Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters
Phase: NA
Conditions: Bronchiolitis
Sponsor: IDeA States Pediatric Clinical Trials Network

 
The BREATHE Study:  
Bronchiolitis Recovery  
and the  
Use of High Efficiency Particulate Air (HEPA) Filters 
 
 
UAMS IRB Protocol Number:  274137 
Version Number:  V-08  
24 September 2024 
 
National Clinical Trial (NCT) Identified Number:  NCT05615870 
 
DCOC Principal Investigator: 
Songthip Ounpraseuth, Ph.D. 
(ISPCTN DCOC at UAMS) 
 
Principal Investigators:  
Dr. Kelly Cowan 
(University of Vermont) 
Dr. Erin Semmens 
(University of Montana) 
 
Sponsor: ISPCTN DCOC 
 
Funded by:  NIH 
 
 
 
 
 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 2 of 67 
 
 
Summary of Key Changes from Version-01 to Version-02: 
Affected 
Section(s) 
Summary of Revisions Made from V-01 to 
V-02 
Rationale 
5.4, Screen 
Failures 
Provided example of “further evaluation.” 
Requested by cIRB as part of pre-review 
contingencies 
5.5, 
Strategies 
for 
Recruitment 
and 
Retention 
Added the following to the last bullet ($50 for 
return of PurpleAir monitors) within the 
subsection “Compensation will be provided 
for completion of study activities,”: 
This is for time spent returning equipment. 
Parent(s)/guardians of participant will 
receive pre-paid materials for returning 
equipment, i.e., at no expense to 
parent/guardian. 
Requested by cIRB as part of pre-review 
contingencies 
8.1 Efficacy 
Assessments 
Specified the role of the University of 
Montana in the last 2 bullet points of the 
subsection “Air Quality Measurements (both 
intervention and control groups):”  
Requested by cIRB as part of pre-review 
contingencies 
 
 
Summary of Key Changes from Version-02 to Version-03: 
Affected 
Section(s) 
Summary of Revisions Made from V-02 
to V-03 
Rationale 
Throughout 
• 
Where “HEPA” written out, changed 
“particle” to “particulate” 
Typographical correction 
1.2, Schema 
• 
Deleted “randomization” from bullet 3 
under “During hospitalization” tab 
• 
Pre-intervention tab itself was changed 
FROM “after randomization” TO “after 
Hospital Discharge”  
• 
Added “UPIRTSO” to 4th bullet of “Pre-
intervention” 
Simple corrections for internal 
consistency. 
1.3, Schedule 
of Activities 
• 
Added word “ideally” in the footer 1 
phrase “set-up the air quality monitoring 
equipment ideally within7 days of 
discharge”   
• 
Added “Intervention ideally starts on day 
14” to footer 2. 
 
Updated footer numbers 1 and 2 to 
provide more flexibility and to ensure 
internal consistency.   
 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 3 of 67 
Affected 
Section(s) 
Summary of Revisions Made from V-02 
to V-03 
Rationale 
5.5, Strategies 
for 
Recruitment 
And 
Retention;  
Changed the following: 
• 
Under “Coordinator contact…” 
o For weeks 5-26, changed check-
in: contact from the enrolling site 
1st bullet FROM “weekly or 
monthly and as needed” TO 
“Monthly and as needed” 
• 
Under “compensation will be 
provided for completion of study 
activities” 
o Reimbursement for time spent 
returning equipment FROM $50 
TO $40 
• 
Under “Healthy Homes kit” 
o Reduced the Healthy Homes kit 
dollar value FROM $65.00 TO 
$42.00 
o Added “outlet covers”  
o Deleted “and a Brita (or 
equivalent/similar) water pitcher 
with a filter”  
• 
Under compensation summary, 
changed: 
o Total possible for study activities 
FROM $590 to $580 
o Grand sum FROM $1411 TO 
$1378 
 
• 
Simple correction on contact timing. 
• 
To keep total cash-type 
reimbursements below $600  
• 
Water pitchers no longer available at 
reasonable price in quantity needed 
 
5.5, Strategies 
for 
Recruitment 
.. last section 
“Return of results” section:   
Deleted: 
Study staff will offer to provide to each 
participating family their own household’s 
average pre-intervention and 
intervention-period PM2.5. Study staff will 
provide these results by letter and/or with 
a follow-up phone call.  This can occur any 
time after the individual participant has 
completed the study.  The staff will 
provide a written lay summary of the final 
study results to families with a letter 
and/or follow-up phone call. 
Replaced with text as written. 
 
In partial response to requests made by 
DSMB at the meeting that occurred June 
2022 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 4 of 67 
Affected 
Section(s) 
Summary of Revisions Made from V-02 
to V-03 
Rationale 
6.1.1, Study 
intervention 
description 
Section “Intervention for both experimental 
and control conditions:”  
Deleted from bullet 3:  
To permit participant blinding, all HEPA 
and control units will have identical 
modifications to cover external air quality 
indicators (these methods were 
successfully used in the KidsAir study). 
  And deleted:  
  … air quality indicator lights on the front 
of the machine will also be taped, and the 
actual.. 
In partial response to requests made by 
DSMB at the meeting that occurred June 
2022. 
 
DSMB requested that participants be able 
to see the color of the Winix air quality 
indicator lights. 
6.1.1, Study 
intervention 
description 
• 
Under “Intervention for both 
experimental and control conditions:” 
• 
At end of 2nd bullet, added “and 
provide information on the lights 
(e.g., sensor light) on the units.” 
• 
Under subsection “Experimental 
condition, Active HEPA filtration unit 
use:,” DELETED: 
• 
“Room size will be measured by the 
family and with remote assistance of 
the study team.  This Winix unit will 
cover usual room size in most homes, 
but if there is a very large room that 
is critical for the study (such as the 
child’s sleep space the study team 
will determine on a case-by-case 
basis whether the solution will be to 
place the unit near the child’s bed or 
supply the participant with a second 
unit.” 
• 
“… or a small residence that would be 
adequately covered by one Winix 
unit.” 
• 
In partial response to requests made 
by DSMB at the meeting that 
occurred June 2022. 
 
• 
Simplification and clarification. 
 
6.2.4, 
Preparation 
Added bullet: 
• 
Basic education on strategies to 
improve indoor air quality 
 
Added in partial response to DSMB 
concerns related to participants’ parents 
having information about the quality of 
the air in their  homes 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 5 of 67 
Affected 
Section(s) 
Summary of Revisions Made from V-02 
to V-03 
Rationale 
6.2.4, 
Preparation 
Added the highlighted wording to the 
following existing bullets: 
• 
2 HEPA or control units (unless home is 
small enough that only one HEPA unit is 
needed),  
• 
2 kW meters (0 kW meters if home has 
only two-prong outlets),  
• 
2 PurpleAir monitors (1 if home using 
only one HEPA unit) and mobile hotspot 
with power adapter, 
 
Clarification 
6.4, Study 
Intervention 
Compliance 
At end of 1st paragraph added: 
• 
Note that the kW meters require 
three-prong outlets. If a home has 
only two-prong outlets, they will not 
use the kW meter. 
Ensure people who live in older homes 
are not excluded. 
8.1 Efficacy 
Assessment 
Table 4.  
Major changes throughout table.  See last row 
of table for screen print of changes. 
Simple corrections to match questions 
that will be asked and in partial response 
to DSMB concerns about air quality in 
homes. 
8.1, Efficacy 
Assessments 
Added highlighted wording as indicated: 
• 
Family-collected with study team 
support (bullet 3), added highlighted 
wording to the following: “University of 
Montana central site staff will perform 
quality checks on the data, and, if issues 
arise, they will communicate with 
coordinators and/or families to 
troubleshoot the problem or opt to rely 
on data from the security digital card 
(see below).” 
• 
Under Equipment use (which is under 
“weekly survey..”): 
HEPA/control unit use: For each room 
with a HEPA/control unit, the 
parent/guardian will be asked to 
respond Yes/No to whether they used 
unit and asked to report the usual 
setting used (1, 2, 3, or 4) 
 
Clarification 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 6 of 67 
Affected 
Section(s) 
Summary of Revisions Made from V-02 
to V-03 
Rationale 
9.4.4.; Safety 
analysis 
Added 2nd sentence. 
In partial response to requests made by 
DSMB at the meeting that occurred June 
2022. 
 
 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 7 of 67 
Section 8.1:  Table 4 changes (screen prints). 
 
 
 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 8 of 67 
 
 
 
 
 
 
Summary of Key Changes from Version-03 to Version-04: 
Affected 
Section(s) 
Summary of Revisions Made from V-03 to V-04 
Rationale 
Protocol 
Summary 1.1. 
Synopsis ;  1.2 
Schema “During 
hospitalization;” 
• 
Changed upper limit for enrollment number 
FROM 218 TO 228.   
• 
Noted that number enrolled is equal to number 
consented.  
• 
To account for participants 
who drop out prior to 
randomization  
• 
To clarify meaning of 
enrollment. 
Protocol 
Summary 1.1. 
Synopsis;   
3. Objectives 
and Endpoints 
Table 3;  
Section 9.1, 
Statistical 
Hypotheses, 
sub-section 
“Secondary 
Objective 3:” 
• 
Secondary endpoint number 3:  Noted that the 
average PM2.5 levels are the weekly average(s). 
Clarification. 
1.3 Schedule of 
Activities table 
• 
Add reference to MOP. 
• 
Added that week 26 means end of participation 
for subject 
Clarification. 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 9 of 67 
Affected 
Section(s) 
Summary of Revisions Made from V-03 to V-04 
Rationale 
Section 5.5, 
Subsection 
“Return of 
Results” 
• 
Added “(PM2.5) typically” to first sentence. 
• 
To first paragraph: 
o added last 3 sentences, starting with 
“Exception: Quality control monitoring…” 
• 
To second paragraph: 
o  indicated that summary will be a lay 
summary. 
DSMB report and study team 
response to DSMB requires 
monitoring of PM2.5 levels 
during initial weeks of 
participation and requires that 
participants be notified if PM2.5 
levels are unusually high. 
Section 6.2.4; 
Preparation 
• 
Indicated the certain checklists do not need to be 
cIRB approved and set-up and checklists are 
referenced the MOP. 
• 
Deleted: 
o A checklist will be used to ensure all study 
equipment necessary for participation is 
dispensed to each participant’s family, and 
that the requirements for correct equipment 
setup in the home are met. The checklist will 
be included in the study manual of 
procedures (MOP). 
Clarification/simple 
corrections.  Pertinent 
information in study-specific 
MOP. 
Section 6.4, 
Study 
Intervention 
Compliance   
Added: 
• 
Intervention compliance will be assessed in two 
ways: through kW meters (see Appendix C) and 
caregiver-reported HEPA/control unit use. 
• 
In bullet 1, added highlighted words: 
o Increasing kWh over the course of 
participation will indicate HEPA/control unit 
use. When available, we will also quantify 
actual kWh usage during the intervention 
period by comparing observed kWh used to 
the usage predicted from laboratory tests. 
• 
In bullet 1, last sentence, changed: 
o  “actual kWh” to “observed kWh”  
• 
Unbulleted last para., added: 
o Since not all participants will have kW meters 
and since power interruptions will change 
kW meter settings, caregiver reported 
HEPA/control unit use on weekly surveys will 
be the primary measure of compliance. 
Clarification. 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 10 of 67 
Affected 
Section(s) 
Summary of Revisions Made from V-03 to V-04 
Rationale 
Section 7.2, 
Participant 
Discontinuation/ 
Withdrawal … 
At end of 3rd para., added that participants may be 
discontinued (by investigator) for “caregiver failure to 
follow study instructions (e.g., failure to set up the 
study intervention).” 
To match reasons listed in 
informed consent form 
(section “Can my child be 
taken out of the study even if I 
want my child to continue?”)  
Section 7.3, Lost 
to Follow-up, 
Second bullet 
• 
Deleted: 
o … (at least three telephone calls, and, if 
necessary, a certified letter to the last known 
mailing address of the parent/guardian of the 
participant. 
• 
Replaced above with: 
o See MOP for details. 
Clarity. MOP has more details 
Section 8.1, 
Table 4 
• 
Deleted “U.S. Census Tract” from bullet for 
“Rural/Urban (RUCA code)…. 
• 
Added “approximately” to the “26 weeks” bolded 
statement in middle of table 
• 
Changed last bullet in table  
FROM “Weekly outdoor PM2.5 concentration 
(These data may be obtained after the 26-week 
study period) 
TO  “Model-estimated weekly outdoor PM2.5 
concentration based on residential location (i.e., 
NOT parental reported) (These data may be 
obtained after the 26-week study period and/or 
after completion of the study.)” 
Corrections/clarifications. 
Section 8.1., 
Efficacy 
Assessments, 
subsection Air 
Quality 
Measurements… 
sub-sub section 
“Family-collect 
with …” 
• 
Throughout section: 
o Numerous minor wording changes (for 
clarity/grammar) 
• 
Added to revised 2nd bullet (previously unbulleted 
2nd paragraph to 1st bullet): 
o That baseline is “(pre-intervention)” 
• 
Added to current bullet 3:  
o When connected to WiFi, PurpleAir sensors 
transmit data to a PurpleAir server in real 
time. 
• 
Current bullet 4 and 5 changes  
o See merged cells below for screen print 
showing substantial changes 
 
To meet requirements set 
forth by DSMB report and 
study team’s responses to 
DSMB report.  Specifically to 
ensure that – FOR NEWLY 
ENROLLED PARTICIPANTS - 
initial PM2.5 data are reviewed 
and participant’s families 
notified if unusually high PM2.5 
levels are noted. 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 11 of 67 
Affected 
Section(s) 
Summary of Revisions Made from V-03 to V-04 
Rationale 
Section 8.1., 
Efficacy 
Assessments, 
subsection 
“Weekly survey 
collection of 
child’s daily …” 
• 
First para. : 
• 
Added:   
If a survey remains incomplete, the research 
team will continue to provide reminders to the 
parent/guardian until it is completed or 
closed. 
• 
Deleted:  
If the weekly survey is not completed within 1 day 
of the reminder, the research team will call the 
participant parent/guardian (ideally within 1 
business day) to obtain the survey data by phone 
or prompt the participant’s parent/guardian to 
submit it electronically. 
Simple correctin/clarification. 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 12 of 67 
Affected 
Section(s) 
Summary of Revisions Made from V-03 to V-04 
Rationale 
Section 8.1 
Efficacy 
Assessments; 
previous end of 
section   
Deleted subsection: 
HEPA unit adherence monitoring: 
Adherence to HEPA filtration unit use will be monitored 
by a kW meter attached to each HEPA device (Intertek 
KILL A WATT® EZ Model P4460.01; 
http://www.p3international.com/products/p4460.html) 
(Appendix C). Families will be instructed to attach kW 
meters to the HEPA/control units at the intervention 
onset. These meters enable assessment of power 
consumption and estimate corresponding costs for 
energy usage. Actual kWh usage during the intervention 
period will be compared to the usage predicted from 
laboratory tests. The actual kWh used as reported by 
participants will be divided by the predicted usage and 
this quantity multiplied by 100 to determine participant 
adherence to the intervention. Parents/guardians of 
participants will report the reading from the kW meter 
(number visible on the screen) on the weekly survey. In 
addition to measuring use of the HEPA unit for the 
analysis, study staff will be able to verify that the 
reading is increasing over time. These data will alert the 
study team to potential non-usage of the HEPA/control 
unit or problems with the kW meter to allow 
troubleshooting. 
 
Information included in section 
6.4.  
Section 8.3.1, 
Definition of 
Adverse Events 
• 
Changed the following sentence  
o FROM:  Information on protocol-specific AEs, 
severe AEs, and SAEs will be collected at 
scheduled visits and interval phone calls, if 
needed. 
o TO: Information on protocol-specific AEs, 
severe AEs, and SAEs will be collected from 
participant reports and via phone calls, as 
well as review of weekly surveys. 
Clarification. 
Section 9.2., 
Sample Size 
determination 
• 
Increase enrollment number from 218 to 228 and 
noted that consent equals enrollment.   
• 
Deleted “or 109 participants per arm” from first 
sentence. 
• 
Changed anticipated attrition rate from 10% per 
arm to 16% per arm 
To ensure sufficient number of 
participants randomized to 
allow for data analysis as 
planned. 
Section 10.1.6, 
Key Roles 
• 
Replaced medical monitor information.   
o Deleted Aaron Chidekel, MD (Nemours) and 
his contact information. 
o Replaced with Rebecaa Latch, MD (UAMS) 
and her contact information 
Medical monitor replaced. 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 13 of 67 
 
Summary of Key Changes from Version-04 to Version-05: 
NOTE:  Version-04 had contingencies from the cIRB (UAMS IRB) and was never a 
cIRB-approved version.  Version-04 will remain as a “DRAFT;” however, all changes 
noted in the table for “Key Changes from Version-03 to Version-04” have been 
incorporated into the protocol effective V-05 
Affected 
Section(s) 
Summary of Revisions Made from V-04 to V-05 
Rationale 
5.5, Strategies 
for recruitment 
and retention; 
subsection 
"Return “f 
Results" 
Added the following to end of 1st paragraph in the 
“Return of Results” subsection: 
• 
For equity, after a participant completes the 
study and air quality results are assembled 
based on returned PurpleAir monitors and/or 
data transmitted through WiFi, the study team 
will notify the participant’s caregiver should 
persistently high air pollutant levels be noticed. 
Response to UAMS IRB 
contingency for Protocol V-04. 
Section 8.1, 
Efficacy 
Assessment; 
subsection “Air 
Quality 
Measurements” 
… 
Added the following to end of the paragraph  
constituting the 4th bullet within the “Family-collected 
with study team support remotely” subsection of the 
“Air Quality Measurements (both intervention and 
control groups)” subsection of  section 8.1: 
subsection: 
• 
Similarly, if the study team notices threshold 
exceedance at the end of a child’s participation 
based on returned PurpleAir monitors and/or 
data transmitted through WiFi, the study team 
will notify the participant’s caregiver and 
provide informational resources on indoor air 
quality. 
Response to UAMS IRB 
contingency for Protocol V-04. 
 
 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 14 of 67 
Summary of Key Changes from Version-05 to Version-06: 
Affected 
Section(s) 
Summary of Revisions Made from V-05 to V-06 
Rationale 
1.3. Schedule of 
Activities (Table 
2). 
5.5. Strategies 
for Recruitment 
and Retention 
8.1 Efficacy 
Assessments, 
Table 4. 
Added sentences related to collection of RSV 
vaccination/immunizations information in the 
following specific locations: 
• 
SOA (Table 2) footnote 6.  Added last sentence 
re: data capture of immunization status. 
• 
In 5.5., subsection “Coordinator contact for 
engagement while collecting study data:” 
o Sub-sub section “Weeks 1-4” added last 
open bullet regarding RSV vaccination 
status 
o Sub-sub section “Weeks 5-26” added last 
open bullet regarding RSV vaccination 
status 
• 
In 8.1, Table 4,  
o 1st group of bullets (i.e.,under “Collect 
information at baseline…”), last bullet 
added - regarding RSV 
vaccination/prevention history 
o 2nd group of bullets (i.e., under “Collect 
information at approximately 26 weeks…”), 
last bullet added - regarding RSV 
vaccination/prevention history 
RSV vaccines/immunizations 
only recently became 
available.  The immunization 
status of the mother (if 
immunized while her baby was 
in utero) and the child are 
important in assessing 
susceptibility of the child to 
RSV and its sequelae.  
10.1.6. Key 
Roles and Study 
Governance 
Updated DCOC PI information.  Deleted information 
for Jeannette Lee, PhD, and added information for 
Songthip Ounpraseuth. 
Dr. Lee is retiring/semi-retired 
and Dr. Ounpraseuth has 
replaced her. 
 
 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 15 of 67 
Summary of Key Changes from Version-06 to Version-07: 
NOTE:  Version-06 had contingencies from the cIRB (UAMS IRB) and was never a cIRB-approved 
version.  Version-06 will remain as a “DRAFT;” however, all changes noted in the table 
for “Key Changes from Version-05 to Version-06” have been incorporated into 
protocol V-07. 
Affected 
Section(s) 
Summary of Revisions Made from V-06 to V-07 
Rationale 
8.1, Efficacy 
Assessment, 
Table 4. 
Added  
“(by report from family or medical record review)” 
to the bullets about RSV vaccination/preventive 
treatment history 
Requested change per 
11/28/2023 cIRB contingency 
letter re: V-06:  
• 
“Page 23 indicates data 
related to RSV vaccination 
may be obtained from the 
medical record. The page 
40-41 tables do not list 
medical record review as a 
possibility for this data 
collection. Please review 
and revise this apparent 
discrepancy. 
 
 
Summary of Key Changes from Version-07 to Version-08: 
Affected 
Section(s) 
Summary of Revisions Made from V-07 to V-08 
Rationale 
Cover page  
Changed overall DCOC PI  
     FROM: Jessica Snowden, MD  
     TO: Songthip Ounpraseuth, PhD  
Jessica Snowden, MD, left 
UAMS/DCOC end of August 
2024 and Songthip 
Ounpraseuth, Ph.D., is the new 
DCOC (operational) PI who will 
sign off in CLARA. 
10.1.6, Key 
Roles and Study 
Governance 
• 
Changed name and associated contact info: 
   FROM: Jessica Snowden, MD 
   TO:  Sherry Courtney, MD 
• 
Added Fred Prior, PhD, as DCOC Co-I 
• 
Updated Medical Monitor’s contact information 
Sherry Courtney is an MD who 
will fill the MD part of Dr. 
Snowden’s role.  Dr. Prior’s 
role within the DCOC has 
recently changed. 
 
 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 16 of 67 
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................ 19 
ABBREVIATIONS ...................................................................................................................... 19 
1 
PROTOCOL SUMMARY ................................................................................................ 21 
1.1 
Synopsis ................................................................................................................... 21 
1.2 
Schema .................................................................................................................... 23 
1.3 
Schedule of Activities (SoA) .................................................................................. 24 
2 
INTRODUCTION ............................................................................................................. 25 
2.1 
Study Rationale ....................................................................................................... 25 
2.2 
Background .............................................................................................................. 26 
2.3 
Risk/Benefit Assessment ....................................................................................... 28 
2.3.1 
Known Potential Risks ........................................................................... 28 
2.3.2 
Known Potential Benefits ...................................................................... 28 
2.3.3 
Assessment of Potential Risks and Benefits ..................................... 29 
3 
OBJECTIVES AND ENDPOINTS ................................................................................. 30 
4 
STUDY DESIGN .............................................................................................................. 31 
4.1 
Overall Design ......................................................................................................... 31 
4.2 
Scientific Rationale for Study Design .................................................................. 31 
4.3 
Justification for Dose .............................................................................................. 32 
4.4 
End of Study Definition .......................................................................................... 33 
5 
STUDY POPULATION .................................................................................................... 33 
5.1 
Inclusion Criteria ..................................................................................................... 33 
5.2 
Exclusion Criteria .................................................................................................... 33 
5.3 
Lifestyle Considerations ......................................................................................... 34 
5.4 
Screen Failures ....................................................................................................... 34 
5.5 
Strategies for Recruitment and Retention ........................................................... 34 
6 
STUDY INTERVENTION ................................................................................................ 37 
6.1 
Study Interventions Administration ...................................................................... 37 
6.1.1 
Study Intervention Description ............................................................. 37 
6.1.2 
Dosing and Administration .................................................................... 38 
6.2 
Preparation/Handling/Storage/Accountability..................................................... 38 
6.2.1 
Acquisition and accountability .............................................................. 38 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ........................ 38 
6.2.3 
Product Storage and Stability ............................................................... 38 
6.2.4 
Preparation .............................................................................................. 39 
6.3 
Measures to Minimize Bias ................................................................................... 39 
6.4 
Study Intervention Compliance ............................................................................. 40 
6.5 
Concomitant Therapy ............................................................................................. 40 
6.5.1 
Rescue Medicine .................................................................................... 40 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................................... 40 
7.1 
Discontinuation of Study Intervention .................................................................. 40 
7.2 
Participant Discontinuation/Withdrawal from the Study .................................... 40 
7.3 
Lost to Follow-Up .................................................................................................... 41 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................ 41 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 17 of 67 
8.1 
Efficacy Assessments ............................................................................................ 41 
8.2 
Safety and Other Assessments ............................................................................ 44 
8.3 
Adverse Events and Serious Adverse Events ................................................... 45 
8.3.1 
Definition of Adverse Events (AE) ....................................................... 45 
8.3.2 
Definition of Serious Adverse Events (SAE) ...................................... 45 
8.3.3 
Classification of an Adverse Event ...................................................... 45 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up
 
46 
8.3.5 
Adverse Event Reporting ...................................................................... 47 
8.3.6 
Serious Adverse Event Reporting ....................................................... 47 
8.3.7 
Reporting Events to Participants ......................................................... 47 
8.3.8 
Events of Special Interest ..................................................................... 47 
8.3.9 
Reporting of Pregnancy ........................................................................ 47 
8.4 
Unanticipated Problems ......................................................................................... 48 
8.4.1 
Definition of Unanticipated Problems (UPIRTSOs) .......................... 48 
8.4.2 
Unanticipated Problem Reporting ........................................................ 48 
8.4.3 
Reporting Unanticipated Problems to Participants ........................... 49 
9 
STATISTICAL CONSIDERATIONS .............................................................................. 49 
9.1 
Statistical Hypotheses ............................................................................................ 49 
9.2 
Sample Size Determination ................................................................................... 50 
9.3 
Populations for Analyses ....................................................................................... 50 
9.4 
Statistical Analyses ................................................................................................. 50 
9.4.1 
General Approach .................................................................................. 50 
9.4.2 
Analysis of the Primary Efficacy Endpoint .......................................... 51 
9.4.3 
Analysis of the Secondary Endpoints ................................................. 51 
9.4.4 
Safety Analyses ...................................................................................... 51 
9.4.5 
Baseline Descriptive Statistics ............................................................. 51 
9.4.6 
Planned Interim Analyses ..................................................................... 52 
9.4.7 
Sub-Group Analyses .............................................................................. 52 
9.4.8 
Tabulation of Individual participant Data ............................................ 52 
9.4.9 
Exploratory Analyses ............................................................................. 52 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS . 52 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ............................... 52 
10.1.1 
Informed Consent Process ................................................................... 52 
10.1.2 
Study Discontinuation and Closure ..................................................... 54 
10.1.3 
Confidentiality and Privacy ................................................................... 54 
10.1.4 
Multi-site Communications (IRB-related) ............................................ 54 
10.1.5 
Future Use of Stored Specimens and Data ....................................... 55 
10.1.6 
Key Roles and Study Governance ...................................................... 55 
10.1.7 
Safety Oversight ..................................................................................... 56 
10.1.8 
Clinical Monitoring .................................................................................. 56 
10.1.9 
Quality Assurance and Quality Control ............................................... 57 
10.1.10 
Data Handling and Record Keeping .................................................... 57 
10.1.11 
Protocol and study Deviations .............................................................. 58 
10.1.12 
Publication and Data Sharing Policy ................................................... 58 
10.1.13 
Conflict of Interest Policy....................................................................... 59 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 18 of 67 
10.2 
Additional Considerations ...................................................................................... 59 
10.3 
Protocol Amendment History ................................................................................ 59 
11 
REFERENCES ................................................................................................................. 59 
Appendix A: Winix® 5500-2 HEPA Filter ................................................................................ 65 
Appendix B: PurpleAir PA-II-SD Monitor ................................................................................ 66 
Appendix C: Kill A Watt EZ Meter ............................................................................................ 67 
 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 19 of 67 
STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Council on Harmonisation Good Clinical Practice (ICH GCP, 
specifically ICH E6(R2)) and the following:  
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies that are not regulated by the 
FDA, specifically, 45 CFR Part 46 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible for the conduct, 
management, or oversight of NIH-funded clinical trials have completed Human Subjects Protection and ICH GCP 
Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be submitted to the 
Institutional Review Board (IRB) of record for review and approval.  Approval of the protocol and the consent form 
(including HIPAA authorization) must be obtained before any participant is enrolled.  Any amendment or modification to 
the protocol will require review and approval by the reviewing IRB before the changes are implemented to the study.  In 
addition, all changes to the consent form will be IRB-approved; a determination will be made regarding whether a new 
consent needs to be obtained from participants who provided consent using a previously approved consent form. 
 
ABBREVIATIONS 
 
Table 1. Abbreviations 
AE 
Adverse Event 
API 
Application programming interface 
CFR 
Code of Federal Regulations 
CMP 
Clinical Monitoring Plan 
COPD 
Chronic Obstructive Pulmonary Disease 
CPAP 
Continuous Positive Airway Pressure 
CRF 
Case Report Form 
DCOC 
Data Coordinating and Operations Center 
DSMB 
Data Safety Monitoring Board 
ECHO 
Environmental Influences on Child Health Outcomes 
ECMO 
Extracorporeal membrane oxygenation 
ED 
Emergency Department 
EDC 
Electronic Data Capture 
EPA 
Environmental Protection Agency 
GCP 
Good Clinical Practice 
HEPA 
High Efficiency Particulate Air 
HFNC 
High Flow Nasal Cannula 
HIPAA 
Health Insurance Portability and Accountability Act  
IAQ 
Indoor Air Quality 
ICF 
Informed consent form 
ICH 
International Council (previously Conference) on Harmonisation  
IRB 
Institutional Review Board 
ISPCTN 
IDeA States Pediatric Clinical Trials Network 
kW 
Kilowatt 
kWh 
Kilowatt Hour 
LRTI 
Lower respiratory tract infection 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 20 of 67 
MOP 
Manual of Procedures 
NCT 
National Clinical Trial 
NIH  
National Institutes of Health 
NO2 
Nitrogen Dioxide 
PI 
Principal Investigator 
PedsQLTM 
Pediatric Quality of Life Inventory 
PM 
Particulate Matter 
PM2.5 
Particulate matter <2.5 micrometers in diameter  
QA 
Quality Assurance 
QC 
Quality Control 
QOL 
Quality of Life 
RCT 
Randomized controlled trial 
RSV 
Respiratory syncytial virus 
RUCA 
Rural-Urban Commuting Area 
RV 
Rhinovirus 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Secure Digital 
SFD 
Symptom-free days 
SMART 
IRB 
a platform designed to ease common challenges associated with initiating multisite research and to 
provide a roadmap for institutions to implement the NIH Single IRB Review policy 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
UAMS 
University of Arkansas for Medical Sciences 
UC 
Urgent Care 
UP 
Unanticipated Problem 
UPIRTSO 
Unanticipated Problem(s) Involving Risk(s) to Subjects of Others  
US 
United States 
 
 
 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 21 of 67 
1 
 
PROTOCOL SUMMARY 
 
1.1 
SYNOPSIS  
 
Title: 
 
The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air 
(HEPA) Filters 
 
 
Study Description: 
This is a multi-center, parallel, double-blind, randomized controlled clinical trial. Children 
<12 months of age hospitalized with bronchiolitis are randomized 1:1 to receive a 24-week 
home intervention with filtration units containing HEPA and carbon filters (in the child’s 
sleep space and a common room) to improve indoor air quality (IAQ) or to a control group 
with filtration units without HEPA and carbon filters. The HEPA intervention units and 
control units will be used for 24 weeks after pre-intervention IAQ measurements. Children 
are followed for respiratory outcomes over the pre-intervention and intervention periods.   
 
 
Objectives: 
 
Primary Objective: 
To determine if use of a HEPA filtration unit home intervention reduces the respiratory 
symptom burden (symptom-free days; SFD) for 24 weeks compared to a use of a control 
unit. 
 
Secondary Objectives:    
1. To test the efficacy of a HEPA filtration home intervention, relative to the control arm, 
on difference in number of unscheduled healthcare visits for respiratory symptoms over 
24 weeks. 
2. To test the efficacy of a HEPA filtration home intervention, relative to the control arm, 
on difference in quality of life (QOL). 
3. To test the efficacy of a HEPA filtration home intervention, relative to the control arm, 
on difference in particulate matter <2.5 micrometers in diameter (PM2.5) levels in the 
home over 24 weeks. 
 
 
Endpoints: 
Primary Endpoint:   
Number of caregiver-reported SFDs over 24 weeks (SFD defined as a 24-hour period 
without coughing, wheezing, or trouble breathing). 
 
Secondary Endpoints: 
1. Caregiver-reported number of hospitalizations, Emergency Department (ED) or Urgent 
Care (UC) visits, or other unscheduled medical visits for respiratory complaints (cough, 
wheeze, or trouble breathing). 
2. Total QOL score, as measured by the PedsQLTM Pediatric Quality of Life Inventory 
Infants Scales questionnaire at the end of the intervention period. 
3. Weekly average PM2.5 levels as measured by 2 in-home PurpleAir monitors over 24 
weeks and scaled to the unit of micrograms per cubic meter (µg/m3) per week.   
 
 
Study Population: 
Up to 228 children consented (enrolled), age <12 months (at admission), with their first 
hospitalization for bronchiolitis  
 
 
Phase: 
Not applicable 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 22 of 67 
 
 
Description of 
Sites/Facilities Enrolling 
Participants: 
Hospitals that admit children with bronchiolitis and that are affiliated or collaborating with 
ECHO IDeA States Pediatric Clinical Trial Network (ISPCTN) clinical sites 
 
 
 
Description of Study 
Intervention: 
Stand-alone HEPA units containing an active HEPA filter and a carbon pre-filter in both the 
child’s sleep space and common area of the home OR control units without a HEPA and 
carbon filter  
 
 
Study Duration: 
24 months 
 
 
Participant Duration: 
Approximately 26 weeks of subject participation beginning after hospitalization for 
bronchiolitis 
 
 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 23 of 67 
1.2 
SCHEMA 
 
 
 
During hospitalization
• Total n=228
• Screen potential participants by inclusion and exclusion criteria
• Informed consent (study enrollment) 
• Review and document baseline characteristics and risk factors for recurrent wheeze
• Equipment package sent home with family at discharge (air quality measurement equipment) (mailing or locally 
arranged pickup/delivery are other options)
Pre-intervention
(Weeks 1-2 After Hospital Discharge
• HEPA units mailed to participants 
• Pre-intervention measurements: continuous PM2.5 measured by PurpleAir monitors in child's sleep space and a  
common room (family set up of equipment with remote support from the research team)
• Weekly collection of symptoms, healthcare visits, time away from home, and equipment use via EDC survey
• Severe AE, SAE, and UP/UPIRTSO review
Intervention 
(Weeks  3-26)
• Continuous HEPA unit use (active or control) in child's sleep space and a common room
• Continuous use of kilowatt hour meter to measure HEPA unit adherence
• Continuous PM2.5 monitoring via PurpleAir monitor in child's sleep space and a common room
• Weekly collection of symptoms, healthcare visits, time away from home, and equipment use via EDC system
• Severe AEs, SAEs, and UP/UPIRTSOs review
Intervention Week 26
• Quality of Life Survey
• Review and update participant characteristics and risk factors for recurrent wheeze

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 24 of 67 
1.3 
SCHEDULE OF ACTIVITIES (SOA) 
Table 2. Schedule of Activities (See MOP for definitions of “weeks.”) 
Evaluation/Procedures 
Screen1 
(hospital) 
Enroll / 
Randomize 
In hospital 
(+1 week) 
Pre-intervention 
Weeks 1-2 after 
hospital 
discharge2 
Intervention2 
 
Weeks 3-26 
Week 26 
(End of 
Participation)  
Review inclusion/exclusion criteria 
x 
x 
 
 
 
Informed consent  
 
x 
 
 
 
Document participant characteristics and 
risk factors for recurrent wheeze3 
 
x 
 
 
x 
Pre-intervention period (in all study 
participant homes – both intervention and 
control): up to 2 weeks continuous home 
PM2.5 monitoring via PurpleAir4 
 
 
x 
 
 
Intervention period (in all study 
participant homes – both HEPA/control 
unit): Continuous home PM2.5 monitoring 
via PurpleAir4 
 
 
 
x 
 
Continuous HEPA/control unit use5 
 
 
 
x 
 
Continuous use of kilowatt meter to 
measure HEPA/control unit adherence5 
 
 
 
x 
 
Weekly submission: Symptom survey, 
number of medical visits, number of nights 
away from home, HEPA/control unit 
adherence7  
 
 
x 
x 
 
Check-in contact with study team6 
 
 
x 
x 
 
QOL Survey7 
 
 
 
 
x 
1 Screening and enrollment ideally will occur during hospitalization. However, enrollment can occur after discharge to home if 
the family can receive and set-up the air quality monitoring equipment ideally within7 days of discharge.  Other procedures 
can occur at home.  
2 Day of hospital discharge is defined as day 1. Intervention ideally starts on day 14. 
3 See Table 4.  
4 Families place PurpleAir monitors in the child’s sleep space and in another common room. Baseline PM2.5 measurements are 
collected for up to 14 days and then the family will begin using HEPA units in the same rooms (child’s sleep space and 
another common room) that contain the PurpleAir monitors while PM2.5 monitoring continues. HEPA units will have active 
filters in the intervention group and no HEPA or carbon filters in the control group.  
5 Kilowatt-hour meter is used to measure actual HEPA unit use. All devices are simple to plug in. The study team will work with 
the family remotely to confirm correct installation and placement of the devices at baseline and at the start of HEPA use and 
confirm data transmission from the PurpleAir monitor. 
6 Weeks 1-4, check-in with the enrolling site will occur weekly and as needed (minimum of weekly). Weeks 5-26, check-in with 
the enrolling site will occur weekly or monthly and as needed (minimum of monthly). During the check-in, the study team 
will assist or prompt EDC documentation as needed, assess equipment questions/concerns, and safety assessments will 
occur (AE, SAE, UPIRTSO). Data capture of RSV vaccination/preventive treatment status will be collected by caregiver report 
or may be obtained from the medical record. 
7 Family will receive an Electronic Data Capture (EDC) system survey link weekly by text (if allowed by the local site) or email. 
The family will submit the brief questionnaire (alternatively, the study staff can call the parent(s)/guardian(s) to read the 
questions and record the responses in the EDC system for the parent(s)/guardian(s)). QOL survey will also be administered 
electronically (with alternative of survey completion by phone with study staff).  
 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 25 of 67 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
Acute viral bronchiolitis is the most common reason for hospitalization of infants less than 2 years of age in the United 
States, with ~130,000 admissions per year.1,2 The prevalence of bronchiolitis is between 18% and 32% in the first year of 
life and between 9% and 17% in the second year of life.3,4 Children hospitalized for bronchiolitis are at high risk for 
shorter-term (recurrent respiratory symptoms and wheeze in the subsequent year) and longer-term (persistent 
childhood asthma) adverse respiratory outcomes for which there are no effective secondary prevention strategies. The 
majority of hospitalizations for bronchiolitis (78-87%) occur in children <1 year old,1 among whom bronchiolitis 
constitutes 18% of all hospitalizations. In these children <1 year old, there may also be higher risk of recurrent wheeze 
and development of asthma relative to older children hospitalized with bronchiolitis.   
The early life event of the first episode of severe (hospitalized) bronchiolitis may be a critical time point to implement 
prevention strategies to reduce respiratory symptom burden in this high-risk population. Multiple factors, including 
environment, contribute to risks of adverse outcomes. Indoor air pollution is a known modifiable environmental risk 
factor for respiratory conditions, and improvement of IAQ following hospitalization for bronchiolitis may be a prevention 
opportunity to improve health outcomes.  
Numerous treatments have been evaluated to prevent symptoms and longer-term respiratory effects in infants 
hospitalized for bronchiolitis,5-13 but no effective strategies have been identified to date. Observational studies have 
repeatedly indicated that the environment, and air pollution in particular, is an important target for intervention with 
decades of research showing that air pollution adversely impacts respiratory health.14-18 Infants are particularly 
susceptible to respiratory impacts of air pollution because their lungs are not fully developed; they have a high 
respiratory rate, and their intake of air relative to bodyweight is greater compared to adults.19 In healthy infants, 
associations have been observed between exposure to higher air pollution and increased risk of respiratory symptoms 
following respiratory tract infections as well as respiratory infections that are longer in duration.18 In its 2021 policy 
statement, “Ambient air pollution: health hazards to children,” the American Academy of Pediatrics highlights the role 
of air pollution in respiratory diseases, lung development, and asthma incidence and the importance of reducing these 
harmful exposures.19  
Fine particulate matter (particulate matter <2.5 microns in aerodynamic diameter; PM2.5) is one of the air pollutants 
most strongly and consistently linked to health effects. Ambient sources include traffic, industry, and wildfires. Examples 
of indoor sources include outdoor PM2.5 that has infiltrated, appliances, woodstoves, and pets. Infants, on average, 
spend approximately 90% of their time indoors.20,21 As a result, it is critical to maximize the quality of indoor air.  
Portable air cleaners (PACs) effectively reduce PM2.5 concentrations in indoor air, with the vast majority of studies 
indicating reductions of at least 50%.22 PACs are appealing as interventions because they are commercially available and 
can be universally implemented. PACs do not disrupt home infrastructure and do not require specialized expertise or 
medical prescription. HEPA is a type of filter in a PAC that is highly efficient in removing PM2.5. In interventional trials, 
use of HEPA filters has been associated with improvement in respiratory outcomes such as asthma in children and 
chronic obstructive pulmonary disease (COPD) in adults. Specifically, HEPA filtration resulted in improvements in 
pulmonary function and asthma control test scores and decreases in asthma-related healthcare visits and symptom 
scores.23 In a recent study of HEPA efficacy in former smokers with COPD, those assigned to the active filter group, 
relative to placebo, had greater reduction in respiratory symptoms and a lower rate of moderate exacerbations and 
rescue medication use after 6 months.24  
In summary, air pollution is associated with respiratory symptoms and disease, particularly in sensitive populations, 
including infants. Air pollution is, therefore, a key intervention target. HEPA filters are efficacious in cleaning the air and 
improving multiple indicators of health. To date, however, no clinical trial has tested the efficacy of HEPA filtration units 
in increasing symptom-free days (SFDs) in infants hospitalized for bronchiolitis. Our study aims to address this important 
gap and improve the health of infants who have experienced this severe and common respiratory event. 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 26 of 67 
Reduction in these symptoms may lead to decreased healthcare utilization and improve QOL for a large population. The 
current bronchiolitis care guidelines lack recommendations for post-hospitalization symptom reduction. If effective, 
HEPA filtration intervention can help fill this gap.  
Research Question: For children <12 months of age hospitalized with bronchiolitis, will those who receive a HEPA 
filtration unit household intervention to reduce PM2.5 have decreased respiratory symptom burden over 24 weeks 
compared to those who receive a control HEPA unit? 
 
2.2 
BACKGROUND  
There is a high burden of respiratory sequelae for children hospitalized with bronchiolitis 
In addition to the recognized morbidity and mortality associated with the acute infection, children often experience 
subsequent, recurrent respiratory symptoms with a high burden of symptomatic days, especially children who are less 
than 12 months old.5 Furthermore, 30-40% of children who are hospitalized for bronchiolitis progress to have recurrent 
episodes of wheezing with or without lower airway infections.25-27 There is also an increased risk of these children 
developing asthma compared to children without a history of bronchiolitis,27,28 with 30-50% of these children developing 
asthma by 5 years of age.29 Data suggest that the airways can be affected into adulthood, resulting in an increased 
incidence of asthma and chronic obstructive pulmonary disease in those with a history of infantile bronchiolitis.30 
Bronchiolitis and recurrent wheezing in this age group also impact QOL. Domains that are negatively impacted include 
overall health, discomfort, and physical abilities of the child, and parental stress.31,32 The frequency of other respiratory 
illnesses, respiratory symptoms and the parental impacts of increased anxiety and associated medical costs is also 
increased in families with a child who has bronchiolitis and recurrent wheeze.33  
Bronchiolitis is a heterogeneous disease in both presentation and later childhood outcomes, but post-acute recurrent 
respiratory symptoms are a common element.  
The case definition of acute bronchiolitis is based on clinical criteria. The American Academy of Pediatrics’ definition of 
infectious bronchiolitis includes children under the age of 2 years with “a constellation of clinical symptoms and signs 
including a viral upper respiratory prodrome followed by increased respiratory effort and wheezing.” 34 There is 
recognized heterogeneity of the disease presentation and outcomes. For example, most infected children are not 
admitted to the hospital, and only a small percentage require intensive care.35,36 Also, time to recovery varies from 
several days to persistent symptoms past the duration of infection.13,37,38 Several conditions other than infections can 
present with wheezing in this age group, so there is confusion in the literature as several terms have been used 
interchangeably, such as reactive airway disease or infantile asthma or wheezy bronchitis.39 Interestingly, there appears 
to be a dose-response relationship between the severity of the infectious episode and risk of recurrent wheeze as 
infants with bronchiolitis who are hospitalized are at increased risk for recurrent wheeze and asthma compared to those 
not hospitalized.40 The viral load (based on quantitative analysis of genomic material in secretions) trends with the 
severity of illness.41,42 These data support the notion that reducing insults to the respiratory tract might have a long-term 
impact on airway health. Even though cases of bronchiolitis are heterogeneous, cases of bronchiolitis requiring 
hospitalization of any severity are a risk factor for recurrent respiratory symptoms and asthma.    
A number of infectious agents are associated with bronchiolitis. The most commonly identified pathogens are 
respiratory syncytial virus (RSV) and rhinovirus (RV), although there are several other infectious agents, including 
influenza, human metapneumovirus, adenovirus and uncommonly, Bordetella pertussis that can cause bronchiolitis.43 
Both the long-term sequelae and presentations of bronchiolitis appear to vary among agents, although there is 
significant overlap, including increased risk of recurrent respiratory symptoms in the subsequent year and increased 
preschool asthma risk. RSV (the most common etiology in infants less than 1 year of age) tends to present with more 
severe illness, increased risk of respiratory failure, and longer hospitalization than RV but may be associated with a 
lower incidence of longer-term wheezing and asthma compared with RV.44,45 RV, in turn, tends to have a milder course 
than RSV but the subsequent development of asthma that persists later in childhood is more common.46,47 It is unclear if 
the long-term consequences of bronchiolitis (recurrent wheezing or asthma) occur because of a genetic predisposition 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 27 of 67 
or as a result of damage to the airways from the initial or repeated infections, and what role household environment 
may play in exacerbating these factors. Certainly, the pathogenesis of bronchiolitis, regardless of infectious agent, could 
lead to long-term airway damage since the virally induced process causes airway inflammation and plugging from 
cellular necrosis and mucous. For safety reasons, it is impractical to sample small airway specimens from infants who 
have fully recovered from the acute infection to study the structural or cellular mechanisms accounting for repeated 
episodes of wheezing or asthma. Evidence for long-term pathologic changes can be extrapolated from a rat model of 
RSV bronchiolitis where airway inflammation and cellular debris in the acute phase of infection precede a prolonged 
period of airway remodeling with airways scarring, smooth muscle hypertrophy, and mucosal thickening. In this animal 
model, there are also increased numbers of eosinophils. These changes would implicate both structural narrowing and 
cellular- or cytokine-mediated sensitization to foreign antigens as mechanisms of wheezing post-recovery.48 
Environmental exposures, including indoor air quality, influence respiratory health and are unstudied targets for 
prevention of recurrent respiratory symptoms after bronchiolitis.  
Because there are no effective treatments for viral bronchiolitis and long-term effects can be serious and/or 
burdensome, disease sequelae prevention is important. Interventions that reduce the risk of recurrent wheeze and 
other respiratory symptoms after the initial episode can immediately affect the burden of illness on the child, family, 
and healthcare system. Interventions that disrupt harmful interactions among the host, subsequent respiratory viruses, 
and the environment might also impact the risk and severity of wheezing illness in the very young, and the long-term 
risk of airway damage and asthma. One preventative measure to reduce respiratory symptoms widely supported in the 
literature is avoidance of air pollution. Predisposition to bronchiolitis appears to increase with exposure to 
environmental air pollution from either outdoor or indoor sources.49-51 Numerous studies show a clear contribution of 
indoor air pollution to childhood lung disease, including bronchiolitis, pneumonia, and asthma.50-52 Of the six air 
pollutants regulated by the U.S. Environment Protection Agency (EPA), particulate matter (PM) is most frequently 
identified in causing or worsening conditions such as COPD, asthma, cardiovascular events, and infections in adults, and 
low birth weight, asthma, and lower respiratory tract infection (LRTI) in children. Similarly, methods of lowering both 
short- and long-term exposure lessen the ill effects of PM.53-61 PM decreases are associated with improved health 
outcomes in children with asthma.62 PM has various components depending on the source, including elemental carbon, 
semi-volatile organic compounds, and heavy metals, all of which have oxidative potential.63,64 PM also can contain 
antigenic particles from animal dander, mites, cockroaches and mold spores, among others, each of which can provoke 
airway sensitization.65 PM is also a major component of tobacco smoke with a separate set of components, but still with 
major health impacts.66,67 The type of PM most frequently associated with health impacts is particulate matter 
<2.5 microns in aerodynamic diameter (PM2.5), which travels deep into the lungs and into the circulatory system.66 
Sources of indoor PM2.5 include infiltration of ambient PM,63,66 as well as biomass combustion (from indoor or outdoor 
sources). PM2.5 generated from biomass combustion has a high percentage of carbonaceous material, which also has 
pro-oxidant properties.64,66 An extensive body of research indicates that it is the small size of these particles that is most 
important to respiratory health.99 Unless removed, PM2.5 can persist in the air for extended periods of time. 
A reliable method for decreasing PM2.5 in residential environments is portable air-cleaning units containing HEPA or 
HEPA-type filters.55,68-74 Most studies show reductions of 50% or greater.22 In addition, larger-sized airborne particulate 
matter, such as pollen and dust, is also effectively cleared by HEPA filters. HEPA filters have greater than 90% removal 
efficiency for airborne particles from multiple sources between 0.001 and 10 microns in diameter.75 In addition to a 
HEPA filter, the proposed system for this study, the Winix 5500-2, also contains a carbon filter, which removes gaseous 
pollutants including nitrogen dioxide,80 a combustion-generated pollutant and respiratory irritant.  
Filter efficacy in removing particles, especially PM2.5, from the air has been demonstrated convincingly, but what is also 
clear is that the unit needs to be turned on for it to work. Filtration units that are too noisy or consume too much 
electricity may be unsustainable long-term. We have selected the Winix 5500-2 for this study because it is relatively 
quiet, energy efficient, and with demonstrated efficacy in lowering PM2.5 concentrations.  
We will measure home levels of PM2.5 in this study because it is a main component of indoor air pollution with a clear 
relationship to respiratory symptoms. It is the most likely component of indoor air pollution to be related to respiratory 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 28 of 67 
symptoms. PM2.5 is expected to be present in all homes, which is not true for all other types of air pollution. With the 
development of low-cost and easily installed sensors, it is now feasible to continuously measure and remotely monitor 
PM2.5 in homes.76-78 In addition to HEPA filters, the filtration units used for this study’s intervention will also be equipped 
with carbon filters, a common component of stand-alone commercially available HEPA filtration units. Carbon filters may 
reduce exposure to non-PM indoor air pollutants, including NO2, thereby potentially enhancing the air-cleaning benefit 
of filtration units.79,80 Therefore, users of HEPA units additionally equipped with carbon filters may experience 
respiratory benefit even if PM2.5 is ultimately not the main or only factor driving symptoms. 
Although it is beyond the scope of this protocol, children in this study may be followed longer term to determine 
whether this intervention reduces asthma rates or improves asthma outcomes. It is plausible that reducing respiratory 
symptom burden in early life, improved air quality in early life, or both can decrease childhood asthma rates after 
bronchiolitis.   
Summary 
Bronchiolitis and respiratory sequelae can cause lasting health and cost consequences with no currently identified 
effective secondary prevention. Accordingly, secondary preventive measures might significantly reduce the incidence of 
recurrent respiratory symptoms and long-term pulmonary consequences such as asthma. Indoor air pollution, 
specifically PM, affects airway health and is associated with childhood respiratory diseases. Therefore, this is a 
reasonable prevention target. However, it is unknown whether an intervention to reduce indoor air pollution can 
effectively reduce symptoms and improve symptom-free days among infants with severe bronchiolitis. Because HEPA 
filters reliably decrease these components of household air pollution and are easy and cost-effective to use, we propose 
to study HEPA filtration to decrease respiratory symptom burden in infants hospitalized with bronchiolitis.   
 
2.3 
RISK/BENEFIT ASSESSMENT   
2.3.1 KNOWN POTENTIAL RISKS  
This study poses minimal risk to participants. Possible risks include the following: 
• 
There is potential for false reassurance that the intervention prevents all adverse home environmental exposures.    
• 
Noise produced by the device may be considered by some to be a “white noise” but could be bothersome or 
harmful if the highest setting is used continuously in close proximity to the child. 
• 
The device may take up space, causing inconvenience.   
• 
Participating individuals could be injured or experience electrical shock during instrument installation or use in the 
home (childproofing required). 
Methods of reducing risk are discussed in Section 2.3.3. 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
There is potential for benefit to the research community and future patients. There is the potential benefit to individual 
participants in decreasing respiratory symptoms, though we cannot estimate the direct impact on the health of the 
individual participants. Interventions provided in the study can improve the health of individuals living within the home 
environment, which may be beneficial to household members beyond the child participant (though this endpoint is not 
studied). HEPA filtration decreases PM in the air to improve IAQ, but we cannot estimate the direct impact on the health 
of the individual participants and household members.  
 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 29 of 67 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
We do not anticipate significant health risks to participants and will minimize the possible risks described above. The 
benefit of understanding relationship between the IAQ environment and the health of children with bronchiolitis 
outweighs the risks. Standard of care medication/treatment will not be altered based on study measurements. To 
minimize potential risks to participants described in Section 2.3.1: 
• 
The study team will provide education that HEPA filtration will not prevent all adverse environmental exposures. 
Even though HEPA filtration can improve IAQ, it does not decrease all of the harmful contaminants that can be in 
the indoor environment. The study team will also emphasize that it is not known if the intervention provides any 
clinical benefit.   
• 
The HEPA unit chosen produces less noise and takes less space than some other available units. In the 
recommended “high” setting, the noise generated is below the American Academy of Pediatrics recommendation 
for sound level in a neonatal intensive care unit81 and quieter than typical speech and rainfall.82 We will instruct 
parent(s)/guardian(s) not to use the max setting and to set up the filtration unit at least 5 feet from where the 
child sleeps. In addition, these instructions will be placed on a label attached to the filtration unit. 
• 
The study team will guide equipment setup, maintenance, and safe use (see Section 8.2). 
 
 
 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 30 of 67 
3 
OBJECTIVES AND ENDPOINTS 
Table 3. Objectives and Endpoints 
Study Objectives 
Study Endpoints 
Justification for Endpoints 
Primary 
To determine if use of a HEPA filtration unit home 
intervention reduces the respiratory symptom 
burden (symptom-free days; SFD) for 24 weeks 
compared to a use of a control unit 
Hypothesis: Children who receive a HEPA filtration 
home intervention after their first hospitalization with 
bronchiolitis will have a greater mean number of SFDs 
over 24 weeks compared to controls. 
Number of caregiver-
reported SFDs over 24 
weeks following the 
child’s first 
hospitalization for 
bronchiolitis (SFD 
defined as a 24-hour 
period without 
coughing, wheezing, 
or trouble breathing) 
Children hospitalized for bronchiolitis 
have a large burden of symptomatic 
days over the subsequent year after 
hospitalization, with the majority of the 
symptom burden occurring over the 
first 6 months. Clinically, it is important 
for the intervention to reduce the 
number of symptomatic days. 
Secondary 
1. To test the efficacy of HEPA filtration home 
intervention, relative to the control arm, on 
difference in number of unscheduled healthcare 
visits for respiratory symptoms over 24 weeks 
Hypothesis: Children who receive a HEPA filtration 
home intervention after their first hospitalization with 
bronchiolitis will have fewer unscheduled healthcare 
visits for respiratory symptoms over 24 weeks (lower 
number of hospitalizations, ED or UC visits, and other 
medical visits) compared to the control. 
Caregiver reported 
number of 
hospitalizations, ED or 
UC visits, or other 
unscheduled medical 
visits for respiratory 
complaints (cough, 
wheeze, or trouble 
breathing) 
 
 
Children hospitalized for bronchiolitis 
are prone to recurrent respiratory 
symptoms. As a result, some children 
need hospitalization, emergency or 
urgent care visits, or other unscheduled 
medical visits for these symptoms. If the 
intervention can reduce healthcare 
visits (by reducing respiratory 
symptoms), this may lead to 
considerable cost savings. 
2. To test the efficacy of a HEPA filtration home 
intervention, relative to the control arm, on 
difference in QOL. 
Hypothesis: Child QOL will be higher in families that 
receive the HEPA intervention compared to controls.  
Total QOL score, as 
measured by the 
PedsQLTM Pediatric 
Quality of Life 
Inventory Infants 
Scales questionnaire 
at the end of the 
intervention period. 
 
Children hospitalized for bronchiolitis 
can have decreased QOL post-
hospitalization for months or longer due 
to a variety of factors, including ongoing 
or recurrent respiratory symptoms, or 
impact on the family of the experience 
of the child’s severe illness requiring 
hospitalization. Increased child QOL is 
expected to follow an intervention that 
improves respiratory symptoms. 
3. To test the efficacy of HEPA filtration home 
intervention, relative to the control arm, on 
difference in PM2.5 levels in the home over 24 weeks  
Hypothesis: PM2.5 levels will be lower in households that 
receive the HEPA intervention compared to controls. 
Weekly average PM2.5 
levels as measured by 
2 in-home PurpleAir 
monitors during the 
24-week intervention 
period and scaled to 
the unit of µg/m3 per 
week   
To demonstrate that a putative agent 
causing increased susceptibility to 
recurrent wheeze in infants is being 
reduced by active HEPA filtration.   
PM2.5 is one of the most heavily studied 
criteria pollutants for causing lung disease.   
 
 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 31 of 67 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
This is a multi-center, parallel, double-blind, randomized controlled clinical trial. Two hundred eighteen children 
<12 months old with their first hospitalization for bronchiolitis will be randomized 1:1 (stratified by site) to receive 
24 weeks of home intervention with active HEPA filtration units to improve IAQ or to a control group without a HEPA or 
carbon filter inside identical-appearing units. Children will be followed for respiratory symptoms during a pre-
intervention period of up to two weeks following randomization and during an intervention period of 24 weeks.  
This study is designed to reduce barriers to participation for rural participants in that there will be no required study 
visits to a distant study site, and all study activities and data collection will be conducted remotely. Participants will be 
identified in hospitals in ISPCTN states, maximizing the chances that rural and medically underserved populations are 
represented. It is common for rural children with bronchiolitis to be transferred to tertiary care centers in 
urban/suburban locales, so inclusion of urban hospitals will allow for recruitment of this population.1 It is important for 
rural children to be represented in a bronchiolitis study in order to increase generalizability. Rural and underserved 
children have a higher risk of decreased access to medical care for symptoms and illness episodes, and a higher burden 
of asthma.83,84 These families may have air pollutant exposure profiles distinct from those residing in urban areas. For 
example, they might experience less exposure to traffic-related pollutants but may have more wood stove use or 
exposure to agricultural pollutants or wildfires. With its diversity of sites, the ECHO ISPCTN is well-positioned to enroll 
rural children that might otherwise be excluded.  
 
Primary Objective:  
To determine if use of a HEPA filtration unit home intervention reduces the respiratory symptom burden (symptom-
free days; SFD) for 24 weeks compared to the use of a control unit. 
 
Hypothesis: Children who receive a HEPA filtration home intervention after their first hospitalization with bronchiolitis 
will have a greater mean number of SFDs over 24 weeks compared to children in control arm. 
 
Secondary Objectives:   
1.  To test the efficacy of a HEPA filtration home intervention, relative to the control arm, on difference in number of 
unscheduled healthcare visits for respiratory symptoms over 24 weeks. 
Hypothesis: Children who receive a HEPA filtration home intervention after their first hospitalization with 
bronchiolitis will have fewer unscheduled healthcare visits for respiratory symptoms over 24 weeks (lower number of 
hospitalizations, ED or UC visits, and other medical visits) compared to children in the control group. 
2.  To test the efficacy of a HEPA filtration home intervention, relative to the control arm, on difference in QOL. 
Hypothesis: Child QOL will be higher in families that receive the HEPA intervention compared to controls.  
3.  To test the efficacy of a HEPA filtration home intervention, relative to the control arm, on difference in PM2.5 levels 
in the home over 24 weeks  
Hypothesis: PM2.5 levels will be lower in households that receive the HEPA intervention compared to controls. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
We propose a parallel, randomized controlled trial (RCT) as the most scientifically robust design to determine the 
efficacy of HEPA filtration in improving the number of SFD over 24 weeks following hospitalization for bronchiolitis. We 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 32 of 67 
considered two alternative study designs to increase acceptability of an inactive filtration unit: randomized crossover 
and stepped wedge. Parallel, crossover, and stepped wedge designs each allow for a control or placebo group, which is 
critical as there is genuine uncertainty regarding the efficacy of the intervention in reducing SFDs in the 6 months 
following hospitalization for bronchiolitis. The parallel design is distinct from the other two in that homes randomized to 
the control arm will not receive the intervention during follow-up.  
Both the crossover and stepped wedge designs are appealing in that they allow all participants to receive an 
intervention that we expect will improve IAQ. However, with a crossover design, it is critical that the participant’s 
disease characteristics are the same at time zero of each time period. Since the eligibility for this study is based on 
hospitalization for bronchiolitis, there is no way that can be achieved. Moreover, the relevant time window of exposure, 
washout duration, and appropriate point in time to crossover is unclear. Although an early benefit of HEPA filtration is 
possible, the intervention may be more effective over a longer duration rather than the immediate period post-
hospitalization, which would require a lengthy study. 
The stepped wedge is a variant of an interrupted time series design in that a site starts in the control arm and switches 
over to the intervention arm at a specific point in time. While participants may be blinded, staff are not, so this might be 
difficult to implement. 
We considered a 1-year study intervention period. However, due to family burden, risk of missing data, and risk of 
nonadherence to the intervention over such a long duration, we ultimately decided that a 24-week intervention 
targeting the time period of highest respiratory burden was preferable. Although a 1-year study period is appealing due 
to capturing potential variability in air quality (heating season, etc.) and viral exposures (cold seasons), the severity of 
respiratory symptoms is not static in rapidly growing infants, and most of these children will be recruited in the same 
seasons and have similar opportunity for repeat viral exposures and heating seasons between the groups.  
We considered including children up to 2 years of age (per the definition of bronchiolitis). However, the under 
12-months age group has the highest symptom burden and likelihood of demonstrating an effect.    
We chose the primary outcome of symptom-free days because assessing the number of wheezing episodes alone can 
underestimate the burden of chronic symptoms (including cough) and prolonged symptoms with illness episodes. In 
addition, clinically it can be difficult to determine the discrete number of wheezing episodes for children with prolonged 
or chronic wheeze (which is a higher risk in this population). 
The KidsAir study at the ISPCTN Montana site successfully implemented and completed a study similar in design to the 
one we propose here.85 The proposed study benefits from methods used in the KidsAir study, lessons learned, and the 
study team’s expertise. Although the current study population is different from that of the KidsAIR study, the KidsAIR 
study targeted for intervention the same exposure to PM2.5 as the current study using the same method, namely HEPA 
filtration, and collected similar covariate data successfully over two winters of study participation.86 In the KidsAIR study, 
field technicians visited homes approximately six times per winter season. Data collection procedures were more 
burdensome for participants and more frequent than those proposed here (see Schedule of Activities, Section 1.3); 
however, participant retention in the other study was still 87% in the first year of the 2-year KidsAIR study. The current 
study requires a relatively shorter duration of study participation (6 months versus 2 years) and less burdensome 
procedures for outcome ascertainment that do not require participating families to accommodate home visits by field 
technicians. 
 
4.3 
JUSTIFICATION FOR DOSE 
The HEPA unit intervention will take place over the approximately 6 months after hospitalization because this period is 
when the majority of post-bronchiolitis respiratory symptoms occur.5,26,31 The intervention involves the placement of 
two HEPA units within the home. The rationale for the placement of one HEPA unit in the child’s sleep space is that 
infants typically spend a continuous number of hours daily in this space. The rationale for placement of a second HEPA 
unit in a common area of the home is to increase the child’s exposure to the intervention during waking hours. 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 33 of 67 
 
4.4 
END OF STUDY DEFINITION 
An individual participant will be considered to have completed the study after completing all final protocol-specified 
assessments at the end of the 24 week intervention period (which is equal to week 26 in SOA due to approx. 2 week pre-
intervention period).  Participants will be considered not to have completed the study if consent was withdrawn or the 
subject was lost to follow-up without submitting all end-of-study questionnaires (at end of 24 weeks of intervention) 
and surveys. The end of study (“study completion”) is defined as the date the last protocol-specified visit/assessment 
(including telephone contact and receipt of questionnaires and surveys) is completed for the last participant in the 
study. Scheduled study activities are shown in the Schedule of Activities (SOA), Section 1.3.   
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
To be eligible to participate in this study, an individual child must meet all of the following criteria: 
• 
Age <12 months at hospital admission 
• 
First-time hospitalization for bronchiolitis 
• 
One primary residence (>5 days per week) 
• 
Parent, legal guardian or other legally authorized representative consents to allow their child to participate and 
agrees to participate in all study activities 
• 
Electricity in the home (required to power the study equipment) 
• 
Wireless internet access or cellular service access in the home* 
• 
English or Spanish-speaking parent or guardian 
*Cellular service allows the study-provided hotspot to transmit PurpleAir monitor data and study surveys.  
 
5.2 
EXCLUSION CRITERIA 
An individual child who meets any of the following criteria will be excluded from participation in this study: 
• 
Chronic airway or respiratory conditions requiring home oxygen, mechanical ventilation, or tracheostomy 
dependence; known immunodeficiency, hemodynamically significant cardiac conditions including those requiring 
medication or oxygen; cystic fibrosis; neuromuscular disease; eligible for palivizumab (per AAP guidelines87) 
• 
Use of stand-alone home HEPA filtration other than study-related HEPA units in the home  
• 
Household member who smokes (any type), vapes, or uses e-cigarettes 
• 
Intention to move in the next 6 months 
• 
Enrolled or plans to enroll in an interventional clinical trial for treatment of acute bronchiolitis or sequelae of 
bronchiolitis, unless permission given by the PI 
• 
Another child in the household is enrolled in this study (one child per household can enroll)  
We will exclude homes with smokers to maximize our ability to determine the efficacy of the HEPA intervention in 
increasing SFDs. Multiple studies have demonstrated efficacy of HEPA filtration units in reducing non-nicotine particle-
bound components of tobacco smoke.67,72,88-90 However, we propose to exclude households with a smoker because even 
if HEPA filtration units reduce tobacco smoke components in the home, the secondhand smoke (SHS) exposures the 
child experiences with the smoker outside of the home (e.g., in the car) may be sufficient to reduce or eliminate any 
health benefits of the indoor HEPA unit. A systematic review and meta-analysis of 60 studies showed that passive smoke 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 34 of 67 
exposure is a major risk factor for lower respiratory tract infections and, in particular, bronchiolitis,91 as well as increased 
respiratory symptoms.92 In addition, infants who live with a smoker may be exposed to more sources of SHS.93 The 
exclusion of homes with smokers is consistent with the majority of RCTs that have evaluated the impact of portable air 
cleaners on health.22 
We acknowledge that excluding children living in households with a smoker will reduce the number of eligible 
participants. Nonetheless, including children from households with a smoker may increase sample size requirements if 
the intervention is less efficacious in smoking households.72,94 We emphasize that the proposed trial is an efficacy study. 
Our primary objective is to determine if HEPA filtration increases SFDs in children hospitalized for bronchiolitis under 
ideal circumstances. There is genuine uncertainty regarding this research question. Although smoking may be more 
prevalent in IDeA states, the percentage of homes with children and non-smokers is still clearly the majority, making the 
study still generalizable to a very large population of children with bronchiolitis.   
If the intervention is efficacious, a next step would be to evaluate if these findings are generalizable to other 
populations, including children living in households with a smoker. 
No children receiving concomitant medical therapies will be excluded. 
 
5.3 
LIFESTYLE CONSIDERATIONS 
Not applicable. 
 
5.4 
SCREEN FAILURES 
A screen failure is a participant who, upon initial evaluation potentially meets inclusion criteria (e.g., through chart 
review, etc.) and does not appear to have any exclusion criteria, but who, upon further evaluation (e.g., discussion with 
parent(s)/guardian(s) about whether there is electricity in the house, whether anyone in the house smokes,  whether 
they plan on moving within 6 months,  etc.) prior to enrollment/randomization, does not meet either all of the inclusion 
criteria and/or has 1 or more exclusion criteria.  Screen failure information will be collected and recorded on the 
appropriate case report form (CRF) and will include all reasons for the failure.  
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a modifiable factor may 
be rescreened. Rescreened participants should be assigned the same participant number as for the initial screening. 
 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Recruitment and retention of eligible participants will be critical to study success. Within a multi-center network, 
optimal recruitment approaches may vary from site to site, and network success may require sharing best practices 
among clinical sites. Though each clinical site is responsible for recruiting, enrolling, and retaining study participants, the 
Data Coordinating and Operations Center (DCOC) will assist each site in creating a site-specific recruitment and retention 
plan. Site initiation visits will include a review of the individual site’s recruitment and retention plans. All recruitment 
and retention materials, general and site-specific, must be approved by the IRB of record, which for all sites except 
Native American sites, will be the UAMS IRB.  
Screening/Recruitment:   
Eligible children will be identified during a primary hospitalization for bronchiolitis. We will request a partial waiver of 
consent consent/HIPAA for the recruitment screening portion of the study, i.e., to allow sites to review medical records 
for potentially eligible participants that meet minimum inclusion criteria. This partial waiver will be required to reach the 
appropriate study population. 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 35 of 67 
Screening. Local sites will obtain a daily list or receive notification of admissions to their pediatric units with a diagnosis 
of bronchiolitis (of the days where the research team is available). This information will be obtained in accordance with 
individual institutional policies and procedures as well as IRB approval from the IRB of record. For non-Native American 
populations, the UAMS IRB (as central IRB), will be the IRB of record.   
Recruitment. Each potential participant on the list should be approached for recruitment if the child meets eligibility 
criteria from prescreening their medical record. Recruitment can occur in person or remotely in accordance with 
institutional requirements, family preference, and healthcare team approval.  Remote consent must be done according 
to the requirements specified in section 10. 
Screening and enrollment ideally will occur during hospitalization, but enrollment can occur after discharge to home if the 
family can receive and set-up the air quality monitoring equipment within 7 days of discharge.  Other procedures can occur 
at home.  Day of hospital discharge is defined as day 1. 
 
If an eligible child is readmitted within 1 week of discharge to home from the initial hospitalization, this can be 
considered part of the same hospitalization and timeframe to obtain the consent (if not already done). The start of 
study activities resets to begin after the second discharge to home. 
If a potential participant appears to meet eligibility requirements (i.e., based on pre- screening assessment) but 
declines participation, the parent(s)/legal guardian(s) will be asked why they do not want to participate. These data 
will be recorded in a screening log without any identifiers that could link responses back to an individual or family. The 
individual/family will be told they do not have to answer any questions they do not want to answer.  
Action if recruitment is low/risk mitigation plan: Methods for screening and recruitment at individual sites will be 
reviewed to determine if there are gaps in offering the study or other factors leading to low recruitment. Sites will 
submit recruitment data (number of bronchiolitis admissions, number approached, number consented, reason for 
declining the study) to the DCOC every 2 weeks. Individual site action plans may be made to improve recruitment.  
Using data from nine ISPCTN sites, we observed 3,209 admissions for bronchiolitis in infants less than 12 months of age 
during the 2019-2020 season. We estimate that we will have a minimum of 10-14 sites in this trial. Therefore, we will 
have a population of approximately 3,500-5,000 infants hospitalized from bronchiolitis to recruit from per year. Given 
that the recruitment period for this study is estimated at 2 years, we should have 7,000-10,000 eligible infants during 
the study period in our recruitment sites. Assuming a conservative recruitment rate of 20% would give us 700-1,000 
infants, which is far greater than the recruitment targets for this trial. Additional sites could be added to the trial if 
recruitment falls short, as the ISPCTN has 18 awardees, some with multiple available recruitment sites.  
Consent:  
The consent process will be conducted as described in section 10 of this protocol.   
Retention/Incentives:  
Some studies reported decreased HEPA filtration unit usage over the course of follow-up.70,95 Study participants 
indicated noise and electricity costs as reasons for turning off the filtration unit or using it below the recommended 
setting. To address these challenges, we selected a filtration unit model that emits low decibels and has low electricity 
demands. A similar unit was used in the KidsAIR study. Evaluation of Kilowatt (kW) meter data in KidsAIR indicated 
strong compliance with filtration unit usage recommendations. In addition, we will compensate participating families 
for electricity costs. Our intervention period of 6 months is favorable for adherence relative to a year(s)-long 
intervention. Additionally, coordinator contacts will provide problem-solving strategies and support for continued use 
of the HEPA filtration unit. 
Coordinator contact for engagement while collecting study data: The research coordinator or other qualified research 
team member will check in with the family periodically. Check-in will typically be via phone call, but if permitted locally 
contact may occur by other means (such as text, email, video conferencing).  

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 36 of 67 
Weeks 1-4: Check-in: Contact from the enrolling site: 
o 
Weekly and as needed check-in: (Site to conduct a weekly check-in at a minimum) 
o 
Assist or prompt EDC documentation as needed 
o 
Assess equipment set-up, questions/concerns 
o 
Safety assessments (AE, SAE, UPIRTSO) 
o 
RSV vaccination/preventive treatment status may be collected as appropriate 
Weeks 5-26: Check-in: Contact from the enrolling site: 
o 
Monthly and as needed: (Site and participant dependent) 
o 
Assist or prompt EDC documentation as needed 
o 
Assess equipment questions/concerns 
o 
Safety assessments (AE, SAE, UPIRTSO) 
o 
RSV vaccination/preventive treatment status to be collected as appropriate 
 
Compensation will be provided for completion of study activities  
• 
Weekly survey collection (26 submissions) – $20 per survey submitted (max $520 per participant) 
• 
$10 for submitting QOL survey  
• 
$5 each for baseline and 6-month (approx. week 26 of participation; week 24 of intervention) history 
question set (max $10) 
• 
$40 for return of the PurpleAir monitors with internal SD cards, hotspot, and kW meter. This is for time spent 
returning equipment. Parent(s)/guardians of participant will receive pre-paid materials for returning equipment, 
i.e., at no expense to parent/guardian. 
Compensation will be provided for anticipated excess energy costs 
• 
$15 per family (The anticipated excess energy cost is approximately $5 per HEPA unit in higher energy cost areas. 
The $15 compensation will account for unanticipated energy costs.) 
Healthy Homes Kit: All participants will receive a Healthy Homes Kit (approximately $42.00 value) near the start of 
their child’s study intervention period. The kit contains a collection of items to improve non-IAQ home environmental 
health and safety. The Healthy Homes Kit is a response to community and stakeholder feedback requesting meaningful 
home environmental tools in all study arms to make the study more acceptable. We do not expect an impact on the 
measured outcomes. The rationale for using the Healthy Homes Kit is that the home environment is generally 
considered important for overall health. The Kit addresses the following concerns: 1) recruitment and retention may 
be affected with a “placebo only” arm, and 2) when introduced to the rationale that a healthy home environment 
helps improve health, some families may want to pursue home environment modifications, and the kit will provide 
standard tools. The kit will contain children’s books, outlet covers, doorknob covers, cabinet and drawer latches, bath 
thermometer, carbon monoxide detector, bedbug traps, and green cleaning supplies.  
Additional incentive at study completion and equipment retained by families: All families will retain the two HEPA 
units (value of $500) and receive a supply of two HEPA and carbon filters (value of $160). They also will keep the tape 
measure (value of $15), four surge protector power cords (value of $10 each) and one USB/AC power adapter (value of 
$4). They will keep their backpack (valued at approx. $22). 
Compensation Summary:  
• 
Total possible compensation (reimbursement for time & equipment return) for study activities: $580 
• 
Compensation for excess energy costs: $15. 
• 
Value (approx.) of equipment and supplies that families keep: $ 806. 
Grand sum value of compensation is, therefore, approximately $1378.  

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 37 of 67 
Return of Results: Indoor air quality results (PM2.5) typically will not be provided to caregivers until after their child’s 
participation has ended (i.e., after 6 months, or sooner if the child’s participation ends early). After a participant 
completes the study, study staff will then send the participant’s caregiver a summary of the data from the PurpleAir 
monitor(s) in their home.  Exception: Quality control monitoring will occur during the first 4 weeks (approximately) of 
study participation.  If persistently high air pollutant levels are noticed during those 4 weeks (approx.), participants 
will be notified as soon as practicable.  Note that quality control monitoring can only be done for those households 
that can transmit their air quality data (PurpleAir data) through wireless methods. For equity, after a participant 
completes the study and air quality results are assembled based on returned PurpleAir monitors and/or data 
transmitted through WiFi, the study team will notify the participant’s caregiver should persistently high air pollutant 
levels be noticed. 
Once the entire study is completed, study staff will provide a lay summary of the overall study results to caregivers of 
participants.  
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTIONS ADMINISTRATION 
6.1.1 STUDY INTERVENTION DESCRIPTION 
The 24-week intervention period captures the period of highest respiratory burden post-bronchiolitis.  
Use of the HEPA units (experimental) or inactive (control) units takes place for 24 weeks beginning after a 
pre-intervention period approximately 2 weeks in duration (methods to be described in the MOP).   
Since previous related work using a pre-/post-design has shown substantial variability in PM2.5 concentrations even in 
relatively small geographic areas, we will collect baseline PM2.5 to control for this potentially important source of 
variability in homes. For example, in a study in homes with wood stoves in the western U.S., baseline median PM2.5 was 
17, 41, and 16 µg/m3 in filter, wood stove change out and placebo arms, respectively.69 Preliminary results from an 
ongoing RCT (NCT02240069) have shown a similar pattern with median baseline PM2.5 ranging from 23 to 41 to 
30 µg/m3 in homes assigned to different intervention arms.96 Note we will not exclude homes based on baseline PM2.5 
measurements because even at low levels (i.e., below U.S. National Ambient Air Quality Standards), PM2.5 has 
demonstrated adverse health effects.97 
The rationale for placing the HEPA unit in the child’s sleep space is that the child will typically spend a continuous 
number of hours daily in this space. The rationale for a second HEPA unit in a common area of the home is to maximize 
exposure to the intervention. 
Intervention for both experimental and control conditions: 
• 
Use of the HEPA units (experimental) or control units takes place from weeks 3-26 (approximately) after hospital 
discharge to home.   
• 
A coordinator or other qualified research team member will contact the family via video or phone to prompt them 
to begin using the HEPA or control units. The research team member will confirm proper installation and that the 
two units are functioning and provide information on the lights (e.g., sensor light) on the units. 
• 
Both the HEPA and carbon filters will be removed from the control units, and interior contents of the unit will be 
masked with black cardstock or similar. The door on the unit will be taped closed to make it difficult to open the 
units.  

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 38 of 67 
Experimental condition, Active HEPA filtration unit use: The intervention group will use two Winix 5500-2 HEPA 
filtration units (Appendix A) (https://winixamerica.com/product/5500-2/). One will be placed in the child’s sleep space 
and one will be placed in another common room with both units running continuously on the “high” (i.e., level 3 / 
second from highest) setting. Each unit is 8.2 x 15.0 x 23.6 inches, and verified for a 360 sq. foot room.  If a home is too 
small to accommodate 2 Winix units (for example, a single room residence`), one Winix unit may be used for the study. 
Additional features beyond HEPA and carbon filter, include plasmawave technology to reduce volatile organic 
compounds and odors. The plasmawave feature will be turned off to avoid ozone production.   
Control condition, Inactive filter unit use: The control group will use identical-appearing Winix 5500-2 units and similar 
setup procedures as described above, but with no HEPA or carbon filters.    
The manufacturer indicates that HEPA filters can last up to 12 months. For this reason, the filters will not be changed 
during the 24-week intervention period. Changeout of filters also adds the additional risk of unintentional unmasking of 
the family or research team members. Ideally, the carbon filter in the HEPA unit is cleaned every 3 months. However, 
since reduction of pollutants (e.g., volatile organic compounds) addressed by the carbon filter are not targets of the 
intervention, the carbon filters will not be changed out during the 24-week study.    
If a HEPA unit or control unit breaks, malfunctions, or stops working, the entire unit needs to be replaced by the study 
team as soon as possible (by mail, pickup, or delivery). While awaiting replacement, the family will be instructed to use 
the working HEPA unit in the room where the infant spends the most hours. 
 
6.1.2 DOSING AND ADMINISTRATION 
Not applicable. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
All PurpleAir and related equipment to be used by participants in the experimental and control conditions will be stored 
at individual sites. Study equipment will be dispensed to participants prior to their discharge to home from their 
hospitalization (ideally), or if not possible by mail, or local pickup/delivery. Experimental and control filtration units and 
related equipment will be stored at the central site and, in most cases, be mailed directly to participants. Local sites may 
store filtration units if preferred and deliver them directly or by mail to participating families. Arrival of the equipment in 
the participants’ home will be confirmed by communication (including phone, text, or email) with the family by study 
staff, who will also arrange a time to assist with equipment set up. 
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
The HEPA and control units are identical in appearance. They will both have a standard manufacturer appearance 
externally with the modifications described in Section 6.1.1.   
 
6.2.3 PRODUCT STORAGE AND STABILITY 
The HEPA/control units are prepared and stored centrally prior to dispensing to participants. PurpleAir monitors with 
hotspots are prepared centrally then stored by individual sites prior to dispensing to participants. Healthy Homes 
Toolkits will be prepared by the DCOC and then shipped in bulk to the central site prior to dispensing to participants. 
 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 39 of 67 
6.2.4 PREPARATION 
Education of parent(s)/guardian(s) of participants regarding equipment use will occur during the child’s hospitalization 
and then remotely (video, phone, or other family-preferred communication means) post-discharge to home. All 
participants will receive:  
• 
2 HEPA or control units (unless home is small enough that only one HEPA unit is needed),  
• 
2 kW meters (0 kW meters if home has only two-prong outlets),  
• 
2 PurpleAir monitors (1 if home using only one HEPA unit) and mobile hotspot with power adapter, 
• 
4 power strips or similar,  
• 
1 tape measure,  
• 
Basic education on strategies to improve indoor air quality, and 
• 
1 Healthy Homes Kit.  
The local site research team will assist participants remotely with setup of all study equipment.   
Study staff will ensure correct placement and setup of the PurpleAir monitors and hotspot, HEPA/control units, and kW 
meter following a checklist (submitted separately or will be included or referenced in MOP).  
Because parent(s)/guardian(s) of participants can set up all study equipment with remote support, the study team 
should not need to enter any participant’s home. However, to reduce barriers to participation, study staff will be 
permitted to assist any parent(s)/guardian(s) of participant’s in their home if all remote options for technical assistance 
are exhausted, and it is necessary to troubleshoot problems in person.  
To facilitate the inclusion of rural children, this protocol allows for providing study equipment at hospital discharge to 
home, mailing equipment, or locally arranged pickup/delivery, and remote study activities. There are no required in-
person study visits.  
 
6.3 
MEASURES TO MINIMIZE BIAS 
Randomization Scheme:  
Participants (within each site) will be randomized 1:1 (stratified by site) to receive HEPA filtration (intervention group) or 
control filtration. Permuted block randomization with a block size of 4 or 6 participants (selected at random) will be 
employed. The block size and block permutation will be selected at random for each site. After selecting the block size 
and block permutation, a participant is assigned to the first control/intervention in the block, and the remaining slots are 
assigned as participants continue to randomize within the site. As randomizations continue and no more slots are 
available in the previously assigned block, a new block is assigned and participants are randomized accordingly. 
 
Masking: 
Families will be masked as to whether their Winix units are equipped with or without HEPA/carbon filters. 
Study coordinators, investigators, and other team members who interact with participants’ parent(s)/guardian(s) to 
obtain surveys, troubleshoot equipment setup and operation, or have other interactions will remain masked through the 
duration of the study for individual participants. This includes masking as to which intervention the participants receive 
and household air quality measurements, including the baseline measurements (separate personnel will need to be on 
the receiving end for air quality measurement data). This will require more than one study coordinator or additional 
staff/technician on the study team. 
Unmasked personnel (separate coordinator, technician, or other qualified personnel) will work on the HEPA units to 
ensure standardized appearance with tape and active or inactive filter setup. They will not assess outcomes.    
 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 40 of 67 
6.4 
STUDY INTERVENTION COMPLIANCE 
Intervention compliance will be assessed in two ways: through kW meters (see Appendix C) and caregiver-reported 
HEPA/control unit use.  
• 
Families will be instructed to place kW meters on the units at the onset of installation within the home to assess 
usage compliance with HEPA/control units. These meters enable assessment of power consumption and 
estimate corresponding costs for energy usage. Increasing kWh over the course of participation will indicate 
HEPA/control unit use. When available, we will also quantify actual kWh usage during the intervention period by 
comparing observed kWh used to the usage predicted from laboratory tests. The observed kWh used will be 
divided by the predicted usage and this quantity multiplied by 100 to determine adherence.  
• 
Weekly surveys will also include prompts for parent(s)/guardian(s) to report whether they used the 
HEPA/control unit that week and on what setting it was most commonly used.  
Note that the kW meters require three-prong electrical outlets. If a home has only two-prong outlets, they will not use 
the kW meter. Since not all participants will have kW meters and since power interruptions will change kW meter 
settings, caregiver reported HEPA/control unit use on weekly surveys will be the primary measure of compliance. 
 
6.5 
CONCOMITANT THERAPY 
No concomitant medications are prohibited.   
 
6.5.1 RESCUE MEDICINE 
Not applicable 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
If the family/participant chooses not to continue the study intervention (i.e., chooses to stop using the HEPA 
unit/control air unit), they may choose to allow their child to remain in the study and complete the remaining study 
procedures as indicated by the study protocol. Participants parents/guardians will still be compensated for study 
activities, keep HEPA units, and receive replacement filters at the end of the study, even if they do not complete the 
intervention. If the study intervention is discontinued, the reason for discontinuation will be documented.  
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
A parent/guardian is free to withdraw (at any time) their child from participation in the study (including intervention, 
data collection, and assessments/surveys) without prejudice to further medical treatment (withdrawal of consent). The 
parent(s)/guardian(s) of the participant will be asked about the reason(s) and the presence of any AEs. The 
parent(s)/guardian(s) will be told they do not need to answer any questions they do not want to answer. If a 
parent/guardian of a participant chooses to withdraw their child from the intervention, they will be asked if they want to 
continue to in the study assessment procedures, including measurement of air quality, submission of symptom diaries 
and surveys. If parent/guardian of a participant chooses to withdraw their child from all further participation in the 
study, then no further study activities or data collection will take place.  
Moving to a new residence is not a criterion for discontinuation unless it is no longer feasible for the parent/guardian of 
the participant to complete the study activities.  

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 41 of 67 
An investigator may discontinue or withdraw a participant from the study for the following reason(s): If any AE, or other 
medical condition or situation occurs such that continued participation in the study would not be in the best interest of 
the participant as determined by the site investigator and/or data safety monitoring board (DSMB) or caregiver failure to 
follow study instructions (e.g., failure to set up the study intervention). 
The reason for participant discontinuation or withdrawal from the study will be recorded on the appropriate CRF. 
Participants will not be replaced. 
 
7.3 
LOST TO FOLLOW-UP 
The following actions must be taken if a parent/guardian of a participant fails to return or complete study assessments 
(on behalf of their enrolled child): 
• 
Study staff will attempt to contact the parent/guardian of the participant and obtain the study survey data within 
2 business days for weekly surveys and within 7 business days for quality of life surveys. They will also counsel the 
parent/guardian of the participant on the importance of maintaining the assigned study activity schedule on behalf 
of their enrolled child and ascertain if the parent/guardian of the participant wishes to have their child continue in 
the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every effort to regain 
contact with the parent/guardian of the participant. See MOP for details. These contact attempts will be 
documented in the participant’s study file.    
• 
Should the participant’s parent/guardian continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
Collection of participant characteristics and risk factors for recurrent wheeze:  
History will be obtained at the start and end of the study to ensure randomization provides similar characteristics of the 
intervention and control groups. If there is an imbalance between arms, we will control for these factors in the primary 
analysis.  
Table 4. Participant characteristics and risk factors for recurrent wheeze 
Collect information at baseline or intervention start (by parental report unless otherwise indicated) 
• 
Age (in months) at initial hospitalization for bronchiolitis (medical record review) 
• 
Gestational age at birth (parental report or medical record review) 
• 
Sex/gender (parental report or medical record review) 
• 
Race/ethnicity (parental report or medical record review) 
• 
Parental education  
• 
Rural/Urban (RUCA code) based on residential address  
• 
Viral test results (first hospital admission for bronchiolitis) if available per standard of care testing (medical 
record review) 
• 
Season of hospitalization for bronchiolitis (medical record review)  
• 
Highest level of respiratory support during bronchiolitis admission (medical record review) 
• 
History of previous wheezing with illness  
• 
Family history of asthma  
• 
Wood stove use in the home (and whether this is the primary heat source) 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 42 of 67 
• 
Central air conditioning in the home  
• 
Type of cooking stove in the home  
• 
Presence of hood above cooking stove in home 
• 
Use of hood while cooking 
• 
Risk of higher frequency of viral exposures 
o Daycare attendance  
o Number of children in home 
o Number of children in home in daycare or school 
o Household crowding  
• 
Presence of plumbed (running) water  
• 
Furry pets in the home  
• 
Baseline weekly average PM2.5 home measurements (Purple Air Monitor data report) 
• 
Atopic dermatitis  
• 
Chronic use of asthma medications preceding bronchiolitis hospitalization  
• 
Use of asthma medications with illness preceding bronchiolitis hospitalization - 
• 
Received systemic steroid during hospitalization for bronchiolitis (medical record review) 
• 
Square footage of rooms containing HEPA units (during intervention set-up) 
• 
RSV vaccination/preventive treatment history (by report from family or medical record review) 
Collect information at approximately 26 weeks (end of 24-week intervention period) by parental report unless 
otherwise indicated 
• 
Smokers who live in the home  
• 
Chronic use of asthma medications -   
• 
New prescriptions for asthma medications or antibiotics with healthcare visits for respiratory symptoms 
(determined from weekly survey entries) 
• 
Atopic dermatitis  
• 
Immunization status  
• 
Average number of nights per week away from home (calculated from study data) 
• 
Average number of days per week where the child was away from home more than 6 hours (calculated from 
study data) 
• 
Model-estimated weekly outdoor PM2.5 concentration based on residential location (i.e., NOT parental 
reported) (These data may be obtained after the 26-week study period and/or after completion of the study.) 
• 
RSV vaccination/preventive treatment history (by report from family or medical record review) 
 
Air Quality Measurements (both intervention and control groups):  
Family-collected with study team support remotely: 
• 
 Continuous PM Assessment: Families will install PurpleAir PA-II-SD (Appendix B) continuous sensors 
(https://www2.purpleair.com/collections/air-quality-sensors/products/purpleair-pa-ii-sd) in the common room and 
child’s sleep space. The sensor measures numerous environmental factors, but PM2.5 concentration is of primary 
interest. The PurpleAir is 3.5 × 3.5 × 5 inches and weighs 25 ounces with the power supply.  The distance from the 
filtration unit to the PurpleAir will be measured by the family with a tape measure and reported to the study team. 
Study team personnel will schedule a phone call or video meeting for each family to assist with equipment setup.  
• 
Mean weekly indoor PM2.5 concentration is a secondary endpoint in the trial. Baseline (pre-intervention) PM2.5 will 
be measured ideally over at least four days.  
Data from the PurpleAir can be stored and retrieved in two ways, both of which will be used in this study. 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 43 of 67 
• 
Each PurpleAir is WiFi-enabled. When connected to WiFi, PurpleAir sensors transmit data to a PurpleAir server in 
real time. So that the monitor use does not interfere with a family’s WiFi usage, each participating home will be 
provided with one mobile password-protected hot spot and necessary data. One hot spot is sufficient to serve 
both PurpleAirs. The PurpleAir monitors will be connected to the hot spot prior to mailing (done centrally prior to 
receipt of the monitors by individual study sites) to simplify set up of monitors by participating families. 
 
• 
PurpleAir sensor data will be kept private to protect participant privacy. Data will be retrieved by University of 
Montana central site personnel from private sensors using a PurpleAir application programming interface (API) key 
using automated methods. For BREATHE homes able to transmit PurpleAir data through WiFi, data evaluation will 
occur  in the first four weeks of study participation (approximately) to ensure the sensor(s) are operating properly. 
University of Montana central site staff will perform quality checks on the data, and, if issues arise, they will 
communicate with local site personnel to troubleshoot the problem or opt to rely on data from the security digital 
card (see below). If needed, staff will provide additional training or a new PurpleAir if there is a sensor 
malfunction. Also during the first four weeks of study participation (approximately), automated alerts to the 
central site to unusually high PM2.5 values will occur for BREATHE homes able to transmit PurpleAir data through 
WiFi. Should a 24-hour average exceed a 100 μg/cubic meter threshold, the University of Montana central site 
team will investigate further. Should a cleaned and corrected weekly average exceed that specified threshold, the 
local site will notify the family and provide informational resources on indoor air quality. Similarly, if the study 
team notices threshold exceedance at the end of a child’s participation based on returned PurpleAir monitors 
and/or data transmitted through WiFi, the study team will notify the participant’s caregiver and provide 
informational resources on indoor air quality. 
 
• 
Each PurpleAir is equipped with a security digital (SD) card that logs PM2.5 data in the event of WiFi interruptions. 
The SD card has sufficient storage to hold at least 6 months of PM2.5 data so that it does not need to be changed 
during participation. The family will be instructed to mail the PurpleAirs back to the ISPCTN site (or designated 
central site, i.e., the University of Montana) at the end of participation. Research staff will then remove the SD card 
and download the data. Data from either WiFi or the SD card can be used to obtain the most complete and high-
quality exposure assessment possible. The University of Montana central site team will provide final summary 
PM2.5 metrics to the DCOC. 
Weekly survey collection of child’s daily symptoms, healthcare utilization data, time away from home, and study 
equipment use:  
The parent(s)/guardian(s) will submit a brief weekly online survey (via the EDC platform) that they receive via text or 
email. The alternative is a scheduled phone call with a standard script with the study coordinator or other qualified 
personnel from the study site research team. Parent(s)/guardian(s) of participants will receive a text or email reminder 
to complete the survey if it is not completed within 1 day of original due date. If a survey remains incomplete, the 
research team will continue to provide reminders to the parent/guardian until it is completed or closed.   
The weekly survey will capture 4 elements: 1) the child’s symptoms for the week, 2) number of healthcare visits, 3) time 
away from home, 4) study equipment use.   
Each family will receive a visual tool (paper form named “Symptom Recall Tool”) with the written questions as a 
prompt/reminder of what will be asked. The family will receive a booklet with a page of the Symptom Recall Tool for 
each week of the study. The Symptom Recall Tool is an aid for reporting and will not be collected. We estimate that the 
weekly survey will take 1-5 minutes to complete electronically.   
• 
Symptom survey: The survey captures three daytime symptoms (cough, wheeze, trouble breathing) and nighttime 
awakenings due to cough. The responses to the symptom survey in the EDC will be used to determine SFDs. The 
questions have been used previously to measure SFDs after bronchiolitis over a similar time frame of 
approximately 6 months in a study testing whether an intervention reduces post-bronchiolitis symptomatic days.5 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 44 of 67 
The questions are based on the Bronchiolitis Caregiver Diary, a validated measurement tool for respiratory 
symptoms after acute bronchiolitis.37 These questions have been used to follow post-bronchiolitis symptoms over 
a 20-week period, similar to this study.5 
o The survey will ask whether the child had any cough, wheeze, or trouble breathing this week (Y/N).  
 
If No, they will move on to the next section for healthcare visits.  
 
If Yes, they will receive a prompt for each day to respond Y/N for the presence of the symptom and if 
there are symptoms present, the survey will ask if any medications were used for respiratory symptoms 
(family to list names of medications). 
• 
Healthcare visits: The parent/guardian will record the number of hospitalizations, ED/UC visits, and other medical 
visits for respiratory symptoms. This will be a (Y/N) for whether they participant (child) had a healthcare visit in the 
past week. If Y, there will be a prompt to enter the number of visits for each visit type. If N, they will move on to 
the next section, “Time away from home.” 
• 
Time Away from home: 
o Days away from home: The parent/guardian will be prompted to enter how many days that week the child 
spent more than 6 hours outside the home (0-7 days). 
o Nights away from home: The parent/guardian will be prompted to enter how many nights that week the child 
spent away from their primary residence (away for vacation, staying with someone else, etc.) (0-7 days).  
• 
Equipment use: 
o HEPA/control unit use: For each room with a HEPA/control unit, the parent/guardian will be asked to respond 
Yes/No to whether they used unit and asked to report the usual setting used (1, 2, 3, or 4). If applicable, the 
parent(s)/guardian(s) will also record the numerical reading visible on the kW meter attached to each 
HEPA/control unit. This will be a simple entry of the numbers displayed on the kW meter to respond to the 
survey prompt.  
o PurpleAir monitor: The parent/guardian will be asked whether the monitor is plugged in with the light on (Yes 
or No). They will also be asked whether the hot spot is on with bar light and 3 lighted dots on (Yes or No). 
Quality of Life: 
• 
The PedsQLTM Pediatric Quality of Life Inventory Infant Scales98 questionnaire will be administered to a 
parent/guardian at the end of the intervention period. This is a validated outcome measure of QOL for infants 1-12 
months (36 items) and 13-24 months (45 items). The constructs include 5 subdomains: physical functioning, 
physical symptoms, emotional functioning, and cognitive functioning.  
The questionnaire will be administered online. The alternative will be for the research coordinator to obtain 
responses verbally. 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
This is a minimal risk study. No changes to standard of care therapies and standard medical treatment will be made for 
participants based on research data. Children will not receive medical care from the research team and will receive their 
usual care (such as from their primary care provider). Childproofing is necessary for all equipment to prevent injury to 
young children, and steps to determine family needs around childproofing will be outlined in the MOP. If circumstances 
arise such as a significant air pollution exposure that is expected to be prolonged (e.g., major wildfire with air quality 
impacts in the area) or other conditions where it is medically recommended by the child’s health provider to use active 
HEPA filtration, the participant may be unmasked.   
 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 45 of 67 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
An AE is any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign, symptom, or 
disease, temporally associated with the volunteer’s participation in research, whether or not it is considered related to 
the research intervention. Stable chronic conditions that are present prior to enrollment and do not worsen are not 
considered AEs and will be accounted for in the subject’s medical history. Exacerbation or worsening of pre-existing 
conditions are defined as AEs. Each AE will be classified by the investigator as serious (SAE) or nonserious. All AEs will be 
evaluated for severity, action taken, seriousness, outcome, and relationship to the study intervention. Information on 
protocol-specific AEs, severe AEs, and SAEs will be collected from participant reports and via phone calls, as well as 
review of weekly surveys. Protocol-specific AEs, severe AEs and SAEs will be collected for the duration of the study. We 
will only record and track severe AEs; SAEs; and AEs associated with the study intervention and/or study equipment. 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
An AE or suspected adverse reaction is considered “serious” if, in the view of either the investigator or sponsor, it results 
in any of the following outcomes:  
• 
Death 
• 
A life-threatening adverse event 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 
• 
Important medical events that may not result in death, be life-threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, they may jeopardize the participant and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition.  
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
8.3.3.1 
SEVERITY OF EVENT 
For AEs, the following guidelines will be used to describe severity.  
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic measures. Moderate 
events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug therapy or other 
treatment. Severe events are usually potentially life-threatening or incapacitating. Of note, the term “severe” does 
not necessarily equate to “serious”. 
 
8.3.3.2 
RELATIONSHIP TO STUDY INTERVENTION 
All AEs must have their relationship to study intervention assessed by the investigator or qualified clinician who 
evaluates the participant based on temporal relationship and their clinical judgment. The degree of certainty about 
causality will be graded using the categories below.  
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible contributing 
factors can be ruled out. The clinical event, including an abnormal laboratory test result, occurs in a plausible time 
relationship to study intervention administration and cannot be explained by concurrent disease or other drugs or 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 46 of 67 
chemicals. The response to withdrawal of the study intervention (dechallenge) should be clinically plausible. The 
event must be pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge 
procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other factors is unlikely. 
The clinical event, including an abnormal laboratory test result, occurs within a reasonable time after 
administration of the study intervention, is unlikely to be attributed to concurrent disease or other drugs or 
chemicals, and follows a clinically reasonable response on withdrawal (dechallenge). Rechallenge information is 
not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event occurred within a 
reasonable time after administration of the intervention). However, other factors may have contributed to the 
event (e.g., the participant’s clinical condition, other concomitant events). Although an AE may rate only as 
“possibly related” soon after discovery, it can be flagged as requiring more information and later be upgraded to 
“probably related” or “definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose temporal relationship 
to study intervention administration makes a causal relationship improbable (e.g., the event did not occur within a 
reasonable time after administration of the study intervention) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant’s clinical condition, other concomitant 
treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or evidence exists that 
the event is definitely related to another etiology. There must be an alternative, definitive etiology documented by 
the clinician. 
 
8.3.3.3 EXPECTEDNESS  
The site investigator or qualified clinician designee will be responsible for determining whether a severe AE or SAE is 
expected or unexpected. A severe AE or SAE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with risks of underlying chronic medical conditions, is not an event measured in study data 
collection (hospitalization, ED visit, etc.), or is not related to function of the study intervention equipment. 
Potential expected events could include the following: 
• 
Cough 
• 
Wheeze 
• 
Trouble breathing 
• 
Medical or emergency department/urgent care visit for respiratory complaint 
 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
All potentially related, severe AEs, and SAEs will be recorded on the appropriate CRF. Information to be collected 
includes event description, approximate date of onset, clinician’s assessment of severity, relationship to study 
intervention (assessed by site investigator or qualified clinician designee), and date of the resolution/stabilization of the 
event. SAEs occurring while on the study must be documented appropriately regardless of relationship; and must be 
followed until one of the following criteria is met: study completion, resolution, the condition stabilizes, the event is 
otherwise explained or is judged by the site investigator or qualified clinician designee to be no longer clinically 
significant, or the participant is lost to follow up.     
Any medical condition that is present at the time that the participant is screened will be considered as baseline and not 
reported as an AE. However, at the onset of the intervention and anytime during the study if the study participant’s 
condition deteriorates and meets the definition of severe AE, SAE, or is possibly related to the study intervention, it will 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 47 of 67 
be recorded as an AE. Changes in the severity of an AE will be documented to allow an assessment of the duration of the 
event at each level of severity to be performed. AEs characterized as intermittent require documentation of onset and 
duration of each individual episode. 
The site investigator or qualified designee will record all potentially related, severe AEs, and SAEs with start dates 
occurring any time after informed consent is obtained until 30 days after the last day of study participation. At each 
study visit or interval phone call, the investigator will inquire about the occurrence of potentially related, severe AEs, 
and SAEs since the last visit. Events will be followed for outcome information until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
All potentially related or severe AEs that occur after informed consent is obtained until the last day of study 
participation will be documented in the participant’s source documents and in the AE section of the CRF. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
The site investigator or qualified delegate will immediately report to the appropriate entities (which may include the 
DCOC, NIH, DSMB, and local and/or reviewing IRBs) any SAE, when required to do so based on that entity’s policies and 
procedures. Reports need to include the information required by the entities policies and procedures. Study endpoints 
that are serious adverse events (e.g., hospitalization) must be reported in accordance with the protocol unless there is 
evidence suggesting a causal relationship between the study intervention and the event (e.g., death from anaphylaxis). 
In that case, the investigator must immediately report the event.  
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to be chronic or the 
participant is stable. Other supporting documentation of the event may be requested by the DCOC and should be 
provided as soon as possible. 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
The parent(s)/guardians of participants will be notified of those study-related (or potentially study-related) SAEs or 
unanticipated problems (UPs) that may affect either the parent/guardian’s willingness to allow their child to continue 
with the study or the future health of the participant. This determination can be made by any of the following: the 
reviewing IRB, the medical monitor, the DSMB, the DCOC, or the NIH. The person or oversight body that makes the 
determination will inform the DCOC, which will instruct the site PIs/study coordinators to contact those participants 
enrolled through their site. Contacts with parent(s)/guardian(s) of participants, if necessary, will be recorded on the 
appropriate CRF and/or study log.     
 
8.3.8 EVENTS OF SPECIAL INTEREST  
Not applicable. 
 
8.3.9 REPORTING OF PREGNANCY  
Not applicable. 
 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 48 of 67 
8.4 
UNANTICIPATED PROBLEMS 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UPIRTSOS) 
Unanticipated problems (UPs or UPIRTSOs) involving risks to participants or others include, in general, any incident, 
experience, or outcome that meets all of the following criteria: 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are described in the 
protocol-related documents, such as the Institutional Review Board (IRB)-approved research protocol and 
informed consent document; and (b) the characteristics of the participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a reasonable 
possibility that the incident, experience, or outcome may have been caused by the procedures involved in the 
research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized. 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
The investigator will report UPS (UPIRTSOs) – and potential UPIRTSOs - to the DCOC (who will in turn report to the 
reviewing IRB when the reviewing IRB is UAMS) and the local IRB as well as any other persons or groups noted in the 
DSMB charter.  Reports to NIH and the DSMB will be made by following the chain of notification. 
These problems must be reported to the reviewing/local IRBs according to the reviewing/local IRB’s contemporaneous 
policies and procedures.   
For most sites involved in the study, the reviewing IRB will be the University of Arkansas for Medical Sciences (UAMS) 
IRB. The UAMS IRB contemporaneous policy, 10.2., Events that must be reported to the IRB and IRB Actions (effective 
July 6, 2020) is available via https://irb.uams.edu/irb-policies/current-irb-policies/  
As of the writing of this section of the protocol (03/23/2022), UAMS IRB reporting requirement per policy 10.2 are: 
UPIRTSO Reporting Requirement  
Unanticipated Problem 
Required Reporting Time to UAMS IRB 
Death or life-threatening 
Immediately to IRB office or IRB Chair 
All other events 
Within 10 days of event or notification of event if non-local 
 
Reports typically require the following information: 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project number 
• 
Event date 
• 
Event location 
• 
Nature of the risk 
• 
How the risk relates to research 
• 
A detailed description of the event, incident, experience, or outcome  
• 
A description of any changes to the protocol or other corrective actions that have been taken or are proposed in 
response to the UP 
Examples of UPs/UPIRTSOs that are not an AE or SAE, but which would need to be reported include: 
• 
Breach of confidentiality 
• 
Manufacturer recall of equipment used in the protocol 
 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 49 of 67 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
The parent(s)/guardian(s) of participants will be notified of those study-related (or potentially study-related) SAEs or UPs 
that may affect either the parent(s)/guardian(s) willingness to allow their child to continue with the study or the future 
health of the participant. This determination can be made by any of the following: the IRB, the medical monitor, the 
DSMB, the DCOC, or the NIH. The person or oversight body that makes the determination will inform the DCOC, which 
will instruct the site PIs/study coordinators to contact those participants enrolled through their site. Contacts with 
parent(s)/guardian(s) of participants, if necessary, will be recorded on the appropriate CRF and/or study log.     
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
Primary Objective: To test the efficacy of a HEPA filtration unit home intervention, relative to the control arm, with 
respect  to respiratory symptom burden (as measured by symptom-free days; SFD) over 24 weeks following activation of 
filtration. 
Primary Endpoint: Number of caregiver-reported SFDs over 24 weeks following activation of filtration (SFD defined 
as a 24-hour period without coughing, wheezing, or trouble breathing) 
Statistical Hypothesis: Mean of SFDs in the HEPA filtration home intervention group is larger than mean of SFDs in 
the control group. 
Secondary Objective 1: To test the efficacy of a HEPA filtration home intervention, relative to the control arm, on the 
number of unscheduled healthcare visits for respiratory symptoms over 24 weeks following activation of filtration. 
Secondary Endpoint 1: Caregiver reported counts of unscheduled healthcare visits from each of the metrics including 
hospitalizations, Emergency Department (ED) visits, Urgent Care (UC) visits, and other unscheduled medical visits for 
respiratory complaints (cough, wheeze, or trouble breathing). A sum of counts (or total counts) of all metrics is also 
used as the secondary endpoint.  
Statistical Hypothesis 1: Mean of counts of unscheduled healthcare visits for respiratory symptoms in the 
intervention group is smaller than mean of counts of unscheduled healthcare visits for respiratory symptoms in the 
control group. 
Secondary Objective 2: To test the efficacy of HEPA filtration home intervention, relative to the control arm, on 
difference in QOL. 
Secondary Endpoint 2: Total QOL score, as measured by the PedsQLTM Pediatric Quality of Life Inventory Infants 
Scales questionnaire at the end of the intervention period. 
Hypothesis 2: Child QOL will be higher in families that receive the HEPA intervention compared to controls.  
Secondary Objective 3: To test the efficacy of HEPA filtration home intervention, relative to the control arm, on PM2.5 
levels in the home over 24 weeks following activation of filtration. 
Secondary Endpoint 3: Weekly average PM2.5 levels as measured by 2 in-home PurpleAir monitors over 24 weeks and 
scaled to the unit of μg/m3 per week. 
Hypothesis 3: Mean of PM2.5 level in the intervention group is lower than mean of PM2.5 level in the control group.  
 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 50 of 67 
9.2 
SAMPLE SIZE DETERMINATION 
Sample Size Justification:  
We plan to enroll (consent) up to 228 participants.  
To account for an anticipated attrition rate of 16% per arm, the power analysis is based upon a sample size of 
196 participants, or 98 participants per arm. From a similar previously published study, it was found the mean of days 
with symptoms was 70 days (equivalently the mean of SFDs was 98 days out of total 24 weeks or 168 days of 
observation), and the standard deviation was 43 days.5 The proposed sample size will provide 90% power to detect an 
effect size of 0.465, or a difference of 20 symptom-free days with a standard deviation of 43 days, using a two sample t-
test.  
Randomization Scheme:  
The randomization will be stratified by site. Within each site, participants will be randomized in a 1:1 allocation to 
receive active HEPA filtration (intervention group) and inactive HEPA unit (control group). Permuted block 
randomization will be employed.  
 
9.3 
POPULATIONS FOR ANALYSES 
Analysis Population:  
Intent-to-Treat (ITT) Population: The ITT population will include all participants who are randomized to either HEPA 
filtration (intervention group) or inactive filter unit (control group) (referred to as two groups in the analysis section). 
Per-protocol (PP) Population: The PP population will include all participants who are randomized to either the HEPA 
filter (intervention group) or inactive filter (control group) and have used HEPA unit on average for both units >80% of 
the time. 
The primary set of analyses for this study will be based on ITT population. A separate analysis will be done with the PP 
population. 
 
9.4 
STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
• 
Descriptive Statistics: All numerical variables will be summarized using mean ± standard deviation and median 
(minimum, maximum). All categorical variables will be summarized using frequency (in %). 
• 
Inference tests: All proposed statistical tests are two-sided. A p-value <0.05 is considered statistically significant.  
• 
Covariates: Covariates will be compared between groups (intervention vs. control) using two sample t-tests, or 
Wilcoxon rank sum tests if they are continuous variables, and Chi-square tests or Fisher’s exact tests if they are 
categorical variables. Each of the continuous covariate variables will be assessed of its correlation to the primary 
endpoint, or each of the secondary endpoints using a Pearson’s correlation coefficient or a Spearman’s correlation 
coefficient. Similarly, each of the categorical covariate variables will be assessed of its association to the primary 
endpoint, or each of the secondary endpoints using an ANOVA model, or a Kruskal-Wallis test. A covariate showing 
a significant association to intervention, a significant correlation or association to the primary (or secondary) 
endpoint will be considered as the adjusting (controlling) covariate and will be added as adjusting independent 
variable in the statistical models proposed for primary and secondary analyses. 
• 
Model assumptions: Primary and secondary endpoints will be inspected of normal distribution assumptions using 
the histogram plots. If the variable is noticeably right (or seldomly left) skewed, then a transformation variable will 
be used in the parametric models to ensure the assumption of normality is met. As an alternative approach, a 
generalized linear model will be proposed to the variable using a distribution assumption fitting the data properly.   

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 51 of 67 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT 
• 
Primary Objective: To test the efficacy of a HEPA filtration unit home intervention, relative to the control arm, 
with respect to respiratory symptom burden (as measured by symptom-free days; SFD) over 24 weeks following 
activation of filtration. 
• 
Primary Endpoint: Number of caregiver-reported SFDs over 24 weeks following activation of filtration (SFD defined 
as a 24-hour period without coughing, wheezing, or trouble breathing) 
• 
Statistical Hypothesis: Mean of SFDs in the HEPA filtration home intervention group is larger than mean of SFDs in 
the control group. The hypothesis testing is the comparison of superiority. 
• 
Statistical Procedures: The hypothesis will be tested using a mixed effect model after accounting for within cluster 
correlation. The model uses the primary endpoint as the dependent variable, and the intervention effect 
(intervention vs. control) as the independent variable or the fixed effect with site as a random effect. 
• 
Missing Data: The primary endpoint will be imputed if there is any missing observation in the ITT. The statistician 
will assess the missing patterns to determine if the cause of missing is missing at random (MAR), missing 
completely at random (MCAR), or missing not at random (MNAR). Imputation methods such as multiple 
imputation (MI) methods and pattern-mixture methods will be used in imputation and analyses.        
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINTS 
• 
Secondary Endpoint 1: Caregiver reported unscheduled healthcare visits. The proposed statistical method will be a 
generalized mixed effect model. The dependent variable will be counts of unscheduled health care visits from each 
of the metrics or the sum of all metrics. Each variable of counts is considered to follow a negative binomial 
distribution and its log link will be used to connect the independent variable, or the fixed effect of intervention 
effect with site as a random effect. 
• 
Secondary Endpoint 2: Total PedsQLTM Infant Scales score. The proposed statistical model will be a mixed effect 
model using Total PedsQL score as the dependent variable, the intervention effect as the fixed effect, with site as a 
random effect. Means (and SEs) of Total PedsQL score estimated from the mixed effect model will be presented in 
the final result and compared between groups through a p-value to reach a statistical conclusion of significance 
and superiority.  
• 
Secondary Endpoint 3: PM2.5 levels. The proposed statistical model will be a mixed effect model using PM2.5 level 
as the dependent variable, and the intervention effect as the fixed effect, and site as a random effect. Means and 
SEs of PM2.5 level from the mixed effect model will be presented in the final result. A p-value of the difference of 
means between groups will be used to reach a statistical conclusion of significance and superiority.  
• 
Missing Data: Missing data of secondary endpoint will be assessed of causes of missing and imputed in analyses, 
following the same methods proposed for the primary endpoint.  
 
9.4.4 SAFETY ANALYSES 
Safety Analysis: Any AE related to the study groups specific to child participant will be documented and summarized as 
overall and by study groups using aforementioned descriptive statistics (see “Descriptive Statistics” in Section 9.4.1 for 
details).  Safety analysis and reports will be made as specified in the Data Safety and Monitoring Plan (DSMP).   
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
See Section 9.4.1 for details. 
 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 52 of 67 
9.4.6 PLANNED INTERIM ANALYSES  
Interim Analysis: An interim efficacy analysis has been planned for this study when 50% of study participants (49 
participants in both groups) have completed the follow-up period. We will employ Lan & DeMets’ alpha-spending 
function together with O’Brien-Fleming boundaries to preserve the overall type I error rate at 0.05 and power at 90% in 
the final analysis. The boundaries and operating characteristics for the proposed analyses are provided in the table 
below. In the event that findings from interim analysis provide evidence in favor of futility, the study team may consider 
halting the study. 
Analysis 
Information 
fraction 
Reject H0 (Efficacy)  
Overall α spent 
Reject H1 
(Futility)  
Overall β spent 
Interim 
0.50 
|𝑧𝑧|> 2.963 
0.0003 
|𝑧𝑧| < 0.200 
0.012 
Final 
1.00 
|𝑧𝑧|> 1.969 
0.05 
|𝑧𝑧| < 1.969 
0.102 
 
9.4.7 SUB-GROUP ANALYSES 
A stratified analysis of primary endpoint and secondary endpoints will be done: a) by site among those sites with ≥ 10 
participants per study groups, b) by sex for those levels/categories of sex with ≥ 10 participants, and c) race-ethnicity for 
those levels/categories of race-ethnicity with ≥ 10 participants. 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
None. 
 
9.4.9 EXPLORATORY ANALYSES 
No exploratory analyses are planned. 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Completed (all signatures affixed) written consent forms, approved by the reviewing IRB and describing the study 
intervention, study procedures, and risks, will be given to the participant’s parent(s)/legal guardian prior to starting 
study intervention.   
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent is a process that starts before the individual agrees to participate in the study (or allows their child to 
be a participant) and continues throughout the individual’s study participation. For sites (i.e., all sites except Native 
American sites) using the UAMS IRB as their reviewing IRB, the contemporaneous version of UAMS IRB policy 15.5, 
Informed Consent Process, is applicable and must be followed. The policy is available at https://irb.uams.edu/irb-

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 53 of 67 
policies/current-irb-policies/   If there are any discrepancies between this protocol and applicable reviewing IRB 
polici(es), the more stringent requirements apply. 
The written informed consent form will generally be signed during the child’s hospitalization. Consent may also be 
obtained in the 7 days after hospitalization provided all study enrollment, randomization and intervention set-up 
procedures can still be completed within 7 days post-hospitalization. The consent form, including site-specific local 
context, will be IRB-approved and the parent or legal guardian of the potential participant will be asked to read and 
review the document. The site investigator or qualified delegate will explain the research study in language that the 
parent/legal guardian of the participant can understand and will answer any questions that may arise. The explanation 
will include the purposes, procedures, and potential risks of the study and include the rights of their child as a research 
participant. Parents/legal guardians of participants must be informed that participation is voluntary and that they may 
withdraw their child from the study at any time, without prejudice. The rights and welfare of the participants will be 
protected by emphasizing to parents/guardians of participants that the quality of their child’s medical care will not be 
adversely affected if they do not allow their child to participate in this study.  
Parents/legal guardians of participants will be given the opportunity to carefully review the written consent form and 
ask questions prior to signing. The parent/guardian of the potential participants must also be given the opportunity to 
discuss the study with their family or surrogates or think about it prior to agreeing to allow their child to be a participant. 
The parent/legal guardian of the participant must sign the informed consent form prior to any study-specific procedures 
being done. A copy of the informed consent form (ICF), signed by all parties – including the person obtaining consent, 
will be given to the parent/guardian of the participants for their records.  
Due to the age (< 2 years old) of the children participating in the study, assent will not be obtained. 
The investigator or qualified delegate will document the processes in the source documents (research or medical record 
of the participant). Consent documentation will include, at a minimum: 
(1) the title of the trial, 
(2) the date the participant entered into the trial, 
(3) the name of the site investigator 
(4) the name of the person(s) obtaining the informed consent and 
(5) a statement that the parent/legal guardian of the participant received a copy of the signed form. 
The following additional documentation is recommended, but it is not required: 
(1) a list of who else was present during the process, 
(2) the type of questions asked by the parent/guardian of the participant, 
(3) a summary of details that demonstrate the parent/guardian of the participant understood the information, and 
(4) a description other specific details related to that case. 
Remote consenting: 
If needed, remote consenting may be used to enroll a participant after the child has left the hospital. All 
communications will be done via HIPAA-compliant methods such as telephone, personal delivery of documents, US 
postal service, REDCap or other compliant electronic platform. The remote consent process will parallel the consent 
processed used for in-person consenting. The only difference will be the method(s) of communication. The study 
team will ensure that, as with in-person consenting, the parent/legal guardian of the participant is given sufficient 
opportunity to ask questions, is able to understand the nature of this study and what participation entails, and is 
provided a copy of the final, completed consent signed by all parties involved, including the research team member 
who obtained consent and, when applicable, the site investigator. This final, signed consent will be provided via a 
HIPAA-compliant method or a method that the parent/legal guardian of the participant has agreed to in writing. The 
site research team members working on the consenting process will ensure that any parent/legal guardian who is 
consenting remotely has the authority to consent for the child. 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 54 of 67 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause. Written 
notification, documenting the reason for study suspension or termination, will be provided by the suspending or 
terminating party to parents/guardians of study participants, investigator, funding agency, sponsor and regulatory 
authorities. If the study is prematurely terminated or suspended, the PI will promptly inform parents/guardians of study 
participants, the IRB, and sponsor and will provide the reason(s) for the termination or suspension. Parents/guardians of 
study participants will be contacted, as applicable, and be informed of changes to study visit schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Evidence of study futility of the primary endpoint as described in section 9.4.6 
If the study is temporarily suspended, it may resume once concerns about safety, protocol compliance, and data quality 
are addressed, and satisfy the sponsor, DSMB, and IRB. 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their interventions. Therefore, the study protocol, documentation, data, and all other information 
generated will be held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, or regulatory agencies 
may inspect all documents and records required to be maintained by the investigator, including but not limited to, 
medical records (office, clinic, or hospital) for the participants in this study. The clinical study site will permit access to 
such records. 
The study participant’s contact information (i.e., contact information of parent/guardian of participant) will be securely 
stored at each clinical site for internal use during the study. At the end of the study, all records will continue to be kept 
in a secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be transmitted 
to and stored at the DCOC. This will not include the participant’s parents/guardians contact or identifying information. 
Rather, individual participants and their research data will be identified by a unique study identification number. The 
study data entry and study management systems used by clinical sites and by DCOC research staff will be secured and 
password protected. At the end of the study, all study databases will be de-identified and archived at the DCOC. 
 
10.1.4 MULTI-SITE COMMUNICATIONS (IRB-RELATED) 
This study will conducted at various sites (approximately 17 hospitals) within the ISCPTN network. All sites, except the 
Native American site in Alaska, will cede to the UAMS IRB as the reviewing IRB (per SMART IRB definitions). The study-
specific IRB-related communications plan was constructed from the SMART IRB template and uses SMART IRB 
recommendations for communications. This plan will be submitted to the IRB as a separate study-specific document. 
The DCOC will serve as the lead study team and will be the intermediary between the sites and the UAMS IRB as the 
central (or single) IRB (i.e., cIRB). Other types of communications (i.e., related to data, study deviations, etc.) between 
DCOC and the sites are detailed in their respective appropriate sections of this protocol. 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 55 of 67 
 
10.1.5 FUTURE USE OF STORED SPECIMENS AND DATA  
Data collected for this study will be analyzed and stored at the DCOC. Permission to transmit data to the DCOC will be 
included in the informed consent.  
No specimens will be collected or stored for this trial. Regarding stored data, study personnel will document all trial 
interactions, and these will be password protected in a secured facility/location. 
The study team will place participant’s de-identified data and other limited information, such as race and ethnic group, 
into one or more centralized database(s). The study team will share this data in compliance with the ISPCTN and NIH 
data sharing policies. 
For future studies using any procedures or analysis not specified in this protocol, IRB approval is required. In the event 
that another investigator/collaborator has a meaningful purpose for accessing the data retrieved in this protocol, the 
DCOC must consult the PIs and the IRB must approve. 
 
10.1.6 KEY ROLES AND STUDY GOVERNANCE 
Protocol Co-Chair 
Name, degree, title 
Kelly Cowan, MD, Pediatric Pulmonologist 
Institution Name  
University of Vermont 
Address 
89 Beaumont Ave, Burlington VT 05401 
Phone Number 
802-847-8600 
Email 
Kelly.Cowan@uvm.edu 
Protocol Co-Chair 
Name, degree, title 
Erin Semmens, PhD, MPH, Associate Professor of Epidemiology 
Institution Name  
University of Montana 
Address 
32 Campus Drive, Missoula, MT 59801 
Phone Number 
406-243-4446 
Email 
erin.semmens@umontana.edu 
Statistician 
Name, degree, title 
Jun Ying, PhD, Professor of Biostatistics 
Institution Name  
University of Arkansas for Medical Sciences 
Address 
4301 W. Markham St, Slot 781 
Phone Number 
501-526-6734 
Email 
jying@uams.edu 
DCOC PIs 
Name, degree, title 
Songthip T. Ounpraseuth, Ph.D., Professor of Biostatistics 
Institution Name  
University of Arkansas for Medical Sciences 
Address 
4301 W. Markham St, Slot 781 
Little Rock, Arkansas 72205 
Phone Number 
501-686-7233 
Email 
STOunpraseuth@uams.edu 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 56 of 67 
 
Name, degree, title 
Sherry, E. Courtney, MD;  
Professor of Pediatrics & Dir. of Clinical Research for Neonatology 
Institution Name  
University of Arkansas for Medical Sciences / Arkansas Children’s 
Hospital 
Address 
c/o ISPCTN DCOC 
4130 Shuffield Drive, Slot 810;  
Little Rock, AR 72205 
Phone Number 
501-364-1028 
Email 
scourtney@uams.edu 
 
Name, degree, title 
Fred Prior, PhD  
Distinguished Professor and Chair Dept. Biomedical Informatics; & Prof. of 
Radiology 
Institution Name  
University of Arkansas for Medical Sciences 
Address 
4301 W. Markham St., Slot 782 
Little Rock, AR 72205 
Phone Number 
(314) 303-2485 
Email 
FWPrior@uams.edu 
 
Medical Monitor 
Name, degree, title 
Rebecca L. Latch, MD, Associate Prof. of Pediatrics 
Institution Name  
University of Arkansas for Medical Sciences  
Address 
4301 W. Markham St., Slot 603 
Little Rock, AR 72205 
Phone Number 
501-686-8499 
Email 
latchrebeccal@uams.edu 
 
 
10.1.7 SAFETY OVERSIGHT 
Safety oversight will be under the direction of a DSMB composed of individuals with the appropriate expertise, including 
pediatrics, environmental health, and biostatistics. Members of the DSMB will be independent from the study conduct 
and free of conflict of interest, or measures will be in place to minimize perceived conflict of interest. The DSMB will 
meet on a regular basis, per the DSMB charter, to assess safety and efficacy data of the study. The DSMB will operate 
under the rules of an approved charter. Data elements that the DSMB needs to assess are defined in the charter. The 
DSMB will provide its input to the NIH and the sponsor.  
The role of the Medical Monitor is to provide input on safety considerations, evaluate safety trends, and to provide 
oversight throughout the life cycle of the clinical research, in accordance with the approved protocol. This role includes 
review and monitoring of safety events on a regular basis, advising the protocol investigators on trial-related medical 
questions or problems, as needed, and to review cumulative participant safety data and make recommendations 
regarding the data to the DSMB. The Medical Monitor will remain blinded to treatment assignment during safety event 
review, unless unblinding is warranted to optimize management of an adverse event or for other safety reasons.  
 
10.1.8 CLINICAL MONITORING 
Clinical site monitoring will be conducted to ensure that the rights and well-being of trial participants are protected, that 
the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial complies with the current 
approved protocol and other IRB-approved documents, with ICH E6(R2), with applicable regulatory requirement(s) and 
other documents, including the study-specific Manual of Procedures (MOP), needed to complete study conduct.  

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 57 of 67 
Monitoring for this study will be performed by a member of the DCOC staff or their designee.  
Monitoring will be planned to be conducted on site, or remotely, according to the Site Monitoring Plan.  Monitors will 
use the Site Monitoring Plan to guide their review and guide the documentation of their activities and findings. The Site 
Monitoring Plan will describe who will conduct the monitoring, the frequency at which monitoring will be done, at what 
level of detail monitoring will be performed, and provide details for the distribution of monitoring reports.  
 
10.1.9 QUALITY ASSURANCE AND QUALITY CONTROL 
Each IRB-approved research site entering data will perform internal quality management of study conduct, data 
collection, documentation, and completion. Sites that ceded to the UAMS IRB (as central IRB) will follow applicable 
UAMS IRB policies, available at https://irb.uams.edu/irb-policies/current-irb-policies/ .  A listing of applicable UAMS IRB 
policies will be provided in the MOP. If local requirements conflict with UAMS IRB policies, sites will consult with DCOC 
to help determine which policies and procedures need to be followed.  Each site will follow the trial-specific MOP and 
any applicable site-specific SOPs and/or local (site-specific) IRB policies. The clinics and ECHO ISPCTN site awardees will 
provide direct access to all their facilities, source data/documents and reports for the purpose of monitoring or auditing 
by the DCOC and inspection by local and applicable authorities with oversight responsibilities. When electronic health 
records are source data/documents, sites must provide read-only access for anyone authorized to inspect or verify 
records.  
Following the applicable monitoring SOPs, the monitors will verify that the clinical trial is conducted and that data are 
generated, documented (recorded) and reported in compliance with the protocol, the trial-specific Site Performance 
Plan, site-specific SOPs, the ICH GCP E6(R2) and applicable requirements. 
We will implement QC procedures for the database and DCOC-maintained records in accordance with the Site 
Performance Plan, MOP, data safety monitoring plan (DSMP) and applicable SOPs. We may communicate information 
about any data anomalies to the sites(s) for clarification/resolution. 
We will address issues uncovered during QA, QC or monitoring activities through simple corrections or root-cause 
analysis, followed by instituting corrective and preventative action (CAPA), as appropriate and as described in the MOP. 
Data quality assurance: Each variable will be provided a predefined entering format a range before data entry. Each 
data entry will be monitored for missing observations and discrepancies based upon predefined variable settings. All 
missing observations and discrepancies will be flagged and reported to study personnel (investigators and site 
coordinators) for further investigating the sources of problems. Problems associated to human errors, system errors, 
and device malfunction at data entry will be corrected following proper steps. All actions will also be recorded for 
backtracking and future reference. The detailed plans for data quality assurance will be specified in the DSMP.    
 
10.1.10 
DATA HANDLING AND RECORD KEEPING  
A formal data management plan will describe and document the data and workflow for the trial. The data management 
plan and associated documentation will specify all operations performed on data from origination to database lock, 
including detailed descriptions of source documentation, CRFs, instructions for completing forms, data handling and 
record keeping procedures, procedures for data monitoring, and reconciliation procedures and coding dictionaries to be 
used, if applicable. The data management plan will also describe the specific data collection and management 
responsibilities required of the sponsor, study PI(s), the sites, and the DCOC. The contents of the data management plan 
will be consistent with those described in the Good Clinical Data Management Practices (GCDMP).  
Data collection is the responsibility of the clinical trial staff at the individual ECHO ISPCTN sites under the supervision of 
the site investigator. The site investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported and will carefully monitor study procedures to protect the safety of research subjects, 
the quality of the data and the integrity of the study. All source documents must be completed using standard good 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 58 of 67 
documentation practices (i.e., the ALCOA-C method [attributable, legible, contemporaneous, original, accurate, and 
complete]).   
It is best practice for ECHO ISPCTN site coordinators to use hard copies of any data recorded on paper CRFs or trial visit 
worksheets/assessment forms as source document worksheets recording data for each participant consented in the 
trial. Study personnel will enter clinical data into an EDC system that complies with HIPAA regulations, provided by the 
DCOC at UAMS. The EDC system includes password protection and internal quality checks, such as automatic range 
checks, to identify data that appear inconsistent, incomplete, or inaccurate. Study personnel will enter clinical data 
directly from the source documents. Data recorded in the EDC derived from source documents must be consistent with 
the data recorded on the source documents.  
 
10.1.10.1 
STUDY RECORDS RETENTION  
Throughout the course of the trial, all site awardees and clinics will retain the source documents on site in accordance 
with current site-specific medical record storage procedures. 
Sites must retain all trial documents in accordance with local and/or federal regulations, whichever is most stringent. 
Sites will not destroy any records without the written consent of the sponsor, if applicable. It is the responsibility of the 
sponsor to inform all investigators when these documents no longer need to be retained. 
 
10.1.11 
PROTOCOL AND STUDY DEVIATIONS  
A deviation is any instance of failure to follow, intentionally or unintentionally, the requirements of the clinical trial 
protocol, ICH E6(R2) (i.e., “GCP”),  the study-specific MOP, or other documents needed to complete study conduct. The 
instance of failure may be on the part of the participant, the investigator, or other study staff personnel.  When 
deviations occur, the sponsor and/or site team(s) will ensure actions are taken to correct the problem and, as needed, 
prevent the deviation from recurring.   
These practices are consistent with ICH E6(R2) (available at https://www.fda.gov/files/drugs/published/E6%28R2%29-
Good-Clinical-Practice--Integrated-Addendum-to-ICH-E6%28R1%29.pdf ).  Specifically, sections:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
Sites must record all deviations in the trial source documents. Whenever a deviation occurs, the DCOC will ensure an 
appropriate assessment is conducted.   The assessment should include documentation of the severity and risk of the 
deviation. Sites that have a system set up for assessing deviations and doing their own corrections via corrective and 
preventive action (CAPA) plans will do so according to their site SOPs/system.  The site will send copies of their CAPA 
plan documentation to the DCOC.  If a site does not have their own quality assurance system to complete adequate 
deviation review and assessments, corrections, and CAPA plans, then the DCOC will provide that function for the sites.  
Details of these processes will be provided in the MOP and/or trial-specific SOPs.  Essentially, the site and/or the DCOC 
will request/ensure that there is either a CAPA plan initiated or a simple one-time correction is performed, as 
appropriate. 
 
10.1.12 
PUBLICATION AND DATA SHARING POLICY 
We will conduct this trial in accordance with the following publication and data sharing policies and regulations: 
• 
NIH Public Access Policy, which ensures that the public has access to the published results of NIH-funded research. 
It requires scientists to submit final peer-reviewed journal manuscripts that arise from NIH funds to the digital 
archive PubMed Central upon acceptance for publication. 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 59 of 67 
• 
ECHO ISPCTN Publications and Presentations Policy, which ensures accurate, responsible, and efficient 
communication of findings from ECHO ISPCTN clinical trials. The ECHO ISPCTN Steering Committee has approved 
and ratified the ECHO ISPCTN Publications and Presentations Policy, which includes representatives from all site 
awardees, as well as representatives from the NIH and the DCOC.  
• 
NIH Data Sharing Policy and the policy on the Dissemination of NIH-Funded Clinical Trial Information and the 
Clinical Trials Registration and Results Information Submission Rule. We will register this trial at ClinicalTrials.gov, 
and we will submit trial results to ClinicalTrials.gov. In addition, we will make every attempt to publish results in 
peer-reviewed journals. Other researchers my request data from this trial by contacting Jeannette Lee, PhD, at the 
DCOC.  
 
10.1.13 
CONFLICT OF INTEREST POLICY 
The independence of this trial from any actual or perceived influence, such as by the pharmaceutical industry, is critical. 
Therefore, we will disclose and manage any actual conflict of interest of persons who have a role in the design, conduct, 
analysis, publication, or any aspect of this trial. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in the design and conduct of 
this trial. The trial leadership in conjunction with the NIH ECHO office has established policies and procedures for all trial 
group members to disclose all conflicts of interest and will establish a mechanism for the management of all reported 
dualities of interest. 
 
10.2 ADDITIONAL CONSIDERATIONS 
Not applicable. 
 
10.3 PROTOCOL AMENDMENT HISTORY 
See table(s) between cover page and table of contents. 
 
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Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 60 of 67 
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Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 61 of 67 
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Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 62 of 67 
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Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 63 of 67 
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Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 64 of 67 
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Jan;74:136-43.  
 
 
  
 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 65 of 67 
APPENDIX A: WINIX® 5500-2 HEPA FILTER 
 
https://winixamerica.com/product/5500-2/ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 66 of 67 
 
APPENDIX B: PURPLEAIR PA-II-SD MONITOR 
 
https://www2.purpleair.com/collections/air-quality-sensors/products/purpleair-pa-ii-sd 
 
 

Title:  The BREATHE Study: Bronchiolitis Recovery and the Use of High Efficiency Particulate Air (HEPA) Filters)  
Sponsor:  ISCPTN DCOC 
cIRB (UAMS IRB) # 274137   Version #: V-08 
Date: 24-September-2024                                                                                                                     Page 67 of 67 
APPENDIX C: KILL A WATT EZ METER 
 
 
http://www.p3international.com/products/p4460.html