized due to asthma during any treatment period, he/she will be considered a 
treatment failure and, after at least 14 days following the completion of oral or 
parenteral corticosteroids, he/she will enter into the next treatment period (window of 
7 days will be permitted to complete next study visit). Finally, if the participant has 
his/her first oral or parenteral corticosteroid treatment for an exacerbation near the 
end of any treatment period, the start of the next treatment period cannot occur until 
at least 14 days have elapsed since the completion of that steroid treatment (window 
of 7 days will be permitted to complete next study visit). During the 14-21 day waiting 
period prior to starting the next double-blind treatment period, the participant will be 
given open-label 5xICS (500 mcg BID for ages 12 and up and 250 mcg BID for ages 
5-11). 
B. Criteria for assigning drop-out status at any point in the study 
 
1. Participant or parent of participant (for children) withdraws consent or child 
withdraws assent 
2. Participant becomes pregnant 
3. Study physician determines that continuation in the study is not in the best 
interest of the participant 
4. Participant suffers hypoxic seizure due to asthma 
5. Participant undergoes intubation due to asthma 
6. Participant suffers serious adverse event related to the use of a study medication 
7. Participant requires long-term systemic corticosteroids for an illness other than 
asthma 
 
Participants meeting any of the above criteria will be seen for an exit visit and 
withdrawn from the study immediately. They will be referred to their primary care 
physician for follow-up care. 
C. Criteria for assigning treatment period drop-out status during any of the 
periods 
If the study physician determines that continuation on the current treatment is not in the 
best interest of the participant, for any reason other than poor asthma control, but that 
study termination is not warranted, the participant will be assigned treatment period 
drop-out status. Participants assigned treatment period drop-out status will stop taking 


 81 
study medications immediately, will go back on run-in medication (ICS dose equivalent 
to fluticasone propionate 100-200 mcg/day) and begin the next treatment period as 
soon as possible. If the participant is currently in the fourth treatment period, he/she will 
be terminated from the study in the same way as a participant assigned study drop-out 
status. 
 
D. Definition and management of asthma exacerbations 
Definition 
In this study an asthma exacerbation will be defined according to the recommendation 
of the NIH Outcomes Workshop (Fuhlbrigge 2012 JACI 129:S34-48) as a worsening of 
asthma requiring the use of a systemic corticosteroid18 to prevent a serious outcome. In 
accordance with the Expert Panel recommendations, data will be captured on the 
following exacerbation-related outcomes: 
1. All worsening asthma events in which systemic corticosteroids were initiated to 
prevent a serious outcome, including use of systemic corticosteroids in 
association with any form of healthcare provider encounter 
2. All asthma-specific emergency department or urgent care visits that involved 
treatment with systemic corticosteroids 
3. All asthma-specific hospitalizations that involved treatment with systemic 
corticosteroids (also reported as a serious adverse event) 
4. All asthma-specific intensive care unit admissions or intubations (also reported 
as a serious adverse event) 
5. All deaths (all cause and asthma-related; also reported as a serious adverse 
event) 
For the purpose of this study, and to standardize our approach among AsthmaNet 
studies, two courses of systemic corticosteroids must be separated by at least one 
week to count as two exacerbations and to be documented as such.  
Management 
The approach to rescue medications will be based on the consensus report presented 
in the National Heart, Lung and Blood Institute Guidelines and structured according to 
the protocols successfully implemented in previous ACRN and CAMP trials. Each 
participant will be given specific guidelines for decision-making and institution of rescue 
management (action plan). Two medications, albuterol and/or oral prednisone, will be 
employed when increasing symptoms and/or fall in peak flow require treatment. 
Participants will be given an adequate supply of albuterol for use throughout the trial. At 
the conclusion of the first screening visit, they will be dispensed a 5-day course of 
prednisone as outlined in Section E below to keep at home for rescue use on the advice 
of a study physician. For a severe acute asthma exacerbation, participants will be 
                                            
18 Given changes in common practice since the Outcomes Workshop paper was published in 2012, we will consider 
one- and two-dose treatments with dexamethasone as constituting treatment for an asthma exacerbation and will 
document and follow these events as such.  


 82 
provided with medication according to the best medical judgment of the treating 
physician. The treatment approaches outlined below have been safely and effectively 
used in previous CARE (CLIC, PACT, and BADGER) and ACRN (LARGE and TALC) 
trials. 
 
Home care: 
The onset of an asthma exacerbation will be recognized by symptoms such as 
coughing, dyspnea, chest tightness and/or wheezing, or by a decrease in the 
participant’s PEF. Caretakers and participants will be educated to recognize the signs 
and symptoms of an asthma exacerbation early and the significance of falls in their 
peak flow readings so that prompt rescue treatment may be instituted and morbidity 
decreased. 
Participants who experience symptoms of cough, dyspnea, chest tightness, wheeze, 
phlegm/mucus and/or PEF less than 80% of their reference value will initiate use of 
albuterol (2-4 puffs) by MDI every 20 minutes for up to 1 hour, and then every 4 hours if 
necessary. If the participant cannot achieve a PEF of at least 80% of their reference 
value, or if symptoms persist after three treatments, the performance site should be 
contacted. If the participant’s peak flow reaches 80% of their reference value, but the 
participant requires albuterol every 4 hours for 24 hours in order to maintain a peak flow 
of at least 80% of the reference value, or if symptoms persist, the performance site 
should be contacted. At the time of performance site contact, a clinic visit may be 
necessary. The initiation of oral prednisone therapy will be based on specific guidelines 
and on physician discretion. 
If symptoms are severe, the participant has retractions, evidence of cyanosis based on 
saturations on room air of < 90% based on pulse oximetry, has evidence of increased 
work of breathing, shortness of breath and/or “air hunger”, and/or the PEF is less than 
50% of reference value after 8 puffs of albuterol, the participant must seek immediate 
medical care and should contact the performance site. 
Physician’s office or emergency room: 
In the primary physician’s office or emergency room, the participant with an acute 
asthma exacerbation will be treated according to usual medical care that may include 
nebulized albuterol or high dose MDI albuterol (6-8 puffs every 20 minutes x three or 
more often, if needed). The dose of albuterol for the doctor-supervised situation is 0.10 
– 0.15 mg/kg up to 5 mg per treatment. Albuterol can be delivered by nebulizer driven 
with oxygen, and treatments will be given every 20 minutes for up to three treatments. If 
after three treatments, the participant is not stable as described below, the physician 
may use additional albuterol treatments or other medications as is in his or her best 
clinical judgment. The participant will be assessed for general level of activity, color, 
pulse rate, use of accessory muscles and airflow obstruction determined by 
auscultation, and FEV1 and/or PEF before and after each bronchodilator treatment.  
Measurement of oxygenation with a pulse oximeter may also be indicated for complete 
participant assessment during the acute exacerbation. The following assessments will 
also be made. 
• If the participant has a favorable response to initial albuterol nebulizer 


 83 
treatment (FEV1 at least 80% predicted and/or PEF at least 80% reference 
value), the participant will be observed for 1 hour prior to being discharged 
home with instructions to continue albuterol every 4 hours, as needed, and to 
report any decline in PEF and/or symptom fluctuation promptly. 
• If the participant does not improve (FEV1 less than 80% predicted or PEF less 
than 80% reference value) after the initial albuterol nebulizer treatment, 
nebulized albuterol therapy will be continued for at least two more trials (for a 
total of three times in 1 hour).  If the participant’s clinical symptoms are 
stabilized and FEV1 or PEF is between 50-80% of predicted or reference 
value, the participant will be discharged home to continue use of albuterol (2 
puffs every 4 hours) and to start a five-day course of oral prednisone. 
• If the participant’s FEV1 is less than 50% of predicted or PEF is less than 50% 
of reference value after three treatments with nebulized albuterol in 1 hour, 
the physician may use his/her best medical judgment to treat the participant. 
Such clinical judgment may include the need for hospitalization and inpatient 
monitoring. 
E. Prednisone courses 
Oral prednisone will be administered for the treatment of impending episodes of severe 
asthma when bronchodilator therapy is inadequate. The decision concerning the 
initiation or continuation of a course of oral prednisone will be at the physician’s 
discretion.  Prednisone should be prescribed if: 
 
• The participant uses more than 12 puffs of albuterol in 24 hours (excluding 
preventive use before exercise) and has an e-diary symptom code of 3 (i.e., 
symptom graded severe) or PEF less than 70% of reference value before each 
albuterol use, or 
• The participant has symptom code of 3 (severe) for 48 hours or longer, or 
• PEF drops to less than 50% of reference value despite albuterol treatment 
For both adults and children, the recommended prednisone dose for acute 
exacerbations is 2 mg/kg/day (maximum 60 mg) as a single morning dose for three 
days followed by 1 mg/kg/day (maximum 30 mg) as a single morning dose for two days.   
All administered doses will be rounded down to the nearest 5 mg in 
children/adolescents (i.e., participants aged 17 or younger).  
F. Characterization of Asthma Exacerbations 
 
The AsthmaNet Investigators are interested in studying interventions for management of 
asthma exacerbations. To accomplish this, better tools and endpoints are required, and 
the Protocol Review Committee previously suggested that AsthmaNet trials might 
provide the opportunity to gather useful preliminary information on exacerbations, which 
was also a major theme of a recent NIH Outcomes Workshop (Fuhlbrigge 2012 JACI 
129:S34-48). Thus, as an exploratory outcome, we will evaluate the responsiveness of 
a range of endpoints to characterize the time-course (onset and resolution) and 
magnitude of morbidity associated with an exacerbation and the use of systemic 


 84 
corticosteroids as part of the BARD action plan. The assessments will be incorporated 
within the main BARD protocol and visits, to minimize both participant and site burden.  
The Asthma Index:  The asthma 
index is a continuous variable 
that reflects the magnitude and 
the timing of changes in asthma 
control, 
with 
objective 
and 
subjective elements weighted 
similarly (Sorkness 2008). Data 
from 15 participants of the 
ACRN-BASALT 
trial 
having 
exacerbations are presented in 
the figure to the left, centered on 
the 
day 
(D0) 
of 
starting 
prednisone. 
This 
tool 
is 
a 
composite 
measure 
that 
assesses 
symptoms, 
rescue 
medication 
use, 
and 
lung 
function 
to 
advance 
the 
understanding of the components of these events, involving a 48-hour rolling calculation 
of an acute-to-baseline difference of scores generated from peak flow and asthma 
symptom diaries. These data are captured twice-daily in the BARD protocol using the 
Spirotel electronic diary recordings of asthma symptoms (0 = no symptoms, 1=mild 
symptoms, 2=moderate symptoms, 3=severe symptoms), nocturnal awakenings, rescue 
albuterol use (# rescue puffs), and peak expiratory flow data. The reference period for 
the asthma index will be derived from the Spirotel-collected diary data during the most 
stable week within the context of the trial, which we have previously defined as that with 
the lowest standard deviation of the asthma scores collected during the course of the 
week (Denlinger 2011). The Asthma Index will be calculated serially using the diary data 
during each treatment period. We will define the peak asthma index as the highest 
value that occurs within 14 days after declaration of a significant exacerbation requiring 
prednisone. The time to resolution of the exacerbation will be assessed by the number 
of days between the peak and the point at which the index has been below 50% of the 
peak for at least 4 consecutive days. This instrument will allow for study of factors 
related to the speed of recovery from exacerbations. 
The Asthma-Specific Work Productivity and Activity Impairment Score (WPAI:Asthma): 
This instrument captures asthma impairment by measuring the patient’s assessment of 
disease impact on productivity at work, school, or daily activities (Chen 2008).  It has 
been validated in >2000 patients with asthma in the TENOR study and administered in 
the AsthmaNet VIDA study. This questionnaire is validated for and applicable to 
individuals ages 12 and up. Baseline values using this instrument (recall of past 7 days) 
will be measured at the initial BARD screening visit (Screen Visit A) for all participants 
ages 12 and older. This survey will be part of an exacerbation kit to be completed at 
home on the day that the participant (ages 12 and up) starts prednisone (day 0). A post-
exacerbation follow-up survey will also be completed at the next study visit occurring 
after an exacerbation. This tool will allow us to assess impairment associated with 
exacerbations in participants ages 12 and greater and the extent to which recovery has 
occurred by the time of the next study visit. 
 
 
AZMA asthma index figure: Time from prednisone burst, n=15, 


 85 
Acute Asthma Assessment Questionnaire (see Appendix 2).  An Acute Asthma 
Assessment will be included in the exacerbation kit, to be completed at home by the 
participant (ages 12 and greater) on the day he/she starts prednisone. Participants will 
be asked to report the precipitating factor for the asthma exacerbation (viral illness, 
exercise, allergen exposure, pollutant/irritant exposure, medication nonadherence), as 
well as a 72 hour review of number of asthma awakenings, albuterol rescue use, and 
missed school/work. Specific medication and health care utilization questions will be 
included on the exacerbation form completed at the next study visit to capture the 
following: 1) additional systemic corticosteroids prescribed by AsthmaNet personnel or 
other healthcare providers due to persistent symptoms and which are not included in 
the initial burst, 2) antibiotics prescribed by health care providers, and 3) unscheduled 
office visit, urgent care/emergency department visit, or hospitalization for respiratory 
symptoms. This tool will help evaluate exacerbation severity with the goal of 
establishing correlation between acute scores and the risk of subsequent adverse 
events. To introduce the questionnaire to the study participants and to establish a 
baseline, the Acute Asthma Assessment will be administered to participants ages 12 
and greater at the first study visit (Screen Visit A). A post-exacerbation follow-up 
questionnaire will be completed at the next study visit occurring after an exacerbation. 
This tool will allow us to assess impairment associated with exacerbations in 
participants ages 12 and greater and the extent to which recovery has occurred by the 
time of the next study visit. 
 
G. Timing of Asthma Exacerbations and Trial Management 
 
Run-In Exacerbations: 
 
Participants who require 2 steps to step down to 1xICS in the run-in and experience an 
exacerbation while on the 2-2.5xICS step are ineligible for further study participation. 
 
Participants who experience an exacerbation while on 1xICS in the run-in may be 
eligible for randomization if they meet all other criteria, including compliance 
requirements for study drug dosing and e-diary/PEF completion. These participants 
must wash out from their final dose of prednisone for 2-3 weeks prior to completing the 
randomization visit (Visit 1). During the washout period they will remain on 1xICS. If a 
second exacerbation occurs prior to randomization, the run-in will be extended further to 
allow for a 2-3 week washout period from the final dose of the second prednisone 
course. If a third exacerbation occurs, then the participant is ineligible for further study 
participation for safety reasons.  
 
Participants who experience an exacerbation while on 1xICS in the run-in and do not 
meet compliance requirements are ineligible for further study participation. These 
individuals will be terminated from the study and may re-enroll, at the discretion of study 
staff, after meeting all applicable washouts. 
 
Post-Randomization Exacerbations: 
 
Participants who experience an exacerbation during the first 2 weeks of a double-blind 
treatment period (prior to the treatment period’s baseline visit) will have their baseline 


 86 
visit delayed for at least 1 week (but no more than 2 weeks) from their final dose of 
prednisone. Participants will remain on their double-blind study medication during this 
washout period. If a second exacerbation occurs during the washout period, then the 
participant meets treatment failure conditions and will follow the procedures outlined in 
section XX.A above. 
 
Participants who experience their first exacerbation of a treatment period near the end 
of the period will delay the start of the following treatment period by 2-3 weeks following 
their final dose of prednisone. Participants will receive open-label 5xICS during the 
washout period. These individuals are treated in the same fashion as those who 
achieve treatment failure status (see section XX.A above).   
 
XXI. 
ADVERSE EVENTS. 
A. Definitions 
Participants are at risk of developing adverse events during study enrollment. A clinical 
adverse event shall be defined as any unintended worsening in the structure (signs) or 
function (symptoms) of the body, whether it is related to an exacerbation of asthma or to 
another unrelated illness, and whether or not it is considered study- or drug-related. 
Adverse events include any side effect, injury, or sensitivity reaction, as well as any 
intercurrent event. An adverse event is deemed serious if it suggests a significant 
hazard, contraindication, side effect, or precaution. Serious adverse events include any 
experience that is fatal or life-threatening, is permanently disabling, requires or prolongs 
inpatient hospitalization, or is a congenital anomaly, cancer or overdose. 
Documentation of an adverse event will be recorded on the Clinical Adverse Event 
Report form and the Concomitant Medications for Asthma/Allergies and Adverse Event 
form and will include the following information: Description of the condition, dates of 
condition, treatment of condition (medications, doses, dates), whether hospitalization or 
emergency treatment was required, treatment outcome, relationship of the adverse 
event to the study medication(s) and severity of the event. Additional information is 
recorded on the Serious Adverse Event Reporting Form when an event is deemed 
serious in nature. 
 
B. Adverse events unrelated to asthma 
Adverse events due to concurrent illnesses other than asthma may be grounds for 
withdrawal: 1) if the illness is considered significant by the study investigator, 2) if the 
illness requires systemic corticosteroids, or 3) if the participant is no longer able to 
effectively participate in the study.  Participants experiencing minor intercurrent illnesses 
may continue in the study provided that the nature, severity, and duration of the illness 
are recorded and that any unscheduled medications required to treat the illness are also 
recorded. Examples of minor intercurrent illnesses include acute rhinitis, sinusitis, upper 
respiratory infections, urinary tract infections, and gastroenteritis. Medications are 
allowed for treatment of these conditions in accordance with the judgment of the 
responsible study physician. 


 87 
 
C. Adverse events related to asthma exacerbations 
In this study an asthma exacerbation is defined according to the recommendation of the 
NIH Outcomes Workshop (Fuhlbrigge 2012 JACI 129:S34-48) as a worsening of 
asthma requiring the use of a systemic corticosteroid (at least 3 days of treatment) to 
prevent a serious outcome. An asthma exacerbation will usually be recognized by the 
development of an increase in symptoms of cough, chest tightness, shortness of breath, 
phlegm/mucus, and/or wheezing or by a decrease in the participant’s PEF.  
Participants developing asthma exacerbations during the double-blind treatment period 
(or during the run-in) will be managed according to a participant specific guide for 
decision-making and rescue management (action plan).  Home care, physician’s office 
or emergency room visit care, and prednisone course algorithms are previously 
described above. 
Participants developing asthma exacerbations during the characterization/assessment 
period or the run-in period will be managed based on their ICS step-down profile. Those 
who require 2 step step-down who experience an exacerbation while on the 2-2.5xICS 
dose will be terminated from further trial participation, as they cannot tolerate a 
decrease to 1xICS. Those in the step-neutral or 1 step step-down group who 
experience an exacerbation while on the 1xICS dose are eligible to be randomized in 
the trial 14 days following their last dose of prednisone. If a given individual experiences 
more than two exacerbations on the 1xICS dose during the run-in period, he or she will 
be terminated from further trial participation due to safety concerns. These individuals 
will be treated appropriately and may re-enroll at Screen Visit A at least 4 weeks 
following their last dose of prednisone, at the study investigator’s discretion. 
During any of the four treatment periods, adverse events related to asthma 
exacerbations will be assigned Treatment Failure status if the event results in 
hospitalization or the need for 10 or more days of treatment with prednisone for asthma 
exacerbation(s). These adverse events will be managed according to rescue algorithm 
described above. Individuals who attain treatment failure status will begin the next 
treatment period after at least 14 days have passed since the completion of their oral or 
parenteral corticosteroids (7 day window). 
 
XXII. 
SAFETY MONITORING 
A Data and Safety Monitoring Board (DSMB) has been established for this study to 
monitor data and oversee participant safety.  The DSMB consists of physicians skilled in 
both pediatric and adult asthma management, asthma pharmacology, and/or asthma 
clinical research, as well as a statistician and a bioethicist experienced in clinical trials. 
The Study Chair, the Director and a senior staff member of the Data Coordinating 
Center, and representatives from the NHLBI participate as non-voting members.  
Specific DSMB procedures are identified in the AsthmaNet Manual of Operations. 
The current study will request DSMB review of study data every 6 months. The DSMB 
will assess the following: 


 88 
• 
Study performance, including assessment of performance sites’ adherence to 
protocol, adequate participant accrual, and quality control of data collection and 
management 
• 
Adverse event reports. These data will be presented to the DSMB in a fashion 
blinded to treatment group assignment.  However, the DSMB will have the option 
of unblinding when and if this action is deemed appropriate. Reports of serious 
adverse events will also be summarized. The DSMB will be notified within 72 
hours of any serious adverse events that are unexpected and deemed related to 
the study procedures or drugs. 
Serious adverse events 
A serious adverse event is defined as any event that results in death, is life-threatening, 
requires inpatient hospitalization or prolongation of existing hospitalization, results in 
persistent or significant disability or incapacity, or is a congenital anomaly/birth defect or 
other medically important condition.  A life-threatening event is one in which, in the 
study physician’s opinion, the participant was at immediate risk of death from the 
reaction as it occurred.  Although not unexpected as an outcome in asthma clinical 
trials, hospitalizations for asthma will be included in the listing of adverse events as 
identified in the AsthmaNet Network Manual of Operations.  Summary reports of the 
DSMB’s review of serious adverse events will be distributed to each AsthmaNet PI by 
the DCC within 30 days following each DSMB meeting. The Summary Reports will 
include the following: a statement that a DSMB review of the data and outcomes across 
all performance sites took place on a given date; a summary of the DSMB review of the 
cumulative serious adverse events without specific disclosure by treatment group 
unless safety considerations require such disclosure; and the DSMB’s conclusion with 
respect to progress or need for potential protocol modification. The AsthmaNet PIs are 
required to forward the Summary Reports to their local IRBs. 
Cost, Liability and Payment 
All tests will be performed without cost to the participants.  Since this is a trial comparing 
established asthma treatments, liability for participant care costs incurred by participants 
during the course of the trial will, in most cases, be borne by the participant or their 
insurer. Details of the NIH policies concerning this issue can be found in NIH 
Documents #5305 and 6352-2, Research Participant Care Costs Supported 
Agreements, in the AsthmaNet Network Manual of Operations.  Each participant will be 
paid a specified amount for study reimbursement that will be equivalent across clinical 
center partnerships. For participants who drop out, reimbursement will be pro-rated for 
the length of time they stayed in the study. 
XXIII. 
SUMMARY/IMPACT 
 
The trial we outline above aims to address the important questions related to best add-
on therapy in Blacks across the ages. The results of this study have the potential to 
significantly impact the asthma guidelines because the provided data will allow for 
evidence based recommendations for the use of asthma pharmacotherapy in Blacks.   
This study will also offer the opportunity to assess whether genetic ancestry markers  


 89 
can help us predict the degree of differential pharmacologic response in Black 
individuals.    
 


 90 
 
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XXV. 
APPENDIX 1- PARTICIPATING PARTNERSHIPS 
 
Nine AsthmaNet Clinical Center partnerships (and their associated satellites) will 
participate in the BARD study.  Each partnership has recruitment and retention plans in 
place to maximize enrollment. These nine partnerships include: 
 
1. Brigham and Women’s Hospital, Boston, MA  
 
2. Chicago Metropolitan Asthma Consortium, Chicago, IL  
 
3. National Jewish Health, Denver, CO  
 
4. University of Wisconsin, Madison, WI  
 
5. University of Pittsburgh, Pittsburgh, PA  
 
6. Washington University, St. Louis, MO  
 
7. University of California, San Francisco, CA  
 
8. University of Arizona, Tucson, AZ  
 
9. Wake Forest University, Winston-Salem, NC 
 
 
 
 


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XXVI. 
APPENDIX 2: ACUTE ASTHMA ASSESSMENT QUESTIONNAIRE 
 


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