Conditions: Asthma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 155
Healthy volunteers: no

Brief summary:
This study evaluates the effects of adding on an environmental home intervention to standard asthma medication management on controller medication requirements among children and adolescents with asthma. The investigators hypothesize that the addition of an individually-tailored, multi-faceted Environmental Control Strategy (ECS) to guidelines-based controller medication will result in less controller medication requirement and allergic inflammation than controller medication alone among urban asthmatic children.

Detailed description:
The study is a parallel arm study of an individually tailored, multi-faceted ECS plus controller medication titration versus controller medication titration alone. After a 4-week run-in period to stabilize the asthma, the investigators will randomize 200 Baltimore children with persistent asthma and a recent exacerbation in a 1:1 ratio to the two arms and follow the children for six months. There will be five clinic visits and three home visits over this time period for clinical and home assessments, respectively. There will be up to four environmental intervention visits for participants randomized to the environmental control plus controller medication group. The environmental modules include mouse, cockroach, furry pets, dust mites, and smoking. Air purifiers and laundered bedding are also included in this arm. Participants randomized to the controller medication group have the option of having one home visit after completing the study at which the participants will receive home intervention services that the environmental control plus controller medication group received. Participants will have repeated assessment of: controller medication requirements; secondary clinical, physiologic, and inflammatory outcomes; and particulate matter (PM), air nicotine, and allergen levels.

Arms:
arm 1: The Environmental Control Strategy ("Home Environmental Intervention") plus inhaled corticosteroids or inhaled corticosteroids plus long-acting beta agonist. (Flovent Diskus or Advair diskus) arm 2: inhaled corticosteroids or inhaled corticosteroids plus long-acting beta agonist. (Flovent Diskus or Advair diskus)

Interventions: intervention 1: Flovent Diskus intervention 2: Home Environmental Intervention intervention 3: Advair Diskus
Intervention descriptions: intervention 1: Inhaled corticosteroids intervention 2: Mouse, Cockroach, Furry pets, Dust mites, Smoking, air purifiers, laundered bedding intervention 3: inhaled corticosteroids + long-acting beta agonist

Protocol document:
Prot_SAP_000.pdf: 
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Environmental Control as Add-on Therapy in 
Childhood Asthma 
 
 
 
 
 
 
 
 
 
NCT02251379 
 
 
 
 
 
 
 
 
 
10/03/2016 
 


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Date: 10/03/2016   
Principal Investigator: Corinne Keet, MD PHD  
Application Number: NA_00093323  
  
  
  
JHM IRB - eForm A – Protocol  
  
  
  
• 
Use the section headings to write the JHM IRB eForm A, inserting the appropriate material 
in each. If a section is not applicable, leave heading in and insert N/A.  
• 
When submitting JHM IRB eForm A (new or revised), enter the date submitted to the field at 
the top of JHM IRB eForm A.  
  
***************************************************************************************************  
  
  
 
1.  
Abstract  
High indoor allergen and pollutant levels have repeatedly been linked to asthma morbidity, especially among urban 
children, who have among the highest asthma morbidity in the US. (1-5) However, environmental intervention trials 
for asthma have typically compared an environmental control strategy (ECS) to no intervention, a design that does 
not reflect the recommended approach to asthma management, which includes ECSs in conjunction with titration of 
controller medication. (6) As a result, it remains unknown whether the addition of an ECS to controller medication 
titration results in improved asthma control, and therefore a reduced controller medication requirement. Another 
unanswered question is whether the addition of an ECS to controller medication titration results in greater reduction 
of allergic inflammation than medication titration alone. ECSs may have a greater effect on allergic inflammation 
than controller medications because ECSs target the most upstream point of the asthma inflammatory pathway by 
reducing pro-inflammatory environmental exposures, while controller medications target a downstream point of this 
pathway. (7-9)  Surprisingly, it is also unknown whether the improvement in asthma in ECS trials is mediated by 
reductions in allergen levels and/or reduction in pollutant levels. Understanding the factors that mediate the effects 
of an ECS on asthma is important for refuting, or supporting, a causal role for indoor allergens and/or pollutants in 
asthma morbidity, and also for optimizing the design of ECSs to target the most influential factors. We therefore 
hypothesize that the addition of an individually-tailored, multi-faceted ECS to guidelines-based controller 
medication titration will result in less controller medication requirement and allergic inflammation than controller 
medication titration alone among urban asthmatic children. We will test this hypothesis and identify the factors that 
mediate the clinical effects of the ECS with a parallel-arm, randomized controlled trial of ECS plus controller 
medication titration vs. controller medication titration alone.  Our aims are: (1) To determine the effect of the 
addition of ECS to controller medication titration on controller medication requirements and allergic inflammatory 
biomarkers, and (2) To determine whether reductions in particulate matter (PM) and/or indoor allergens mediate the 
effects of an ECS on asthma. This proposed trial will answer a pivotal question because if ECSs do not provide 
additional benefit in the context of treatment with controller medication, the role of ECS in asthma management 
should be downgraded. On the other hand, if ECSs do indeed reduce controller medication requirements, greater 
emphasis should be placed on the importance of ECSs in asthma management, studies should be conducted to 
identify best ECS practices, and policies should be changed to require third party payers to cover ECS costs.    
  
 
2.  
Objectives   
  
We hypothesize that the addition of an individually-tailored, multi-faceted environmental control strategy (ECS) to 
guidelines-based controller medication titration will result in less controller medication requirement and allergic 
inflammation than controller medication titration alone among urban asthmatic children. We will test this hypothesis 
and identify the factors that mediate the clinical effects of the ECS with a parallel-arm, randomized controlled trial of 
ECS plus controller medication titration vs. controller medication titration alone.  The aims are:   


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(1) To determine the effect of the addition of ECS to controller medication titration on controller medication 
requirements and allergic inflammatory biomarkers.  
  
a) To compare the effect of the active intervention (“ECS+Medication Group”) to control (“Medication 
Group”) on controller medication requirement (“treatment step”) and inhaled corticosteroid dose.   
b) To compare the effect of the active intervention to control on FENO, serum allergen-specific IgE levels.   
  
(2) To determine whether reductions in particulate matter (PM) and/or indoor allergens mediate the effects of an 
ECS on asthma.  
  
a) To measure the change in fine and coarse particulate matter (PM2.5 and PM2.5-10, respectively) and indoor 
allergen concentrations (cat, dog, mouse, cockroach, and dust mite) among study participants.  
b) To estimate the causal effects of PM and allergen exposure reduction on controller medication requirements 
and allergic inflammatory outcomes, using a novel statistical approach, principal stratification analysis.  
  
(3) To evaluate whether a child’s personal bacterial exposures, particularly those of animal origin, contribute to 
asthma morbidity.  
a) To compare bacterial community profiles and S. aureus genotypes in children versus pet and pest animals 
(dog, cat, mouse, cockroach others) in the home.  
b) To examine associations between the child’s bacterial communities and asthma morbidity.  
c) To determine relationships between the child’s S. aureus colonization and asthma morbidity.  
  
 
3.   
Background   
  
Despite the marked reduction in asthma morbidity across the US as a whole since the widespread use of inhaled 
corticosteroids,(10, 11) there has been little to no effect on asthma morbidity among urban children with asthma.  
Although this disproportionate burden of asthma morbidity has many causes, one major cause is thought to be the 
high levels of certain indoor allergens and pollutants found in homes in urban communities.(2)  Although we know 
that an individually-tailored, multi-faceted ECS that targets these allergens and pollutants is effective in reducing 
asthma symptoms and exacerbations in urban children,(12-14) this type of intervention is rarely a component of the 
clinical care of urban children.  There are several reasons why ECSs have not moved from the research to the clinical 
care arena.(15) For health care providers, there are fewer barriers to writing prescriptions for medications than to 
counseling patients about ECS; and for patients, there are fewer barriers to taking medications than to implementing 
an ECS. These barriers include little reimbursement of health care providers for ECS counseling and lack of coverage 
for ECS durable goods and services. Until there is clinical trial data that directly demonstrates that the addition of an 
ECS to controller medication titration results in meaningful reduction of controller medication needs, it will be very 
difficult, if not impossible, to make the compelling argument that is needed in order to remove these barriers.  This 
type of clinical trial data would also allow direct comparisons of the cost of the ECS intervention to the cost of the 
controller medication that would have been needed without the addition of the ECS. When framed in terms of 
medication equivalency (for both effectiveness and cost), a much more compelling argument can be made to require 
third party payers to cover ECS services, and to place greater emphasis on ECS in practice guidelines. However, even 
if an ECS provides little controller medication sparing effect, this will be a critically important result because it 
would provide a strong evidence base for placing greater emphasis on, and allocating resources towards, improving 
implementation of controller-medication titration protocols.    
  


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Environmental Control Strategy: As the next logical step following a large body of work linking indoor allergen and 
pollutant exposure to asthma morbidity in urban children, members of the investigator team have led several ECS 
trials focusing on both indoor pollutant and allergen reduction. 
The pollutants and allergens targeted in our studies are all present 
in high concentrations in Baltimore homes and have all been 
repeatedly implicated in asthma morbidity in this population.  
  
PARTICULATE MATTER  
The Particulate Reduction Education in City Homes (PREACH) 
trial was an RCT in 126 Baltimore asthmatic children living with 
a smoker.(14) Participants were randomized to one of three arms: 
high efficiency particulate air (HEPA) purifiers, HEPA purifiers 
plus a behavioral intervention, or delayed air purifiers (control  
Figure 1. Boxplots reflect the change in PM2.5 in 
the control and air cleaner groups, respectively.  
group). Participants were followed for six months. Participants who received air purifiers had ~50% reduction in both 
PM2.5 and PM2.5-10 concentrations (Figure 1) and an increase in symptom-free days of 1.9 days/2 week period 
compared to the control group.  In a second intervention study, twenty-six adult former smokers with COPD had 
placement of two HEPA purifiers in their non-smoking homes and PM2.5 and PM2.5-10 measured before and after air 
purifier placement. Both PM2.5 and PM2.5-10 concentrations were reduced by ≥60%, demonstrating that even in 
nonsmoking homes, air purifiers alone result in a substantial reduction in PM.(16)   
  
INDOOR ALLERGENS   
(1) Pest Allergen Reduction: The Mouse Allergen and Asthma Intervention Trial (MAAIT) is a multi-center RCT of 
a mouse allergen exposure intervention (U01AI083238). Currently, ~300 of 350 mouse sensitized children and 
adolescents have been randomized to either the Integrated Pest  
 Management (IPM) or the Education arm and retention is ~90%.   Because the trial is still underway, we do not yet 
know the effect  of the intervention on mouse allergen levels or clinical  outcomes.  However, participants are 
repeatedly assessed for  persistent or recurrent mouse infestation to determine if they  will receive additional 
professional pest management, so we do  know that >60% of participants in the IPM arm have had  
 complete eradication of their infestation.  As a result, we expect  
  
cockroach allergen with an IPM intervention.  These studies  
provide strong preliminary data to support the efficacy of IPM 
interventions in reducing home pest allergen levels.  
  
(2) 
Airborne Allergen Reduction with Air Purifiers: Furry animal 
allergens are readily detected in air samples because they are found on 
small particles, typically those ≤10microns. Air filtration is effective not 
only in reducing indoor PM, but also furry animal allergens, so will be 
included as a component of our ECS intervention. For example, a 
Baltimore-based environmental intervention study indicates that room air purifiers reduce airborne mouse allergen 
levels. In this study, 65 asthmatic children were randomized to receive either a bedroom filter or no intervention. At 
six months, airborne mouse allergen levels had decreased by 68% in the intervention group, but had increased in the 
control group. This marked degree of reduction was achieved even though there was no IPM intervention targeting 
 
Figure 2.  Room air filters and airborne Mus m 1 
concentrations. 65 homes were randomized to receive 
bedroom air HEPA filters or no intervention. Airborne Mus m 
1 was quantified at baseline and 6 months. Mus m 1 
concentrations are depicted on the y-axis and expressed in 
ng/m3.  Intervention (solid line, hollow diamonds), n=34; 
Control (dashed line, solid squares), n=31; p = 0.26.  
that the IPM arm will also have a marked reduction in mouse 
allergen levels in their homes.  Indeed, a pilot study using a 
similar IPM protocol observed a 75% reduction in home mouse 
allergen levels by five months post intervention.  Several other 
trials with a focus on cockroach allergen, including one in 
Baltimore, have also demonstrated substantial reductions in  


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mouse infestation in this study. (Figure 2) Other studies have also demonstrated reductions in other airborne animal 
allergens, including cat and dog.(17, 18)   
  
(3) Microbial exposures: While bacterial exposures are known to influence the development of asthma, less is known 
about their impact on symptoms and lung function among children diagnosed with asthma. Further, it is not known 
whether the profile of bacterial exposures (e.g. in the nasal microbiome) or exposure to a single bacterium is 
important. A leading candidate bacterium is the Gram-positive Staphylococcus aureus, which colonizes a third of the 
U.S. population. S. aureus is known to exacerbate atopic eczema through its pro-inflammatory activity, primarily via 
a Th2, or allergic, immune response to bacterial superantigen proteins such as staphylococcal enterotoxins (SE). 
Emerging data indicate that S. aureus exacerbates upper respiratory disease via the same pathway, and there is 
evidence for a causal role of S. aureus in the development of chronic rhinosinusitis with nasal polyposis.(19) A number 
of limited but provocative studies suggest that S. aureus may also exacerbate asthma;(20, 21) and our study using 
NHANES data demonstrates that S. aureus colonization is an independent risk factor for current asthma and 
emergency department (ED) visits for asthma among children and young adults. Our pilot work demonstrates that the 
presence of pet and pest animals in the household contribute to bacterial exposures and may modify risk for 
colonization with S. aureus. Presence of pest mice in urban households was associated with a two-fold increased 
likelihood of environmental S. aureus contamination. In a controlled trial of people with S. aureus infection, we 
identified both pet carriage and presence of pests in the home as risk factors for human S. aureus colonization, and 
we found that pets generally enhanced bacterial sharing among household members.  
  
  
This combined experience in ECS trials demonstrates that air purifiers reduce airborne PM2.5 and PM2.5-10 in homes 
with and without smokers, and mouse allergen.  In addition, our IPM intervention eradicates mouse infestation in 
most homes. Others have also found that IPM reduces cockroach and mouse allergens and air purifiers reduce other 
furry animal allergens, including cat and dog.(22-24) Because we are combining strategies that have proven successful 
for individual pollutants or allergens, we expect that the proposed ECS will be more effective at reducing 
proinflammatory environmental exposures than any of the single exposure interventions, and will therefore have 
greater effects on asthma control, resulting in reduced medication needs.   
  
  
3.  Study Procedures a. Study design, including the sequence and timing of study procedures    
  
Overview:  The study is a parallel arm, randomized, controlled trial (RCT) of an individually tailored, multi-faceted 
ECS plus controller medication titration versus controller medication titration alone.  After an approximate 4-week 
run-in period to stabilize their asthma, we will randomize 200 Baltimore 5-17 year olds with persistent asthma and a 
recent exacerbation in a 1:1 ratio to the two arms and follow them for six months. Participants will have repeated 
assessment of: controller medication requirements; secondary clinical, physiologic, and inflammatory outcomes; and 
PM, air nicotine, and allergen levels.  
  
Table 1. Study Visits  
 
 
 
 
 
 
 
  
Screening 
CV  
HV-1  
CV-1  
INT  
1  
CV- 
2  
INT 
2**  
HV-2  
INT  
3  
CV-3  
INT  
4  
CV-4  
HV- 
3  
Months  
-1.5  
-1.5-0  
0  
  
2  
  
3  
  
4  
  
6  
6  
Windows  
  
  
~ + 2 
wks  
  
+/- 2 
wks  
  
+/-2 
wks  
  
+/- 2 
wks  
  
+/- 2 
wks  
+/- 2 
wks  
Consent Process  
X  
  
  
  
  
  
  
  
  
  
  
  
Allergy Skin Testing  
X  
  
  
  
  
  
  
  
  
  
  
  
Physical Exam  
X  
  
X  
  
X  
  
  
  
X  
  
X  
  
Venipuncture  
X  
  
  
  
  
  
  
  
  
  
X  
  
Urine collection  
X  
  
X  
  
X  
  
  
  
X  
  
X  
  
Buccal swabs  
  
  
X  
  
X  
  
  
  
X  
  
X  
  


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Microbial swabs  
  
  
X  
  
X  
  
  
  
X  
  
X  
  
Nasal Mucus Sample  
  
  
X  
  
X  
  
  
  
X  
  
X  
  
Questionnaires  
X  
  
X  
  
X  
  
  
  
X  
  
X  
  
Spirometry  
X  
  
X  
  
X  
  
  
  
X  
  
X  
  
FeNO  
X  
  
X  
  
X  
  
  
  
X  
  
X  
  
Adherence Assessment  
  
  
X  
  
X  
  
  
  
X  
  
X  
  
Medication adjustment  
X  
  
X  
  
X  
  
  
  
X  
  
X  
  
Randomization  
  
  
X  
  
  
  
  
  
  
  
  
  
Home assessment  
  
X  
  
  
  
  
X  
  
  
  
  
X  
Settled dust collection  
  
X  
  
  
  
  
X  
  
  
  
  
X  
Air sampling including  
PM2.5 & PM10  
  
X  
  
  
  
  
X  
  
  
  
  
X  
Air nicotine sample 
collection  
  
X  
  
  
  
  
  
  
  
  
  
X  
Surface swabs  
  
X  
  
  
  
  
X  
  
  
  
  
X  
Bacterial Questionnaire  
  
X  
  
  
  
  
X  
  
  
  
  
x  
Pet sampling/Questionnaire 
(if pet present)  
  
X  
  
  
  
  
X  
  
  
  
  
X  
SES Questionnaire  
  
X  
  
  
  
  
  
  
  
  
  
  
Intervention Module  
  
  
  
X  
  
X**  
  
X  
  
X  
  
  
**Only participants sensitive to mouse or cockroach will receive INT 2.  
 
 
 
 
 
 
 
  
Screening Visit  
  
Skin testing: Allergy skin testing will be performed to 14 allergens, using the MultiTest device (Lincoln Diagnostics, 
Decatur, IL). The allergen extracts to be used are: dog, cat, Dermatophagoides pteronyssinus, Dermatophagoides 
farinae, rat epithelia, German cockroach, American cockroach, mouse epithelia, tree pollen mix, grass mix, 
Alternaria, Aspergillus, common ragweed, and Cladosporium. A positive skin test will be defined as a net wheal  
≥2mm. Skin test results performed by the study team within the last year may be used for inclusion criteria. We 
define the mean wheal diameter as the average of the largest diameter and the corresponding midpoint diameter.  
Participants who are not able to have skin testing done at the screening visit or who are skin test negative may have 
blood drawn for specific IgE test to dog, cat, rat, Dermatophagoides farinae along with mouse and cockroach.  
  
FENO and Lung Function:  FENO is a known marker of pulmonary inflammation and will provide a non-invasive 
means of assessing pulmonary inflammation in a large cohort that includes children. Measurement of exhaled nitric 
oxide will be obtained prior to lung function according to the American Thoracic Society Guidelines(25) using a 
handheld, FDA-approved analyzer (NIOX TM System, Aerocrine, Sweden).  Pre- and post-bronchodilator lung 
function testing will be performed according to ATS guidelines.(26)  After the pre-bronchodilator lung function testing 
is done, the participant will be given one unit dose of nebulized albuterol (2.5mg and spirometry will be repeated 
approximately 15-20 minutes following administration of albuterol. Bronchodilator reversibility will be defined as a 
≥12% increase in FEV1 after short-acting bronchodilator.    
  
Venipuncture:  A venous blood sample will be obtained so that the serum can be used to measure mouse, cockroach, 
staphylococcal enterotoxin-specific IgE levels in the Matsui laboratory using the ImmunoCAP system  
(ThermoFisher, Uppsala, Sweden).  Participants who are not able to complete prick puncture skin testing, or have a 
negative skin test but strong clinical evidence, will have specific IgE test to dog, cat, Dermatophagoides farinae, and 
rat along with mouse and cockroach.   
  
Questionnaires: Questionnaires that capture medication use, asthma symptoms, asthma-related health care utilization 
will be administered at all clinic visits.  The questionnaires are based on questionnaires used in urban populations and 


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will capture symptoms over a two week period of time, and medication use over a two week period of time as well as 
asthma control as assessed by the validated Asthma Control Test.(27, 28)  Asthma severity will be assessed by the 
validated Composite Asthma Severity Index (CASI).(29)  Asthma control will be assessed at CV1-4 slightly different 
from the screening visit. (See assessment Tables 2 and 2a).   
  
  
Because school age children 
and adolescents will be 
enrolled, we will administer the 
questionnaires to the primary 
caregiver of children 5-11 
years, and to both the study 
participant and his/her 
caregiver for adolescent study 
participants, age 12-17. The 
questionnaires will be modified 
accordingly. Although previous 
studies have indicated 
concordance between the 
adolescent’s and the caregiver’s 
responses,(30) we will collect data from both so that we have the ability to assess the concordance rate within our 
study population.  
  
Urine collection: Urine will be collected for pregnancy testing in females of childbearing capacity.  Urinary cotinine 
will be assessed by a rapid detection method to exclude active smokers in children 12 and older.  In children 12 and 
older, a NicAlert value of 4 or greater will exclude them from eligibility for randomization. Urine will also be stored 
for later analysis of cotinine in all children to assess second hand smoke exposure.  
  
Buccal swabs for RNA, DNA extraction: The inside cheek will be swabbed to collect RNA and DNA. Approximately 
7 swabs will be collected. Samples will be analyzed to determine if the environmental intervention is associated with 
epigenetic changes in candidate allergy-, asthma-, inflammation- or immune-related genes (DNA methylation and 
related RNA expression).   
  
  
Physical Exam: A brief physical exam will be performed by the study physician.  Height, weight, and waist 
measurements may be performed by study team.  At follow-up clinic visits a focused exam will be performed.    
  
Adherence Assessment:  Participants will be required to bring their medications to all study visits and provided a 
small monetary incentive to do so (see below under Payment and Remuneration). Medications that will be used (see 
treatment algorithm below) will include dose counters. At the screening visit, since participants will be on a range of 
treatment regimens, many of which will not include dose counters, adherence will be assessed by questionnaire.  At 
all other visits, adherence will be assessed both by questionnaire and the dose counter. Participants with <25% 
adherence at CV1 will not be eligible to be randomized.    
 
Table 2.  Assessment of Control Level at CV0  
  
  
  
  
  
  
  
  
  
  
  
  
Days of asthma 
symptoms or 
rescue  
medication  
use/previous 2 
weeks  
Nights of 
wakening with 
asthma  
symptoms or 
for rescue  
medication  
use/previous 2 
weeks  
FEV1 
percent 
predicted  
Steroid 
bursts,  
previous six 
months  
  
Control Level 1  
0-3  
0-1  
>85%  
0  
Control Level 2  
4-9  
2  
80-<85  
1  
Control Level 3  
10-13  
3-4  
70-<80  
2  
Control Level 4  
>13  
5-14  
<70  
>2  
 
Table 2a.  Assessment of Control Level at CV1-4  
  
Days of asthma 
symptoms or 
rescue  
medication  
use/previous 2 
weeks  
Nights of 
wakening with 
asthma  
symptoms or 
for rescue  
medication  
use/previous 2 
weeks  
FEV1 percent of 
best (the best  
FEV1 they’ve 
had since  
starting the 
study)  
Steroid 
bursts,  
since last 
visit  
  
Control Level 1  
0-3  
0-1  
>85%  
NO  
Control Level 2  
4-9  
2  
80-<85  
YES  
Control Level 3  
10-13  
3-4  
70-<80  
-  
Control Level 4  
>13  
5-14  
<70  
-  


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Table 3. Treatment Steps  
Step 0  
albuterol prn  
Step 1  
fluticasone 50mcg QD  
Step 2  
fluticasone 50 mcg BID  
Step 3  
fluticasone 100mcg BID  
Step 4  
fluticasone 250mcg BID  
Step 5  
fluticasone/salmeterol 250/50 
BID  
Step 6  
futicasone/salmeterol 500/50 
BID  
  
  
 


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Treatment Algorithm:  The treatment algorithm is based on national asthma treatment guidelines and adapted from 
algorithms that have been successfully implemented by the NIH-funded Inner-city Asthma Consortium and Rho 
Federal Systems Division, Inc.(32, 33) At each clinic visit, the participant’s control status will be assessed using recent 
symptom history, exacerbation history, and lung function. The participant’s treatment will be prescribed based on a 
combination of his/her current treatment step, control level, and 
adherence. This algorithm-driven medication  
titration approach has been used successfully in other inner-city 
asthma studies. Participants who meet eligibility criteria at the 
screening clinic visit will have the treatment algorithm applied and 
will be sent home after education about asthma and their prescribed 
medication and dispensing of the prescribed medication by the 
pharmacy.  (Note: the pharmacy or study staff may deliver 
medication to the participant’s home).  On call coverage will be 
provided for participants. If participants have a primary care 
provider, a letter will be sent notifying the provider that we will be 
taking over the participant’s asthma care while in the study. 
Participants who are not eligible will be referred back to their asthma 
care providers for continued asthma management.  
  
Control Assessment (Tables 2 and 2a): The participant’s level of 
control will be assessed according to the rubric depicted in Tables 2 
and 2a.   
Assessment of Current Treatment Step (Table 3): At the screening 
visit, the participants will be assigned a current treatment step based 
on their current medication regimen and level of adherence to this 
regimen.   Although almost 100% of participants’ insurance is 
expected to cover the drugs in Table 3, for the participants whose 
insurance will not cover the drugs listed in Table 3, alternative 
comparable regimens that are appropriate are listed below.  
  
Treatment Assignment (Tables 4 and 4a):  The treatment step that 
will be assigned will be based on the participant’s current control 
level, current treatment step, lung function, and adherence. The study 
doctor may override the algorithm when it is in the best  
interest of a participant’s care.  The participant’s asthma will be 
managed by the study physicians for the duration of the study and 
the participant’s parent/guardian will be provided a 24 hour pager 
number to access study physicians for concerns related to their 
child’s asthma.   
  
  
 
Table 4a.  Treatment Algorithm CV1-CV4  
For CVs 1-4, adherence is 
taken into account for the  
treatment assignment as 
follows: Control level  
Treatment Algorithm for  
Participants with   
  
Unacceptable Adherence 
(<50%)  
Treatment Algorithm for Participants with   
  
  
Acceptable Adherence (≥50%)  
  
1  
Continue same controller 
regimen  
If on treatment steps 1-6, decrease controller regimen by 1 
step.  If on step 0, continue step 0.  
Table 4. Treatment Algorithm CV0  
Current Regimen  
Current  
Control 
Level  
Treatment 
Assigned  
No Controller  
1  
Step 0  
  
2  
Step 2  
  
3  
Step 2  
  
4  
Step 3*  
Step 1  
1  
Step 1  
  
2  
Step 2  
  
3  
Step 2  
  
4  
Step 3*  
Step 2  
1  
Step 2  
  
2  
Step 3  
  
3  
Step 3  
  
4  
Step 4*  
Step 3  
1  
Step 3  
  
2  
Step 4  
  
3  
Step 4  
  
4  
Step 5*  
Step 4  
1  
Step 4  
  
2  
Step 5  
  
3  
Step 5  
  
4  
Step 6*  
Step 5  
1  
Step 5  
  
2  
Step 6  
  
3  
Step 6  
  
4  
Step 6*  
Step 6  
1  
Step 6  
  
2  
Step 6  
  
3  
Step 6*  
  
4  
Step 6*  
*may also require prednisone burst  


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2  
Continue same controller 
regimen or place on step 2 
therapy, whichever is higher.  
  
Increase controller regimen by 1 step, or continue step 6 
therapy if already on step 6.  
  
  
3  
  
  
  
  
  
  
  
Continue same controller 
regimen or place on step 2 
therapy, whichever is higher  
SYSTEMIC STEROID USE=0 (no)  
• 
If on steps 0-5, increase controller regimen by 1 step.  
• 
If on step 6, continue step 6 or treat with step 6 and a 
4 day burst of prednisone.  
SYSTEMIC STEROID USE=1 (yes)  
• 
If on steps 0-4, increase controller regimen by 2 
steps.         (continued on next page)  
  
  
3 (continued)  
 
• 
If on treatment step 5, increase controller regimen to 
step 6 or treat with step 6 and a 4 day burst of 
prednisone.  
• 
If on treatment step 6, continue step 6 or treat with 
step 6 and a 4 day burst of prednisone.  
  
  
  
  
  
  
4  
Continue same controller 
regimen, or place on step 3 
therapy, whichever is higher  
OR  
Treat with 4-day prednisone 
burst and continue same  
controller regimen or place on  
step 3 therapy, whichever is  
higher  
  
• 
If on steps 0-4, increase controller regimen by 2 
steps.  
• 
If on step 5, increase to step 6 OR treat with step 6 
and a 4 day prednisone burst.  
• 
If already on step 6, continue step 6 or treat with step 
6 and a 4 day prednisone burst.  
Adherence is assessed by the dose counter and calculated as the (number of doses taken/number of doses prescribed)*100.  
  
If the participant does not bring his/her controller medications to the visit, the Medication Adherence Review will be used to 
estimate adherence.  
  
  
Household Members with Asthma:  The parent/guardian will be asked about other members of the household who 
have asthma. These household members will be identified by number only.  Age, sex, and information about asthma 
related health care utilization will be collected from the participant’s guardian about other household members who 
have asthma.  If there are other children with asthma, not including the study participant (index child), we will ask 
the child, 5-17 years of age, and his/her parent/guardian to participate in a sub study.  We will ask to draw one tube of 
blood for specific IgE to cat, dog, mouse, rat, German cockroach, and D. farinae and ask that the Asthma Control 
Test questionnaire be completed by the child around the time of randomization and the end of the study. This will 
require a separate consent form.   If there is more than one child 5-17 years of age in the household with the index 
child, the child who will be asked to participate in the study will be chosen based on convenience.   The purpose of 
this sub study is to generate preliminary data to understand how many other household members have asthma and 
whether the intervention affects asthma control of other children with asthma in the household.  
  
URI Assessment: The parent/guardian and/or adolescent child will be asked questions about recent respiratory 
illnesses (colds) and a nasal mucus sample will be collected. The child will use a nasal saline spray in each nostril 
and blow his/her nose into a plastic baggie for the collection of a nasal sample.  This will be collected at CV1-4.                  
  
Run-in Period and Follow-up Clinic Visits: There will be an approximate 4 week run-in period following the 
screening visit to stabilize the participant’s asthma.  Participants will return for CV1 for randomization if they meet 
adherence eligibility requirements.  Once randomized, participants will be prescribed a steroid burst to have at home 
in the event of an exacerbation.  They will then have follow-up CVs every two months with clinical assessment of 
their asthma, collection of outcome data, and application of the treatment algorithm as described above (Table 2).  
  


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Swabs for microbial assessment: The nares, oropharynx, and skin will be sampled using Copan E-swabs™ (Copan 
Diagnostics, Murrieta, CA) for staphylococcal culture and Catch-All™ sample collection swabs (Epicentre 
Biotechnologies, Madison, WI) for bacterial community analysis at CV1,2,3,and 4.  The child may self-swab with the 
help of a parent/guardian.  
  
At HVs: Home Assessment Visits (HV) will occur at baseline, 3 and 6 months.  Home inspection, settled dust 
collection, PM10, PM2.5, airborne allergen measurements, and microbial air sampling may occur at all HVs. The air 
sampling of microbes and their products will be compared to dust samples collected.  PM2.5-10 will be calculated, as 
done in previous studies, by subtracting the PM2.5 concentration from the PM10 concentration that is measured 
adjacent to, and simultaneously with, the PM2.5 measurement.   A passive filter for air nicotine monitoring will be 
placed in the home at baseline and 6 months.  
  
Home inspection: A trained technician will conduct a home inspection to collect data regarding the home 
environment, including condition of dwelling, evidence of tobacco smoking, evidence of pets and pests.    
  
Dust sample collection: Dust will be collected from the bed and bedroom floor using a standard procedure. The dust 
samples will be analyzed for the major relevant indoor allergens: Mus m 1, Der f 1, Fel d 1, Can f 1, and Bla g 1. A 
portion of the bedroom dust sample will be saved for future studies.  A separate dust sample will be analyzed for 
bacterial communities and S. aureus, including staphylococcal enterotoxin proteins that may be secreted by the 
bacterium.  Additional dust will be collected from standardized home surface sites using sterilized electrostatic cloths 
(autoclaved Swiffer™, Proctor & Gamble, Cincinnati, OH) for bacterial culture. Temperature and humidity data may 
also be collected.   
  
If a participant moves between home visits, and the participant is randomized to receive intervention, an attempt will 
be made to collect another dust sample prior to the intervention visit.  
  
URI Assessment: A respiratory illness questionnaire will be completed at the 3 month (HV2) home visit.  
  
Socioeconomic Questionnaire: A questionnaire about specific socioeconomic factors will be administered at the first 
home visit.  
  
Bacterial Questionnaires: At the home visit we may collect data on established risk factors for acquisition of S. 
aureus and other bacteria, such as daycare, gym use, and antibiotic use, and household location (which will be 
collected on a separate form, then geocoded into X, Y coordinates from address data before linkage with health or 
demographic data).     
  
Pet Questionnaire: We may collect data on participant contact with and characteristics of pet animals in the home. 
These data will include notations from visual inspection of the pets and areas of the house related to pets (e.g. pet 
crates).   
  
Sampling of pets and pests: Under an approved ACUC protocol (Davis, SP14H352, 9/18/2014-9/18/2017), Copan 
Eswabs™ (Copan Diagnostics, Murrieta, CA) for bacterial culture and Catch-All™ sample collection swabs  
(Epicentre Biotechnologies, Madison, WI) for bacterial community analysis may be collected from all pet animals at 
multiple anatomical sites and from freshly trapped rodents and other trapped pests.  The informed consent process for 
these pet swabs will be conducted under the approved ACUC protocol and conducted by the Davis group.  Study 
participants randomized to pest control will be given a magnet with a number to call to schedule optional pick-up of 
freshly trapped rodents and other pests from the home to transport to the laboratory for bacterial sampling.  
  
Particulate Matter and Airborne Animal Allergens: Particulate matter monitoring will be conducted in the child’s 
bedroom using integrated sampling direct-reading methods for an approximate 5 day period. Air samples for PM2.5 
and PM10 will be collected using methods developed during previous childhood asthma studies.(34) After gravimetric 
analysis, the PM10 filters will be assayed for allergen content in the Matsui laboratory.  PM10 samples will be 
analyzed because previous research indicates that the bulk of airborne animal allergens is contained on particles less 
than 10µm in aerodynamic diameter.(35, 36)  Microbial air sample measurements may be obtained.    


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Inspirotec air monitors will be deployed in a subset of homes to establish correlation between our PM10 
measurements of airborne biomass and Inspirotec spectroscopic measurements of biomass.  We will also compare the 
limits of detection of the two methods and validate the utility of the Inspirotec sampler as easily deployable in home 
environments.  
  
Randomization:  Participants will be randomized within 6 weeks (+/- 2 wks) of the screening clinic visit in a 1:1 
ratio using a statistical software package to generate random numbers. The randomization scheme will be developed 
by the Data Management and Analysis Core (DMAC). Participants will be randomized in random block sizes of 4 to 
8. The randomization scheme will be embedded into the recruitment/tracking database so that once a participant 
meets all eligibility criteria the site study coordinator can activate randomization through a secure user interface.  The 
DMAC database programmer will have access to the computer code for the randomization scheme. Participants 
randomized to the ECS+Medication Group will be scheduled for an intervention prior to their next clinic visit.  
  
ECS Intervention  
Skin test data, home inspection data, and environmental history will be used to tailor an ECS to participants 
randomized to the ECS+Medication Group.  Randomization will occur at CV1 and all of the information needed to 
assign ECS modules will have been collected before randomization. The 5 modules are listed below along with the 
qualifying criteria to receive the module and a summary of the components of each module (Table 5).  
  
  
  
Table 5. Individually-Tailored, Multi-Faceted Environmental Control Strategy Intervention  
  
Qualifying criteria  
Components of Module  
Rodent module  
Positive skin test or IgE* to mouse or rat plus 
any evidence of infestation on home inspection 
OR parent report of evidence of infestation in 
the past month  
Professional IPM  
Targeted cleaning  
IPM education  
Allergen-proof mattress and pillow encasements  
Cockroach module  
Positive skin test or IgE* to cockroach plus any 
evidence of infestation on home inspection OR 
parent report of evidence of infestation in the 
past month  
Professional IPM  
Targeted cleaning  
IPM education  
Allergen-proof mattress and pillow encasements  
Furry pet module  
Positive skin test or IgE* to cat or dog  
Education  
Allergen-proof mattress and pillow encasements 
Targeted cleaning  
Dust mite module  
Positive skin test or IgE* to dust mite  
Education  
Allergen-proof mattress and pillow encasements 
Targeted cleaning  
SHS module  
Smoker in the home  
Education  
Air purifiers/Clean  
Bedding   
None – everyone assigned to the  
ECS+medication arm will receive air purifiers 
and child’s bedding will be replaced with study 
bedding for study duration.  
Deployment of 2 portable air purifiers, one in the child’s 
bedroom and one in the TV/living room. Child’s bedding will 
be replaced with study bedding for study duration.  
*≥2mm net wheal or specific IgE ≥ 0.35   
  
Professional IPM will be delivered by a local pest management company using protocols we have developed for 
other studies.  For rodents, the intervention will include placement of traps, application of rodenticide in cracks and 
sealing of cracks and holes that can serve as an entry point for rodents. For cockroaches, the intervention will be 
based on previous successful protocols(22, 24) and will include placement of Advion (indoxacarb), a low-toxicity gel 
bait, and sticky traps for monitoring of cockroach infestation.  Indoxacarb is the active ingredient in pesticides used 
on pomme fruits such as apples and in products used to kill fleas on cats and dogs.  It is a commercially available 
pesticide for cockroach control and will be applied by licensed exterminators according to the manufacturer’s 
instructions.  
  


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Parents/guardians will be asked to place the sticky traps 3-4 days prior to the IPM visit so that the location(s) of 
cockroach activity can be accurately identified.  They will be given detailed instructions along with the sticky traps.  
The study team may assign a team member to place the traps for the family if this seems necessary.  If for some 
reason, traps are not placed prior to the intervention visit the IPM team may place the traps and return to the house 
after 3-4 days for the placement of gel bait.  The IPM team will count the number of cockroaches caught on the 
sticky traps and use a vacuum as a cockroach removal tool.  The local pest management company, Innovative Pest 
Management, provides protocolized IPM services for a current study.  As many as four IPM visits may occur for 
persistent or recurrent infestation. If new evidence of mouse or cockroach is seen or reported any time between HV1 
and INT 3, the appropriate module will be completed in the home before CV3.  
  
Allergen-proof mattress and pillow encasements will be installed by study staff.  These encasements block particles 
down to 1 micron in size so are optimal for blocking allergens such as furry animal allergens that are found on 
smaller particles than dust mite and cockroach allergens.   
  
Targeted cleaning will be included in all allergen-related modules.  Targeted cleaning will take place at Intervention 
1 and 4.  For the rodent and cockroach modules, cleaning will focus on removing allergen reservoirs and cleaning 
areas that have the greatest pest activity, such as the kitchen. For the furry pet and dust mite modules, the targeted 
cleaning will focus on the child’s bedroom with the goal of reducing allergen levels in the bedroom.    
  
IPM Education will focus on counseling participants about storage of food and housekeeping practices aimed at 
reducing food and water sources for pests.  Participants receiving the rodent module will be provided an IPM kit that 
includes traps and other supplies so that families can implement IPM measures in addition to the professional IPM 
services that are provided.   
  
Replacement Bedding will be included in all modules. The study will provide bedding (sheets, pillowcases, and 
comforter) to the participant throughout the study.  The child’s bedding will be replaced at Intervention 1 and 3 with 
bedding provided by the study.  The participant’s bedding will be removed from the bed and replaced with study 
bedding at Intervention 1.  At Intervention 3 the study bedding will be removed and replaced with another set of 
study bedding.  At Home Visit 3 the study bedding will be removed and replaced with the participant’s original 
bedding. All study bedding will be laundered by the JHH laundering facility after it is removed from a home before 
being deployed to another participant. Families will also be counseled to wash all of the child’s bedding in the hot 
water cycle every 1-2 weeks.  
  
Furry pet and dust mite education will be delivered by study staff.  For pets, it will focus on encouraging the family 
to find the pet a new home or, at the least, to restrict the areas of the home that the pet can be in, particularly the 
child’s bedroom. For dust mite and furry pets, families will be counseled to wash all of the child’s bedding in the hot 
water cycle every 1-2 weeks.     
  
SHS Education will include provision of resources for smoking cessation and tools and support for instituting a home 
smoking ban.   
  
Air Purifiers will be provided to everyone randomized to the ECS + Medication Group as the targeted community is 
known to have high levels of PM2.5, PM10, and airborne mouse allergen.  Portable HEPA purifiers with the same clean 
air delivery rate and performance characteristics of the purifiers used in our earlier studies will be used.(12, 14) The 
purifiers will be suitable for use in rooms up to 17’x10’, so will appropriate for use in rooms found in typical 
Baltimore housing.  A random 10% sample of air filters will be monitored using electric current data loggers that 
record the presence of an electric current every hour in order to estimate air purifier use.   
  
  
The first ECS module will be delivered between CV1 and CV2. Intervention 2, delivered only to those participants 
receiving the rodent and/or cockroach modules, will be delivered between CV2 and HV2. If possible, Intervention 3 
will be delivered immediately following HV2 on the same day.  If this is not possible, Intervention 3 will be 
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will be reinforced to participants randomized to the ECS+Medication Group to support the family’s efforts in 
reducing allergen and pollutant exposures.  
  
The Medication Group will receive skin test results at CV0 and educational materials about environmental control 
practices at CV1.  The same educational materials will also be given to the ECS+Medication Group.  The Medication 
Group will be offered the intervention after completion of the study with the exception of bedding being replaced.  
This visit is to be scheduled within 2 months of their last study visit.  
  
All procedures and tests are part of the research protocol with the exception of study drugs, which are typically 
covered by health insurance.   
  
b. Study duration and number of study visits required of research participants.  
  
Participants will be enrolled for approximately 7 months.  There will be five clinic visits and three home visits over 
this time period for clinical and home assessments, respectively.  There will be up to four environmental intervention 
visits for participants randomized to the environmental control plus controller medication group.  Participants 
randomized to the controller medication group have the option of having one home visit after completing the study at 
which they will receive home intervention services that the environmental control plus controller medication group 
received with the exception of bedding being replaced.   
  
c. Blinding, including justification for blinding or not blinding the trial, if applicable.  
  
Participants will not be blinded because it is not practical and impossible to create a sham environmental intervention 
without exorbitant costs.   The study physicians applying the treatment algorithm, which drives the primary outcome, 
will be blinded to the extent possible.  For example, study staff will be trained not to divulge the participants’ 
randomization group to the physician during the clinic visit.  
  
d. Justification of why participants will not receive routine care or will have current therapy 
stopped. Participants will be asked to stop anti-histamines for approximately 5 days prior to skin testing at 
the screening visit.since anti-histamines interfere with the skin test results.  Otherwise, all participants will 
receive nationalguidelines-based titration of controller medication and education about asthma management.  
  
e. Justification for inclusion of a placebo or non-treatment group.  
Although there are two groups being compared in this trial, there is no group that is not receiving guidelines-based 
asthma treatment.  
  
f. 
Definition of treatment failure or participant removal criteria.  
A study participant will be discontinued from further study intervention if any clinical adverse event, other medical 
condition or situation occurs such that continued participation in the study would not be in the best interest of the 
participant.  
  
This includes: (1) an asthma hospitalization that results in intubation and (2) a second asthma hospitalization during 
the course of the study.  
  
g. Description of what happens to participants receiving therapy when study ends or if a participant’s 
participation in the study ends prematurely.  
Participants may withdraw consent or be dropped from the study at any time. Every effort will be made to contact the 
participant by phone to conduct a final telephone interview.  Participants will be referred back to their primary care 
provider (or subspecialist, if receiving subspecialty care) for asthma management.  
All participants exiting the study after randomization without having received CV2 will be replaced.  
  


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4.  
Inclusion/Exclusion Criteria  
Inclusion Criteria  
  
• 
Males and females who are 5-17 years of age, inclusive, at the baseline visit  
• 
Have physician-diagnosed asthma at least 1 year prior to the baseline visit, or asthma symptoms for at 
least 1 year  
• 
Meet criteria for current persistent asthma defined as either:  
  
1. On a long-term controller medication for asthma, or   
  
2. Meet NAEPP guideline requirements for persistent disease:)(6)   
  
• 
Asthma symptoms 3 or more days per week over the past 2 weeks OR   
• 
Nocturnal asthma symptoms at least 3 times in the past month  
  
• 
Have evidence of uncontrolled disease as defined by at least one of the following:  
  
1. One asthma-related unscheduled visit to an emergency department (ED), clinic or urgent care facility in 
the previous 18 months  
2. One asthma-related overnight hospitalization in the previous 18 months  
3. One or more bursts of oral corticosteroids in the previous 18 months   
  
  
• 
Reside within a geographic area of the study site so that home visits are feasible.  • Have no plans to 
move within the upcoming 6 months  
• 
Have insurance to cover prescription medications.  
• 
Have a positive skin test (net wheal ≥2mm) to cat, dog, mouse, rat, cockroach, or dust mites or have a 
positive cat, dog, mouse, rat, German cockroach, or D. farinae-specific IgE test, as quantified using the 
ImmunoCAP system (≥0.35 kU/L)   
  
  
Exclusion Criteria  
• 
Lung disease, other than asthma, that requires daily medication  
• 
Cardiovascular disease that requires daily medication, excluding hypertension  
• 
Taking a beta-blocker •  Allergy to dairy  
• 
On Xolair < 5 months  
• 
On immunotherapy and has not reached maintenance dose  
• 
Sleeping in another home 4 or more nights/week  
• 
Active smoker defined as a positive urine screen for high levels of urine cotinine  
• 
Unable to access areas of home necessary to conduct extermination • Pregnancy  
  
 
5.  
Drugs/ Substances/ Devices  
a. The rationale for choosing the drug and dose or for choosing the device to be used.  
The intervention being tested is the environmental intervention, but all participants will receive asthma 
medication based on national guidelines.  All will receive a short-acting beta agonist, albuterol, for use as a 
reliever medication.  All participants, at least at the start of the study, will also receive a controller 
medication, Flovent or Advair or an equivalent alternative medication.   
  


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b. Justification and safety information if FDA approved drugs will be administered for non-FDA 
approved indications or if doses or routes of administration or participant populations are 
changed.  N/A  
Justification and safety information if non-FDA approved drugs without an IND will be administered.   NA  
  
 
6.  
Study Statistics  
a. Primary outcome variable.  The primary outcome variable is the treatment step that the 
participant is assigned at the 6 month clinic visit (see treatment algorithm above).   
  
b. Secondary outcome variables.  
Secondary outcomes include:  (1) daily inhaled corticosteroid dose, (2) allergic inflammation markers 
(allergen-specific IgE, FENO, (3) measures of asthma control (days of short-acting beta agonist use, days of 
slowed activity due to asthma, days of exercise-induced symptoms, days of cough without an upper 
respiratory infection, nights of wakening due to asthma symptoms), and (4) measures of exacerbations (oral 
corticosteroid bursts, hospitalizations, emergency department visits, and unscheduled physician visits). Other 
secondary outcomes include FEV1/FVC, % change in FEV1 after albuterol, and asthma severity, as 
measured by the CASI.(29)  
  
c. Statistical plan including sample size justification and interim data analysis.  
  
Power Estimate  
  
The power estimate is based on assessment of the primary outcome, 
treatment step, at 6 months. In the ICAS trial, the ECS resulted in a 
reduction of 0.8 symptom days/2 weeks within two months of 
randomization.(13) The authors of the paper make the point that this effect 
size is similar to that seen with controller medications. In PREACH, the 
SHS intervention trial, there was an increase of 1.9 symptom-free days/2  
weeks at six months in the group receiving air purifiers compared to the 
control group. This effect, which was observed with air purifiers alone and 
no other environmental intervention, is also similar in magnitude to low 
dose, inhaled corticosteroids, which resulted in an increase of 2 symptom-free days/2 weeks compared to placebo 
among children with persistent asthma (CAMP).(9)  With a multi-faceted intervention as proposed for this study, we 
expect a significantly larger effect size than observed with air purifier deployment alone. In terms of treatment step, 
low dose ICS is one “step-up” from no controller medication, which reflects the difference in controller medication 
requirement that our proposed study is powered to detect.  Further, a 1 step reduction in controller medication 
requirement would also be the point at which an ECS would likely be cost effective.  For example, in the ICAS 
trial,(13) the intervention, which was effective for two years, cost approximately $1500, similar to the cost of a one 
year supply of low dose ICS. There will be 7 possible treatment steps (Table 6) and, based on the distribution of 
participants across treatment steps in other studies, we will assume a mean treatment step of 4.0 at baseline among 
participants in both groups and have estimated the power to detect a difference of 1 treatment step between the two 
groups, with a standard deviation between 1.5 and 2.  With a sample size of 200, and assuming alpha=0.05, we will 
have a power of 0.94 to detect a difference of this magnitude. With a drop-out rate of ~12%, there will be a power of  
0.90. (Table 6)     
  
Analysis Plan  
The primary outcome will be the treatment step that is assigned at the final clinic visit at six months. The six month 
time point has been chosen because successful ECS trials have observed an effect by six months, but an effect may 
not be observed before this time because it takes several months for indoor allergen levels to fall after implementing 
an environmental intervention. The secondary outcome will be total daily ICS dose assigned at this same visit, 
expressed in milligrams. The primary analysis dataset will be an intent-to-treat (ITT) dataset and will include 
participants with six month outcome data collected, regardless of whether they completed all of the ECS activities.  A 
per-protocol analysis will also be performed and will be performed on the dataset of participants with six month 
Table 6. Power Estimates  
 
Treatment step 
difference  
SD  Power for 
n=200  
Power for 
n=175  
0.75  
1.5  0.94  
0.90  
  
2.0  0.75  
0.69  
1.00  
2.0  0.94  
0.90  
  
2.5  0.80  
0.74  


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outcome data who completed at least one intervention visit (one IPM visit or for the Medication Group, receipt of 
ECS educational materials). Exploratory data analysis for both Aims 1 and 2 will include compilation of descriptive 
statistics to detect any outliers or discrepancies in data and to compare baseline characteristics and demographics 
between ECS+Medication and Medication Groups.  Continuous variables will be summarized using means, medians, 
standard deviations, ranges, and interquartile ranges.  Continuous variables will be analyzed using non-parametric 
approaches or will be transformed to meet assumptions of normality required for parametric statistics. Categorical 
variables will be tabulated.  The percent of participants who complete the study, losses to follow-up, missed visits, 
and reasons for discontinuation will be presented.   
  
The primary outcome will be the participant’s assigned treatment step at the six month clinic visit (as described 
above).  Secondary outcomes include:  (1) daily inhaled corticosteroid dose, (2) allergic inflammation markers 
(allergen-specific IgE, FENO,), (3) measures of asthma control (days of short-acting beta agonist use, days of slowed 
activity due to asthma, days of exercise-induced symptoms, days of cough without an upper respiratory infection, 
nights of wakening due to asthma symptoms), and (4) measures of exacerbations (oral corticosteroid bursts, 
hospitalizations, emergency department visits, and unscheduled physician visits). Other secondary outcomes include 
FEV1/FVC, % change in FEV1 after albuterol, and asthma severity, as measured by the CASI.(29) We will subtract 
baseline levels of the treatment step from the step assigned at the 6 month CV to assess the within-person change in 
treatment step over time. Differences over time in the intervention group will be compared to those in the control 
group using a generalized linear modeling approach and a significance cutoff of 0.05. Assessment of significance 
adjusting for multiple comparisons will be done using the method of Benjamini and Hochberg.(37)  Regression models 
will be used to adjust for potential confounders and to test for interactions with potential effect modifiers. A similar 
analytic approach will be used for other clinical and inflammation outcomes, with appropriate statistical tests and 
models for the different types of outcome variable data, such a Chi-Square test and logistic regression for 
dichotomous outcomes.  
  
Potential confounders will be explored by examining any differences between the intervention and control groups and 
also assessing the association between the potential confounders at baseline and at the final study visit.  In addition, 
potential confounders will be included in the models to determine the impact the variables have on the relationship 
between group assignment and the outcome. Some specific confounders that will be carefully examined include 
baseline allergen and pollutant levels, treatment step at baseline, and season.  Potential effect modifiers, such as 
baseline pollutant and allergen levels, baseline asthma severity, baseline asthma control, baseline lung function, and 
number of positive skin tests, will also be examined by stratifying analyses and creating an interaction term to 
include in the final models.  Analyses will be stratified by these potential response predictors and interaction terms 
will be included in models to determine of any of these factors predict responsiveness to the intervention.  
  
To measure the change in home airborne particulate matter (PM2.5 and PM2.5-10) and indoor allergen concentrations 
(cat, dog, mouse, cockroach, and dust mite) among study participants. Distributional properties of baseline levels of 
pollutants (PM2.5 and PM2.5-10) and allergens will be assessed using histograms and boxplots and any necessary 
transformations to these variables will be conducted to obtain approximately Normal distributions. We will subtract 
baseline levels of these exposures from levels recorded 6 months post-randomization to assess the within-person 
change in exposure over time. Differences over time in the intervention group will be compared to those in the 
control group via standard t-tests using a significance cutoff of 0.05. Assessment of significance adjusting for 
multiple comparisons will be done using the method of Benjamini and Hochberg.    
  
To evaluate the role of bacterial communities and S. aureus colonization on asthma morbidity, we will perform 
exploratory data analysis to identify outliers and missing data, and to generate descriptive summaries of multiple 
outcome variables related to asthma morbidity. The primary predictive variable will be S. aureus colonization. We 
will test S. aureus association with asthma outcomes over multiple visits using random effects models. In order to 
adjust for potential confounders, such as child demographic characteristics, etc., we will construct multivariate 
random effects models that account for repeated assessment of the outcomes and time-varying covariates. For 
bacterial community analysis, we will compare taxonomical relative abundances using the Wilcoxon rank-sum test. 
Accounting for clustering within home and host, we will identify the influence of demographic and other factors on 


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microbial composition by calculating the weighted and unweighted UniFrac and the non-parametric ANOSIM 
(ANalysis of SIMilarities) test.  
  
  
d. Early stopping rules.  
The protocol may be halted by the DSMB, IRB or Sponsor upon review of SAEs.  
  
 
7.  
Risks  
a. Medical risks, listing all procedures, their major and minor risks and expected frequency.  
  
Questionnaires  
The risk of the questionnaire is breach of confidentiality.    
  
Blood draw  
The risk of blood drawing is discomfort, bruising, lightheadedness, and rarely infection.    
  
Lung function and exhaled nitric oxide testing  
The risk of lung function and eNO testing is the discomfort of exhaling forcefully, light-headedness 
and occasional minor chest soreness.    
  
Home visits  
The risk of the home visit for collection of environmental data is breach of confidentiality.    
  
Skin testing  
The risk of skin testing is primarily the discomfort from any positive skin tests, which would result 
in wheal and flare responses and pruritus. Approximately 2-3 in 10,000 skin prick tests results in 
allergic symptoms away from the site of the skin testing, such as sneezing, rhinorrhea, or rash.(38, 39)  
Very rarely, an individual who experiences this type of reaction may develop life-threatening 
symptoms such as persistent coughing or wheezing.  A study published in 1987 reported six fatalities 
from skin testing since 1945.(39) From 1985-1989 there were no fatalities from skin testing 
reported,(40) and one fatality was reported from 1990-2001.(41)    
  
Buccal Cell Collection   
There is no known risk associated with the collection of buccal cells using swabs such as this Q-tip 
like device.  
  
Copan e-swab™ and Catch-All™ sample collection   
There is little known risk associated with collection of microbial cells from the nares, oropharynx 
and skin using swab devices. Some participants may experience a gag reflex with oropharyngeal 
sampling.  
  
Nasal Mucus Sample Collection   
There is no known risk associated with the collection of a nasal mucus sample using a nasal spray 
and blowing the nose.  
  
Rodenticides  
Rodenticides are long-acting anticoagulants and there is a risk of developing a coagulopathy with 
intentional ingestion. There have also been case reports of accidental ingestion of these products 
resulting in coagulopathy.(42, 43)  Several prospective studies of accidental rodenticide ingestion in 
children indicate that almost all accidental ingestions can be managed by observation at home since 
they rarely result in coagulopathy. In one series, among more than 200 children with reported 


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accidental ingestion of superwarfarin, two patients had an INR of 1.5 or greater, both of whom were 
asymptomatic.(44) In another series, the National Poisons Unit for London reported no serious 
adverse outcomes over a five year period, during which they received an average of 200 reports per 
year.(45) Of 542 reports of accidental ingestion by children to a US poison control center, follow-up 
coagulation laboratory tests did not detect any significant coagulation abnormalities, no child 
developed bleeding complications, and no child required or received vitamin K.(46) For the purposes 
of this study, rodenticides will be used by licensed exterminators who will be trained specifically on 
procedures for the MAAIT. Rodenticide will only be placed in areas that are not accessible to 
children or pets.  Specifically, rodenticide will be placed in holes and cracks, which will then be 
sealed to prevent extrusion of the rodenticide into the home or access to the rodenticide by children 
or pets.  
  
Pesticides for cockroaches  
The primary insecticide for cockroaches will be Advion (indoxacarb 0.6%) gel bait, which has been 
highly successful in cockroach abatement.  A search of PubMed revealed a few case reports of 
methemoglobinemia and renal failure in adults who intentionally ingested the pesticide in suicide 
attempts.(47-49)  The Material Safety Data Sheet indicates that: “based on animal testing, no 
biologically significant effects are expected from skin or eye contact or by ingestion” 
(http://www.syngentacropprotection.com/pdf/msds/advion cockroach gel bait 11012013.pdf, 
accessed 06/17/2014)).  To minimize risks, bait will be applied in areas targeting cockroach 
infestation and in the smallest quantities to achieve an effect and will not be placed in areas easily 
accessible to children and pets.  
Cleaning agents and caulking agents  
Commercially available, non-bleach cleaning agents (e.g. 409®, Fantastik®) will be used during the 
cleaning that occurs during the first and last intervention visits.  Commercially available foam 
caulking agents (Pur-fill®) will be used to seal holes and cracks during the IPM visits.  Both of these 
agents contain potential irritants that could cause asthma symptoms.  The risk of developing asthma 
symptoms serious enough to require emergency medical attention is very small. The cleaning agents 
will be used as directed by the manufacturers.  The caulking agents will be used as directed by 
manufacturer instructions.  
  
Flovent® Diskus®, Advair™ Diskus®  
Flovent® Diskus®, and Advair™ Diskus® includes an inhaled corticosteroid. The risks include 
upper respiratory tract infection, throat irritation, sinus infection, upper respiratory inflammation, 
rhinitis, a fungal infection inside your mouth, nausea and vomiting, gastrointestinal discomfort, viral 
gastrointestinal infection, non-specific fever, viral infection, viral respiratory infection, cough, 
bronchitis, headache, muscle injury, musculoskeletal pain, and injury. Rinsing after taking this 
medicine may help reduce some of these side effects. At high doses, children taking inhaled steroids 
may grow more slowly. This is usually temporary.   
  
Advair™ Diskus®   
Advair™ Diskus® contains a long acting beta agonist (LABAs). The risks include diarrhea, nausea, 
asthma exacerbation, lung infections, anxiety, fever, dizziness, difficulty sleeping, and chest pain.  
There is a rare risk of asthma-related death. This study will follow black box guidelines by using 
LABAs with inhaled steroids and only when you are not adequately controlled on inhaled steroids.  
  
Albuterol  
Albuterol is a short-acting beta agonist. The risks include increased heart rate and blood pressure, 
nausea, headache, and a jittery or nervous feeling. These symptoms usually end within one hour.  
  
Prednisone  
Prednisone is an oral corticosteroid.  It will only be used if you develop asthma symptoms that are 
not controlled by albuterol. Oral corticosteroids can cause hoarseness, sore throat, and yeast infection 


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of the mouth or throat if taken in high doses for long periods of time. They can also cause effects on 
the body such as weight gain, growth delay, bruising of the skin, cataracts, and diabetes. These 
effects are more likely if the medicine is taken at very high doses for long periods of time. These side 
effects are not likely in this study because of the length of time (typically 4-5 days on any occasion) 
that oral corticosteroids will be taken.  
  
The following medications will only be used if the above medications are not covered by insurance:  
  
Pulmicort Flexhaler® is an inhaled corticosteroid. The risks include weakness, tired feeling, nausea, 
vomiting, low blood pressure, skin rash, hives, swelling, breathing problems, higher chance of infection, 
wheezing, worsening asthma symptoms, headache,, sore throat, rhinitis, stuffy nose, chest pain, anxiety, 
low bone density, glaucoma, cataracts, slow growth or a fungal infection inside your mouth, Rinsing 
after taking this medicine may help reduce some of these side effects.   
  
QVAR® is an inhaled corticosteroid.  This risks include weakness, tired feeling, nausea, loss of appetite, 
skin rash, wheezing, worsening asthma symptoms, headache, dryness in mouth, nose or throat, 
hoarseness, or a fungal infection inside your mouth, Rinsing after taking this medicine may help reduce 
some of these side effects.  
  
Flovent® HFA is an inhaled corticosteroid.  The risks include weakness, tired feeling, nausea, vomiting, 
low blood pressure, skin rash, hives, swelling breathing problems, higher chance of infection, wheezing, 
worsening asthma symptoms, headache, dryness in your mouth, nose, or throat, stuffy nose, sinus pain, 
cough, hoarseness or a fungal infection inside of the mouth. Rinsing after taking this medicine may help 
reduce some of these side effects.  
  
Asmanex® is an inhaled corticosteroid.  The risks include skin rash, hives, swelling breathing problems, 
higher chance of infection, wheezing, worsening asthma symptoms, low bone density, glaucoma, 
cataracts, slow growth, or a fungal infection inside of the mouth. Rinsing after taking this medicine may 
help reduce some of these side effects.  
  
Advair® HFA   
The risks include rash, hives, swelling of face, mouth, or tongue, breathing problems, increased blood 
pressure, fast and irregular heartbeat, chest pain, tremor, nervousness, loss of energy, change in sugar or 
potassium levels, or white blood cells, higher chance of infection, low bone density, glaucoma, cataracts, 
slow growth, throat tightness, throat irritation, hoarseness, voice changes, headache, dizziness, nausea 
and vomiting.  
  
Symbicort® is a combination inhaled corticosteroid and long acting beta agonist. The risks include 
palpitations, cheat pain, rapid heart rate, tremor, or nervousness, a fungal infection inside your mouth, 
higher chance of infection, low bone density, glaucoma, cataracts, and slow growth. Rinsing after taking 
this medicine may help reduce some of these side effects.   
  
Dulera® is a combination inhaled corticosteroid and long acting beta agonist. The risks include inflamed 
nose, throat, or sinuses, headache, increased wheezing, rash, hives, swelling of face, mouth, or tongue, 
breathing problems, loss of energy, change in sugar or potassium levels, higher chance of infection, low 
bone density, glaucoma, cataracts,  and slow growth.  
  
  
b. Steps taken to minimize the risks.  
  
The risk of breach of confidentiality will be guarded against by using unique identifiers for participants and 
labeling all specimens and data with the identifier rather than name. Likewise, databases will only use unique 
identifiers with the exception of one database that will contain the tracking and contact information for the 


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participants.  All databases will be kept on a network drive, and permissions for this drive can be controlled to 
allow only study staff to have access to the databases.  The drive is backed up twice daily.  Only study staff 
trained in phlebotomy will perform venipuncture, and the questionnaires, spirometry, eNO, and urine collection 
for cotinine will be collected by a trained research assistant.  Home visits and collection of environmental 
samples will be collected by a trained research technician. Extermination procedures will be performed by a 
trained and licensed pest exterminator.  Skin testing will be supervised by the Study Coordinator or PCRU nurse 
who will have direct access to the study physician. Appropriate medications, including antihistamines and 
epinephrine will be immediately available during all of the skin testing procedures.  In addition, a short acting 
beta agonist will be available.   
  
An independent Data Safety Monitoring Board (DSMB) will be populated by experts in clinical trials, data and 
safety monitoring, and asthma. The DSMB will review the protocol prior to beginning the trial.  In addition, the 
DSMB will meet annually to review accrual and adverse events.    
The DSMB will review any event as requested by the Investigators or the sponsor. They will review the study 
annually, including accrual and adverse events and submit a report following their meeting. Related adverse 
events and serious adverse events, whether deemed related to study procedures or activities or not, will be 
tracked.  
There will also be weekly meetings of the investigators and study staff, which will include an update of all 
related adverse events and drop-outs.  All serious adverse events will be reported in an expedited manner to the 
IRB.  All unexpected and related serious adverse events will be reported to the DSMB per their request.  
  
c. Plan for reporting unanticipated problems or study deviations.    
Unanticipated problems or study deviations will be reported to the IRB and DSMB in an 
expeditious manner, in adherence with institutional policies.    
  
Adverse events will be documented on an individual adverse event log for each participant.  An adverse event 
form will be used for reporting all related adverse events. An additional form will be required for serious adverse 
events to collect additional information. Information that will be documented includes a brief description of the 
event, onset and duration of the event, severity/grade of the event, resolution status of the event, and relatedness 
to the study procedures. Any medical intervention will also be documented.  
  
A serious adverse event (SAE) is defined as any adverse experience that suggests a significant hazard, 
contraindication, side effect, or precaution. This includes, by may not be limited to, any of the following events:   
  
1. 
Death: A death occurring during the study or which comes to the attention of the investigator during the   
protocol-defined follow-up after the completion of the therapy whether or not considered treatment- related,   
must be reported.   
2. 
Life-threatening: Any adverse therapy experience that places the subject or subjects, in the view of the   
investigator, at immediate risk of death from the reaction as it occurred (i.e., it does not include a reaction   
that had it occurred in a more serious form, might have caused death).   
3. 
Inpatient hospitalizations or prolongation of existing hospitalization.  4. Persistent or significant 
disability or incapacity   
5. Congenital anomaly or birth defect.   
6. An event that required intervention to prevent permanent impairment or damage.  
  
For reporting purposes only, when a participant is hospitalized for an asthma exacerbation, the date of onset of 
the exacerbations will be the date of hospital admission and the date of resolution will be the discharge date.   
For the purposes of this protocol, a pregnancy is considered an SAE and will be reported and followed until 
resolution of the pregnancy with the exception of participants in the Household Asthma Sub study.  Pregnancy is 
not an exclusion for these participants.   


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d. Legal risks such as the risks that would be associated with breach of confidentiality.  
The primary legal risk is breach of confidentiality.  See above for description of how this risk 
will be minimized.   
  
e. Financial risks to the participants.   
Prescription drugs will not be covered by the study.  Prescription drugs are typically covered by 
health insurance.  Participants are responsible for medical care if injured in this study.  
  
  
 
8.  
Benefits  
 
a.  
Description of the probable benefits for the participant and for society.  
  
The potential benefits for the study participant includes receiving an assessment of allergic sensitivities, lung 
function, exhaled nitric oxide, assessment of home environmental exposures, room air filters, allergen-proof 
mattress and pillow encasements and IPM.  This knowledge will impact the way physicians provide care for 
inner-city asthma patients, and will impact policy decisions regarding environmental interventions to reduce 
home exposures that may trigger asthma symptoms.  This information will directly impact the medical care 
provided to this patient population.  
  
The findings from the proposed trial may directly impact patient care and policy.  This proposed trial will answer 
a pivotal question because if ECSs do not provide additional benefit in the context of treatment with controller 
medication, the role of ECS in asthma management should be downgraded. On the other hand, if ECSs do indeed 
reduce controller medication requirements, greater emphasis should be placed on the importance of ECSs in 
asthma management, studies should be conducted to identify best ECS practices, and policies should be changed 
to require third party payers to cover ECS costs.    
  
 
9.  
Payment and Remuneration  
a.  
Detail compensation for participants including possible total compensation, proposed bonus, 
and any proposed reductions or penalties for not completing the protocol.  
  
Participants will receive $40 for each clinic visit completed plus an extra $10 if they bring their medications 
to the visit (x5). Participants who do not meet eligibility requirements at clinic visit 1 will not be able to 
complete the visit but will be paid $10 for the visit. At each clinic visit the child will receive a toy or gift card 
valued at $10.  Participants will receive $25 for each home visit (x3).  Participants will receive an additional 
$5 per pet per home visit for sampling of pets.  Transportation to and from the clinic visits will be paid for by 
the study.  
Participants who use the pest hotline and allow pick-up of fresh rodents will be compensated $20.  
  
  
 
10.  
Costs  
a.  
Detail costs of study procedure(s) or drug (s) or substance(s) to participants and identify who 
will pay for them.    
Participants will be prescribed asthma medications during this study.  Typically these medications are covered by 
health insurance and participants are only eligible if they have insurance.  
  
  
References  
  
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and childhood asthma morbidity. EnvironHealth Perspect. 2009;117(2):294-8.  


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