A Prospective, Randomized, Controlled Study to Assess Medication Adherence in Children With Asthma Managed on BreatheSmart and Feedback
Phase: NA
Conditions: Asthma
Sponsor: Connecticut Children's Medical Center

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A prospective, randomized, controlled study to assess 
medication adherence in children with asthma managed 
on BreatheSmart and feedback. 
Spring 2017 
 
PRINCIPAL INVESTIGATOR: Jessica Hollenbach  
DEPARTMENT:  The Asthma Center  
INSTITUTION:  CT Children’s Medical Center 
PHONE: (860) 837-5333 
EMAIL: jhollenbach@connecticutchildrens.org 
 
 
CO-INVESTIGATOR: Tregony Simoneau 
CO-INVESTIGATOR: Craig Schramm 
DEPARTMENT: Pediatric Pulmonary 
DEPARTMENT: Pediatric Pulmonary 
INSTITUTION: CT Children’s Medical Center 
INSTITUTION: CT Children’s Medical Center 
PHONE: (860) 545-9440 
PHONE: 
EMAIL: tsimoneau@connecticutchildrens.org 
EMAIL: cschram@connecticutchildrens.org 
 
 
CO-INVESTIGATOR: Craig Lapin, M.D. 
 
 
DEPARTMENT: Pediatric Pulmonology 
 
INSTITUTION: CT Children’s Medical Center 
 
PHONE: 
 
EMAIL: clapin@connecticutchildrens.org 
 
 
 
CO-INVESTIGATOR: Anne McLaughlin, M.D. 
CO-INVESTIGATOR: Umit Emre, M.D. 
DEPARTMENT: Pediatric Pulmonology 
DEPARTMENT: Pediatric Pulmonary 
INSTITUTION: CT Children’s Medical Center 
INSTITUTION: CT Children’s Medical Center 
PHONE: 
PHONE: 
EMAIL: amclaughlin@connecticutchildrens.org 
EMAIL: uemre@connecticutchildrens.org 
 
CO-INVESTIGATOR: Melanie Collins, M.D. 
Co-Investigator: Natalie Shilo 
DEPARTMENT: Pediatric Pulmonology 
Department: pediatric Pulmonology 
INSTITUTION: CT Children’s Medical Center 
Institution: CT Children’s Medical center 
PHONE:  
Phone: 860-545-9440 
EMAIL: mcollin@connecticutchildrens.org 
Email: nshilo@connecticutchildrens.org 
 
 
DOES THIS PROJECT INVOLVE ANY NICU RESOURCES?                                _X_ NO     ___ YES  
(patients/families, clinical/non-clinical staff, medical records) 
 
     IF YES, HAS IT BEEN REVIEWED BY DR. MOORE OR HIS DESIGNEE?      ___ NO     ___ YES 
 
     IF YES, SPECIFY REVIEWER: ________________________________________ 
 
 
 
 
IS THIS A STUDENT OR TRAINEE PROJECT?                                                     _X_ NO     ___ YES 
  
   
 
            
 

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     IF YES, INDICATE LEVEL:  
___ Medical/Dental Student 
 
 
 
 
 
___ Resident 
 
 
 
 
 
___ Fellow 
 
 
 
 
 
___ Undergraduate 
 
 
 
 
 
___ Other (specify ________________________)      
 
 
     IF YES, HAS FACULTY ADVISOR REVIEWED THE PROTOCOL?                 ___ NO     ___ YES 
                 
Note:  Student researchers are required to attend the Scientific Review Committee  
           meeting when their protocol is discussed.            
 
TITLE: A prospective, randomized, controlled study to 
assess medication adherence in children with asthma 
managed on BreatheSmart and feedback. 
 
SPONSOR 
CCMC 
 
PROTOCOL NUMBER: V.5 
 
  
 
  
  
  
  
  
  
  
  
 
 
 
 
 

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Contents 
1. 
INTRODUCTION/BACKGROUND .................................................................................. 6 
2. 
STUDY TITLE ...................................................................................................................... 7 
A prospective, randomized, controlled study to assess medication adherence in children with 
asthma managed on BreatheSmart and feedback. ........................................................................... 7 
3. 
JUSTIFICATION ................................................................................................................. 7 
5. 
BREATHESMART............................................................................................................... 7 
5.1. 
BreatheSmart .................................................................................................................. 7 
5.3. 
CoheroConnect ............................................................................................................... 8 
6. 
STUDY DESIGN ................................................................................................................... 8 
6.1. 
Endpoints ........................................................................................................................ 9 
6.1.1 Primary: ............................................................................................................................ 9 
The study's primary objective is to estimate the relative improvement in medication adherence 
among children using BreatheSmart with feedback compared to control at 6 months. ............. 9 
6.1.2 Secondary: ........................................................................................................................ 9 
Important secondary objectives include the extent to which BreatheSmart system improves the 
following when compared to control from baseline to 6-months: .............................................. 9 
 
asthma control as measured by the Childhood Asthma Control Test (ACT) ...................... 9 
 
lung function as measured by FEV1 and FEV1/FVC ratio compared to standard of care .. 9 
 
the correlation between changes in medication adherence and changes in FEV1 and 
FEV1/FVC ratio. ......................................................................................................................... 9 
 
the overall number of provider visits for asthma related adverse events (number of 
exacerbations leading to acute Provider intervention, ER visits, hospitalizations, or requiring 
oral systemic corticosteroid therapy) .......................................................................................... 9 
 
number of missed school days ............................................................................................. 9 
7. 
STUDY POPULATION ....................................................................................................... 9 
7.1. 
Inclusion and Exclusion Criteria .................................................................................. 9 
7.2. 
Sample Size Estimates .................................................................................................. 10 
7.3. Recruiment   …………………………………………………………………………............................10 
7.4. Informed Consent ............................................................................................................ 10 
7.5. Participant Numbering .................................................................................................... 11 
8. 
STUDY PROCEDURES .................................................................................................... 11 

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8.1. 
Screening Assessments ................................................................................................. 11 
8.2. 
Randomization .............................................................................................................. 11 
8.3. 
Baseline Assessments.................................................................................................... 11 
8.3.1. 
Control Participants ............................................................................................. 11 
8.3.2. 
Active Participants ................................................................................................ 12 
8.4. 
Follow-up....................................................................................................................... 12 
8.5. 
End of Study Visit ........................................................................................................ 13 
8.6. 
Participant Withdrawal ............................................................................................... 13 
9. 
ADVERSE EVENT REPORTING ................................................................................... 14 
9.1. 
Recurrent Exacerbation of Asthma ............................................................................ 14 
9.2. 
Adverse Drug Reactions .............................................................................................. 14 
9.3. 
Serious Adverse Event Definition ............................................................................... 14 
9.4. 
Death .............................................................................................................................. 15 
10. 
DATA MANAGEMENT ................................................................................................. 15 
10.1. 
Data Confidentiality ................................................................................................. 15 
10.2. 
Data Monitoring ....................................................................................................... 16 
10.3. 
Data quality ............................................................................................................... 16 
10.4. 
Data analysis ............................................................................................................. 16 
10.5. 
Statistical Analysis .................................................................................................... 17 
11. 
STUDY CONDUCT ......................................................................................................... 18 
11.1. 
Good Clinical Practice.............................................................................................. 18 
11.2. 
Ethical Considerations ............................................................................................. 18 
11.3. 
Institutional Review .................................................................................................. 18 
11.4. 
Participant Information and Informed Consent ................................................... 18 
11.5. 
Participant Confidentiality ...................................................................................... 18 
11.6. 
Protocol Compliance ................................................................................................ 19 
11.7. 
On-site Audits ........................................................................................................... 19 
11.8. 
Record Keeping and Retention ............................................................................... 19 
11.9. 
Site Master File ......................................................................................................... 19 
11.10. 
Study Report and Publication ................................................................................. 20 
 

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ABBREVIATIONS 
  
EMD 
Electronic Monitoring Devices 
ICS 
Inhaled Corticosteroids 
BTE 
Bluetooth Low Energy sensor 
MA 
Mobile application 
ACT 
Asthma Control Test 
mHealth 
Mobile Health 
pMDI 
Pressurized metered dose inhaler 
ED 
Emergency Department 
PFT 
Pulmonary Function Test 
eCRF 
Electronic case report forms 
EDC 
Electronic data capture 
FEV 
Forced expiratory volume 
FeNO 
Fractional exhaled nitric oxide 
 
  
  
  
  
  
 
 
 
 
  
 
 
 
 
 
 
 

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1. INTRODUCTION/BACKGROUND 
Asthma affects more than 235 million people worldwide, including approximately 8.6% of U.S 
children (6.3 million children).1,2  Asthma treatment is a substantial burden to the healthcare 
system and is responsible for more than 10 million medical office visits (close to 6% of all US 
medical office visits) and 1.8 million ED visits each year.3 Regular use of controller medication 
is essential to prevent symptoms and relieve asthma exacerbations and thus decrease healthcare 
utilization and expenditure.4 
 
Non-adherence to asthma medication is a common problem in patients with asthma, and young 
people are known to have particularly low medication adherence.5,6 Non-adherence leads to 
overuse of reliever medication and more frequent severe asthma exacerbations including ED 
visits and hospital admissions.4,7 Self-report consistently overestimates medication adherence 
making accurate assessment and intervention difficult for clinicians.5  However, two recent 
reviews found mean controller adherence ranging from 20% to 34% and 38% to 71% as 
measured by medication possession ratio (MPR) and electronic monitoring respectively.8,9 Thus, 
even the commonly cited statistic of 50% average medication adherence may underestimate the 
true scope of the problem.10-12 Non-adherence is multifactorial, with contributing factors 
including lack of patient knowledge about asthma, poor understanding of the benefits of 
medication, forgetfulness, and negative attitude toward asthma.9 
 
Telemanagement of chronic diseases is increasingly being employed to improve medication 
adherence and health outcomes, and has been shown to be cost-effective.13 A recently developed 
process model for optimal asthma care demonstrates the need for improved understanding of 
patient medication use behavior and how adherence interventions can impact clinical outcomes.14 
A number of studies have improved medication adherence through incorporation of electronic 
reminders such as text messages across the spectrum of chronic diseases.15 Recently a number of 
studies have looked specifically at the use of such messages along with medication-use tracking 
in asthma have been able to show mean improvement in adherence from 10-52 percentage 
points.16-23 While promising, these interventions have focused on the use of audiovisual reminder 
systems16, 21-23 that rely on having access to the inhaler itself or are simply based on SMS 
messages.17,18 Such interventions are limited in their ability to engage participants for improved 
disease self-management and self-monitoring compared to more comprehensive approaches, 
known to be key for sustained asthma telemanagement and mHealth approaches.13  
 
Importantly, mobile applications allow for better sustained patient engagement and have been 
successfully implemented in other disease spaces to improve medication adherence and 
outcomes.13 Mobile applications offer the opportunity to be scaled to the U.S. population-at-large 
and can be sustained due to the front-end cost of development and low staff resources required 
for maintenance once the product is built.  Additionally, the ability to relay adherence data 
directly to clinicians either via a patient portal or into the EMR provides opportunity to direct 
care coordination efforts and resources towards those participants who are most in need, and 
provides information that can be used for point-of-care treatment decision making.  
 

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2. STUDY TITLE 
A prospective, randomized, controlled study to assess medication adherence in children with 
asthma managed on BreatheSmart and feedback. 
 
3. 
JUSTIFICATION  
Non-adherence to controller medication is a common problem in children with Asthma, resulting 
in overuse of reliever medication, increased asthma symptoms, more frequent Asthma attacks, 
and increased emergency room visits and hospital admissions.4 Additionally, current absence of 
a gold standard to measure adherence forces clinicians and researchers to rely on patient-self 
report, which is notoriously inaccurate, to support clinical decision making. Many young patients 
suffer from both intentional and non-intentional non-adherence, thus an appropriate intervention 
must address both types. Current studies using electronic monitoring devices (EMDs) primarily 
focus on non-intentional non-adherence through reminder systems and thus are limited in their 
ability to engage patients for long-term behavior change.  
 
This trial addresses an important knowledge gap by evaluating whether EMDs with a 
combination of reminder system and patient education can prove to be effective in increasing 
adherence rates and can be used in clinical practice to achieve better asthma control and 
outcomes through improved patient and clinician engagement. 
 
4. OBJECTIVES 
The objectives of this study are to determine if the addition of the BreatheSmart platform 
improves medication adherence and health outcomes in children with persistent asthma who are 
managed with inhaled corticosteroids. 
5. BREATHESMART 
5.1. BreatheSmart  
A mobile application designed for use with iOS and Android operating systems. Using 
Bluetooth to connect, this mobile application syncs with HeroTracker to facilitate the 
collection of medication adherence data.  
 
5.2. HeroTracker  
A wireless Bluetooth-enabled inhaler sensor that tracks medication dosage and 
adherence. Designed for both controller and rescue medications in diskus and MDI 
formats. 
 
 
 

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5.3. CoheroConnect  
A HIPAA compliant cloud-based application allowing data to be aggregated and readily 
available as actionable information for clinicians and caregivers managing children on 
BreatheSmart. 
 
 
6. STUDY DESIGN 
This is a prospective, randomized, controlled study of children with persistent asthma who are 
managed on daily inhaled corticosteroids (ICS). 75 children will be randomized 2:1 into one of 
two arms:  
● 50 children will be randomized to BreatheSmart, comprised of: 
○ BreatheSmart mobile application that tracks medication usage and sends real time 
reminders 
○ HeroTracker sensor that counts dosage and monitors real-time medication 
adherence 
○ CoheroConnect provider portal that allows the Investigator to monitor real-time 
adherence and to provide targeted outreach to children with low adherence 
(intervention arm)   
● 25 children will be randomized to “standard of care” (control arm). These patients are 
reminded to adhere to the prescribed standard of care therapy provided by their clinician 
during their clinical encounters and when the family calls to report an illness. 

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6.1. Endpoints 
6.1.1 Primary:  
The study's primary objective is to estimate the relative improvement in medication 
adherence among children using BreatheSmart with feedback compared to control at 6 
months. 
6.1.2 Secondary:  
Important secondary objectives include the extent to which BreatheSmart system 
improves the following when compared to control from baseline to 6-months: 
 asthma control as measured by the Childhood Asthma Control Test (ACT) 
  lung function as measured by FEV1 and FEV1/FVC ratio compared to standard 
of care 
 the correlation between changes in medication adherence and changes in FEV1 
and FEV1/FVC ratio. 
 the overall number of provider visits for asthma related adverse events (number of 
exacerbations leading to acute Provider intervention, ER visits, hospitalizations, 
or requiring oral systemic corticosteroid therapy) 
 number of missed school days  
7. STUDY POPULATION 
This study will enroll children who have been diagnosed with persistent asthma for at least 6 
months’ duration and who are showing evidence of poorly controlled disease.  75 children will 
be recruited from CT Children’s Medical Center Pulmonary Clinic and East and West Primary 
Care. 
 
7.1. Inclusion and Exclusion Criteria 
Inclusion and Exclusion Criteria  
 
Inclusion criteria:  
 Age 8 to 17 
 
Diagnosis of persistent asthma  
 
Prescribed an inhaled corticosteroid (ICS) for at least one month prior to enrollment 
 
Use of a pressurized metered dose inhaler (pMDI) compatible with the Cohero mHealth 
Herotracker (See Appendix) 
 
Parent/child possess a compatible smartphone (iOS 8.0 or higher) 
 
English or Spanish speaking  
 
Exclusion criteria:  

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 
Presence of another chronic lung disease or condition such as cystic fibrosis, interstitial 
lung disease, chronic lung disease of prematurity, recurrent aspiration, or presence of 
tracheostomy 
 
Presence of other chronic medical condition such as congenital heart disease or 
immunodeficiency 
 
Presence of other comorbidities that, in the opinion of the investigator, will interfere with 
collection of study procedures, or limits life expectancy to < 1 year 
 
Currently pregnant or planning to become pregnant during the trial period 
   
7.2. Sample Size Estimates 
There is no pilot data available to inform a sample size analysis. In addition, our sample size 
is limited by our supply of HeroTracker devices (50). As this is an exploratory study, we 
hope our findings will inform future sample size analyses for studies of similar focus with a 
larger cohort.  
 
7.3. Recruitment 
Due to the shortage of space and high patient volume at the CCMC pulmonary office, based on 
the scheduled patients for the day, research personnel will identify potentially eligible patients 
based on information will be gathered from the “Pulmonary Snapshot” feature in EPIC.  These 
data include patient age, asthma diagnosis and prescribed medicines. Research personnel will 
also be identifying potentially eligible patients at the East and West Primary care through the 
“Primary Care Sanpshot” features in EPIC. Potential participants will only be approached if 
he/she meets the following inclusion criteria: age between 8-17 years, documented diagnosis of 
persistent asthma and/or prescription of an inhaled corticosteroid.  Once this is confirmed, the 
research personnel will approach the patient to administer the screening questionnaire to confirm 
that the child meets all the inclusion and exclusion criteria. Children could also be referred to this 
study by their healthcare provider if he/she feels that the patient qualifies for entry into the study 
based upon the Inclusion/Exclusion Criteria. If eligible, the parent will be asked to participate in 
the study and presented with the informed consent document which will include the parent’s 
consent to utilize the relevant screening and baseline data for the purposes of this study. 
7.4. Informed Consent 
The primary investigator (or designee) will discuss the study in detail with the child and parent 
and describe the potential risks and benefits. If the parent agrees for their child to participate, a 
legally effective informed consent will be obtained.  The consent process will be documented in 
the study chart and the parent will receive a copy of the fully executed informed consent form for 
their records. All children participating in this study will complete assent.  

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7.5. Participant Numbering 
To maintain confidentiality, the participant’s name will not be recorded on any study documents 
other than the informed consent form.  All participants that provide informed consent will be 
assigned a unique alphanumeric code that will identify them throughout the course of the study. 
8. STUDY PROCEDURES 
All participants will be seen at screening/baseline, 90 and 180 days’ post randomization where 
the following assessments will be performed. 
8.1. Screening Assessments 
The study staff will interview the parent and child and document the following: 
 Type of mobile device and version number of the operating system in use 
 Email address 
 Age/gender/ethnicity 
 Parent Income level/education level/medical insurance type 
 Date of asthma diagnosis 
 Other comorbidities 
 Use of inhaled corticosteroids and other inhaled therapies for asthma 
 Use and timing of oral systemic corticosteroids 
 Use of other concomitant medications 
 Medication refill information (obtained through pharmacy records) 
 ACT 
8.2. Randomization 
If the child is eligible and they wish to participate they will be randomized in a 2:1 allocation to 
BreatheSmart or to standard of care. As we have a limited supply of HeroTracker devices and 
the CoHero platform does not provide a feasible way to execute any degree of blinding, this will 
be conducted as an open trial where both groups (control and intervention groups) will be treated 
as equally as possible. Randomization will be stratified by age at the time of enrollment (8-13 
years, 14-17 years) and blocked in randomly permuted sequences of 4. 
8.3. Baseline Assessments  
8.3.1. Control Participants 
Control participants will be reminded to adhere to the standard of care therapy, as prescribed.   
The following assessments will be recorded: 
 Concomitant medications 

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 Measurement of lung function including FEV1, FEV1/FVC ratio, FeNO (standard clinic 
measurement only assessed in the Pulmonary clinics) 
 Child Asthma control test (ACT) questionnaire 
 Exacerbation of asthma episodes (obtained through self-report and chart review) 
requiring: 
○ Courses of oral steroids     
○ Doctor visits outside of standard of care 
○ ER visits 
○ Hospitalizations 
 Missed school days  
 PedsQL asthma module (patient and parent report)  
 Test of Adherence to Inhalers 
 Pharmacy refill data for asthma prescriptions during the previous 6 months 
 
8.3.2. Active Participants 
Active participants will be reminded to adhere to the standard of care therapy, as prescribed. 
They will be trained to and provided with the BreatheSmart application and Herotrackers. 
The following assessments will be recorded: 
 Concomitant medications 
 Measurement of lung function including FEV1, FEV1/FVC ratio, FEF25-75, FeNO 
(standard clinic measurement, completed by participants recruited for the pulmonary 
clinic) 
 Child Asthma control test (ACT) questionnaire  
 Exacerbation of asthma episodes (obtained through self-report and chart review) 
requiring: 
○ Courses of oral steroids     
○ Doctor visits outside of standard of care 
○ ER visits 
○ Hospitalizations 
 Missed school days  
 PedsQL asthma module (patient and parent report)  
 Test of Adherence to Inhalers 
 Pharmacy refill data for asthma prescriptions during the previous 6 months 
8.4. Follow-up 
All participants in both groups will be seen at 90 and 180 days’ post randomization (+/-20 days 
correlating with routine pulmonary clinic follow up and East and West Primary Care Follow up) 
where the following assessments will be recorded: 
 Medication changes/refills (obtained through pharmacy record) 

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 
FEV1, FEV1/FVC, FEF25-75 and FeNO per clinical standard of care (only assessed in 
the Pulmonary clinic) 
 
Child Asthma control test (ACT) questionnaire  
 
Serious Adverse Events will be recorded at each visit 
 
Missed school days  
 
PedsQL asthma module (patient and parent report) 
 
Test of Adherence to Inhalers 
 
Exacerbation of asthma episodes (obtained through self-report and chart review) 
requiring: 
○      Doctor visits outside of standard of care 
○      ER visits 
○      Hospitalizations 
 
In addition, active participants (test group) will be continuously monitored via the 
CoheroConnect dashboard which allows the Investigator to monitor the child’s medication 
adherence in real time.  If a period of participant inactivity of 3 days is registered in the system, 
the Investigator (or designee) will be notified and he/she will be prompted to contact the 
participant to remind them to take their medication as prescribed. The Investigator or designee 
will review patient specific data (% adherence since last visit and graph of adherence patterns 
over time since enrollment) through the CoheroConnect dashboard within two days before a 
follow up visit. At the follow-up visit, these data will be reviewed with the patient and 
parent/caregiver. The adherence rate and barriers identified will be discussed and, if necessary, 
personalized strategies for improvement will be devised. These data will also be shared with the 
clinician during these follow up visits.  Medication adherence data for control participants will 
be obtained by measure of pharmacy record refill information and self-report (Test of Adherence 
to Inhalers) throughout the duration of the study.  
 
We understand that the self-report of missed school days due to asthma may be unreliable and 
subject to recall bias, however, this is the method we currently use clinically to assess this 
measure. 
 
If a participant is unable to complete the follow-up visit at their routine pulmonary appointment, 
the coordinator will either mail, text a link, or email a link of the follow-up surveys to the 
participants. They will be reminded 3 times via text, email or phone to complete the follow-up 
questionnaires.  
 
8.5. End of Study Visit 
 Participants who finish the 180-day visit will be considered “complete”. They will then be 
provided with a $35 gift card for completing the study and returning their devices (HeroTracker). 
8.6. Participant Withdrawal 
If premature withdrawal from the study occurs for any reason (including death) the investigator 
must determine the primary reason for withdrawal and record this information on the study 

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Withdrawal CRF. For participants who are lost to follow-up (i.e., those participants whose status 
is unclear because they fail to appear for study visits without stating an intention to withdraw), 
the investigator will show "due diligence" by documenting in the source documents the steps 
taken to contact the participant, e.g., dates of telephone calls, letters, emails, etc. If the 
participant fails to respond after 3 attempts they may be withdrawn from the study. 
 
     8.7 Accrual and Study Duration 
We anticipate enrolling 4-5 subjects/week through the pulmonary clinic at the Hartford and 
Farmington locations. The Pulmonary Clinic at CCMC sees 15-30 patients/day at the Hartford 
location with 75% of the children having a diagnosis of asthma (~10-20/day), half of whom will 
be in the desired age range (~5-10) and will be screened. We will focus recruitment efforts on 2 
days per week when the greatest number of patients are scheduled. To minimize selection bias, 
we will vary the time of day and day of the week in which we recruit. Therefore, enrollment 
should take approximately 16 weeks to complete and the study will conclude 6 months after that 
last subject is enrolled.  
 
9. ADVERSE EVENT REPORTING 
This is a non-significant risk study exploring the use of the BreatheSmart System in the 
management of children who present with poorly controlled asthma symptoms despite being 
managed on inhaled corticosteroids.  
For the purposes of this study, the following anticipated adverse events and those meeting the 
definition of serious must be reported.  
9.1. Recurrent Exacerbation of Asthma 
An exacerbation of asthma requiring an intervention by the investigator must be recorded. The 
occurrence of these events will be obtained through both self-report and chart review. These 
events include: 
● change in/or addition of prescribed medications for the treatment of asthma, or  
● doctor visits outside of standard of care, or 
● ER visits, or 
● Hospitalization  
9.2. Adverse Drug Reactions 
Adverse reactions to medications prescribed for the treatment of asthma are well described in the 
literature. If an event related to a prescribed asthma drug meets the definition of serious it must 
be reported. 
9.3. Serious Adverse Event Definition 
A serious adverse event or reaction is any untoward medical occurrence that: 
● Results in death 
● Is life-threatening 

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● Requires inpatient hospitalization or prolongation of existing hospitalization 
● Results in persistent or significant disability/incapacity, or  
● Results in a congenital anomaly/birth defect 
  
NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. The investigator will be 
responsible for assigning causality to all serious adverse events. 
 
In the event that a SAE leads to hospitalization, every effort should be made by the 
investigational site to obtain the medical records/discharge summaries and complete a 
Hospitalization CRF. 
9.4. Death 
In the event that the SAE leads to death, the Investigator should provide a narrative summary of 
circumstances, the events related to the death, and the primary cause of death, if known.  
Information regarding a participant’s death must be reported within 24 hours of the knowledge of 
the death, and recorded on a Mortality form.  
10. DATA MANAGEMENT 
Prior to study enrollment, all research staff will be trained in principles of human subjects 
protection and maintenance of confidentiality of participant data.  
10.1. Data Confidentiality 
Participants limited PHI and the investigator's personal data, which may be included in the 
sponsor database, will be treated in compliance with all applicable laws and regulations. The 
sponsor will take all appropriate measures to safeguard and prevent access to these data by any 
unauthorized third party. 
The investigator must take all appropriate measures to ensure that the protection of data for 
each study participant is maintained. The investigator, and all site staff involved in this study, 
may not disclose (or use for any purpose other than performance of the study), any data, record, 
or other unpublished confidential information disclosed to those individuals for the purpose of 
the study. Prior written agreement from Cohero Health must be obtained for the disclosure of 
any said confidential information to other parties. All information recorded on CRFs must be 
traceable to source documents in the participant’s research file and/or medical chart with the 
exception of participant questionnaires that are completed directly in BreatheSmart or 
Qualitrics. 
Study data will be directly captured into BreatheSmart. Participants and study personnel 
requiring access to research systems will be trained and must use their own login and password. 
Access to clinical study information in these systems will be based on individuals' roles and 
responsibilities and the minimum rule.   These applications provide hierarchical user permissions 
for data entry, viewing, and reporting options.  For optimum security, all communications 
between the users and the applications operate on a secured socket layer (SSL) using 128 and 

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256-bit encryption. The web servers are protected by a managed firewall from potential web and 
network attacks, and the networks are guarded by an intrusion detection and protection 
surveillance system against malicious threats.  These applications are designed to be in full 
compliance with International Conference on Harmonization and Good Clinical Practices (ICH-
GCP), the FDA’s Code of Federal Regulations (CFR) Number 21 Part 11 Electronic Record and 
Electronic Signatures, the FDA's "Guidance: Computerized Systems Used in Clinical Trials, the 
Privacy Rule of the Health Insurance Portability and Accountability Act of 1996 (HIPAA), and 
Subtitle D of the Health Information Technology for Economic and Clinical Health (HITECH) 
Act, 2009 
10.2. Data Monitoring 
All questionnaires will be administered using the Qualtrics HIPAA-compliant web-based data 
collection software and app presented on encrypted and password protected iPads. All surveys  
administered at each visit (including the TAI, PedsQL, baseline data collection form, and follow 
up data collection form) are built into the Qualtrics platform. Qualtrics is a HIPPA-compliant 
electronic survey development and analytic tool. All data collected through Qualtrics will be 
stored into a pass-word protected Qualtrics account. PHI will not be entered into the database. 
Upon enrollment, subjects will be designated a study number. Once data is entered in the 
database, they will only be identified by study number. All communications with enrolled 
participants will be documented in a password protected ACCESS database on password-
protected and encrypted computers in the Asthma Center. No PHI will be entered into this 
database.   
Original source documents including the original signed consent form, HIPPA form, and any 
other relevant documents will be kept in a locked filing cabinet in a locked office until data 
analysis is complete. The PI will be responsible for monitoring the quality of the CRF 
completion and source documents.   
10.3. Data quality 
10% of the records will be spot checked on three separate occurrences: after completion of all 
data entry for baseline visits, 90 day follow-up visits and end of study visits (180 days post 
randomization). The rate of error and location of errors will be recorded as de-identified data in 
an excel document. 
10.4. Data analysis 
All data will be analyzed in accordance with the statistical analysis plan (SAP) to be developed 
at the beginning of this study.  Both primary and secondary analyses will be based on an 
intention-to-treat (ITT). 
The study's primary objective is to estimate the relative improvement in medication adherence 
among children using the BreatheSmart compared to control participants using “standard of 
care”. 
Important secondary objectives include the extent to which the Cohero system improves: 
●      asthma control as measured by ACT 

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●      FEV1,  FEV1/FVC ratio, FEF25-75 and FeNO compared to standard of care, and the 
correlation between changes in medication adherence from baseline and changes in FEV1 and 
FEV1/FVC ratio. 
●      the overall number of provider visits for asthma-related adverse outcomes (number of 
exacerbations leading to Provider intervention, ER visits, hospitalizations, or requiring oral 
systemic corticosteroid therapy) 
 Missed school days 
Data results may be used to inform a study of a larger cohort with similar focus with regard to 
sample size estimates, efficacy of the BreatheSmart platform, feasibility in a low-income 
pediatric population and study design.  
10.5. Statistical Analysis 
Between group differences in the change in mean adherence from baseline over will be based 
on a 0.05 level t-test. The corresponding 95% confidence interval for the between group mean 
difference will provide an interval estimate of benefit obtained using the Cohero 
system.  [NR1]  
In addition to the frequentist analysis of adherence, a Bayesian approach that focuses on 
estimating the probability distribution of differences in mean adherence using the Cohero 
system compared to standard of care.  The Bayesian approach begins with the premise that the 
Cohero system yields no improvement in adherence. This is an exact correspondence to a “null 
hypothesis”. This assumption is incorporated through a prior distribution for improvement in 
mean adherence; for example, by assuming that the mean improvement is characterized by a 
normal distribution with mean 0, the expected difference should the Cohero system offer no 
benefit, and some small variance (e.g. 0.01). This is also a statement that the probability that 
the Cohero system improves response compared to standard of care is 50% (i.e., the prior odds 
that active therapy is effective is 1:1, consistent with the notion of equipoise). 
The essence of the Bayesian approach is to use the data collected during the study to update 
the prior probability density based on the observed data (this updated density is the posterior 
probability distribution) using Bayes Theorem.  This posterior distribution provides estimates 
of the probability that the Cohero system improves adherence relative to standard of care by 
any amount greater than δ.  For example, choosing δ=0 corresponds to the frequentist test of 
the null hypothesis. 
The analysis of lung function will be performed in a corresponding manner to that described for 
adherence. Additionally, the correlation between change in FEV1, FEV1/FVC ratio and FEF25-
75 and change in adherence will be computed. Graphical analysis will be used to visually inspect 
the relationship between improvement in adherence and improvement in lung function. Based on 
the general form of the relationship, additional exploratory analyses will be performed. For 
example, if the relationship is approximately linear, standard regression methods will be used to 
estimate the relationship; if, however, a clear discontinuity is seen, splines might be used to 
estimate the relationship. 
 
 

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11. STUDY CONDUCT 
11.1. 
Good Clinical Practice 
The study will be conducted in accordance with the International Conference on Harmonization 
(ICH) for Good Clinical Practice (GCP) and the appropriate regulatory requirement(s).  The 
investigator will be familiar with evidenced-based standard of care practice in the treatment of 
patients with asthma, the prescribing information of medications, and with the risks and potential 
benefits of the study. Essential clinical documents will be maintained to demonstrate the validity 
of the study and the integrity of the data collected.  Master site files will be established at the 
beginning of the study, maintained for the duration of the study, and retained according to the 
appropriate regulations.   
11.2. 
Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki.  The Institutional Review Board (IRB)/Independent Ethics Committee (IEC) at each 
participating institution will review all appropriate study documentation in order to safeguard the 
rights, safety, and well-being of the participants.  The study will only be conducted at sites where 
IRB approval has been obtained.  The protocol, informed consent, recruitment advertisements (if 
applicable), written information given to the participants (including user manuals), safety 
updates, annual progress reports, and any revisions to these documents will be provided to the 
IRB by the investigator or study sponsor.  
11.3. 
Institutional Review 
Prior to initiation this study must be approved by the CT Children’s institutional review board 
(IRB) committee as defined by Federal Regulatory Guidelines (Ref. Federal Register Vol. 46, 
17, January 27, 1981, part 56) and the Office for Protection from Research Risks Reports:  
Protection of Human Subjects (Code of Federal Regulations 45 CFR 46). 
11.4. 
Participant Information and Informed Consent 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risk Reports:  Protection of Human Subjects (Code of Federal Regulations 45 CFR Part 46).  
They must be followed to comply with IRB regulations for the conduct and monitoring of 
clinical investigations. Freely given written informed consent must be obtained from every 
participant prior to clinical study participation. 
11.5. 
Participant Confidentiality 
In order to maintain participant privacy, all CRFs, study reports, and communications will 
identify the participant by the assigned alpha-numeric study number.  Only study personnel will 
have access to the participant’s original medical records for verification of data gathered on the 
CRFs and to audit the data collection process.  The participant’s confidentiality will be 

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maintained and will not be made publicly available to the extent permitted by the applicable laws 
and regulations. 
11.6. 
Protocol Compliance 
The investigator will conduct the study in compliance with this protocol and supporting 
documents.  Any changes to the protocol will require approval from the IRB prior to 
implementation, except when the modification is needed to eliminate an immediate hazard(s) to 
participants. Any departures from the protocol must be fully documented in the source 
documents and the EDC. 
11.7. 
On-site Audits 
The IRB may request access to all source documents, data capture records, and other study 
documentation for on-site audit or inspection.  Direct access to these documents must be 
guaranteed by the investigator, who must provide support at all times for these activities. 
11.8. 
Record Keeping and Retention 
Data generated for the study will be stored in a limited-access file area and be accessible only to 
study personnel. All reports and communications relating to study participants will identify 
participants only by participant identification code.  Complete participant identification will be 
kept by the investigator.  This information will be treated with strict adherence to professional 
standards of confidentiality. An investigator must in reasonable time, upon request from any 
properly authorized officer or employee of FDA/relevant health authority or regulatory agency, 
permit such officer or employee to have access to requested records and reports, and copy and 
verify any records or reports made by the investigator. The investigator will also grant the 
representatives the same privileges offered to FDA/relevant health authority or regulatory 
agents/officers/employees. 
  
11.9. 
Site Master File 
The following documents will be retained in the site master file:  
  
● Current signed curriculum vitae and medical licenses (within 1 year) for the Principal 
Investigator and all co-investigators. 
● A copy of the IRB approval letter. Renewals must be submitted at annual intervals or as 
required by IRB policy. 
● A copy of the IRB approved informed consent form 
● IRB member list and DHHS General Assurance Number (FWA number). 
● A fully executed clinical study agreement 
● Signed Financial Disclosure Form  
● The Investigator Protocol Agreement Form signed and dated by the Principal Investigator 
at each site. 
  

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In addition to the documents listed above, the PI will also retain the following items: 
  
● All original informed consent forms with required signatures 
● All IRB correspondence (i.e., informed consent [including any approved revisions], 
protocol, advertisements, newsletters) 
● Training Logs 
● Copies of all correspondence pertaining to the study between the Sponsor, Site and the 
Participants 
● Study Monitoring Log 
● Delegation of Authority Log 
● Device Accountability Log 
  
All study-related records must be maintained in accordance with local IRB policies.  The 
investigator will not discard any records until completion of the study.   
  
11.10. 
Study Report and Publication 
The data resulting from this study may be published. A publications committee consisting of 
investigators, statisticians, and Cohero representatives will be convened to establish a publication 
policy. 
  
 
REFERENCES 
 
1. World Health Organization, Fact Sheet 307 – Asthma. 
http://www.who.int/mediacentre/factsheets/fs307/en/  Web.  16 Dec. 2016. 
2. Bloom B, Freeman G. Tables of Summary Health Statistics for U.S. Children: 2014 National 
Health Interview Survey. 2015. Available from: http://www.cdc.gov/nchs/nhis/SHS/tables.htm. 
3. Center for Disease Control, National Center for Health Statistics, “FastStats.” Asthma, 
http://www.cdc.gov/nchs/fastats/asthma.htm. Web. 16 Dec. 2016. 
4. Stern L, Berman J, Lumry W, et al. Medication compliance and disease exacerbation in 
patients with asthma: a retrospective study of managed care data. Ann Allergy Asthma Immunol 
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5. Bender BG, Rand C. Medication non-adherence and asthma treatment cost. Curr Opin 
Allergy Clin Immunol. 2004;4(3):191–195.    
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Children. Am J Respir Crit Care Med. 2016. Oct 6. 
8. Engelkes M, Janssens H, de Jonhste J, Sturkenboom M, Verhamme K. Medication 
Adherence and the risk of  severe asthma exacerbations: a systematic review. Eur Respir J 
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to Asthma Self-Management in Adolescents: A systematic review of qualitative and quantitative 
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11. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose 
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Relationship between adherence to inhaled corticosteroids and poor outcomes among adults 
with asthma. J Allergy Clin Immunol 2004;114:1288-93. 
13. Van Gaalen JL, Hashimoto S, Sont JK. Telemanagement in asthma: an innovative and 
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14. Dima AL, Linn AJ, Schweitzer AM. Where we are now and how we can improve: a 
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15. Fenerty SD, West C, Davis SA, Kaplan SG, Feldman SR. The effect of reminder systems on 
patients' adherence to treatment. Patient Prefer Adherence 2012;6:127-35. 
16. Chan AH, Harrison J, Black PN, Mitchell EA, Foster JM. Using electronic monitoring devices 
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17. Petrie KJ, Perry K, Broadbent E, Weinman J. A text message programme designed to 
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preventer medication. Br J Health Psychol 2012;17:74-84. 
18.    Vasbinder EC, Goossens LM, Rutten-van Molken MP, et al. e-Monitoring of Asthma 
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19.    Strandbygaard U, Thomsen SF, Backer V. A daily SMS reminder increases adherence 
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20.    Charles MS, Blanchette CM, Silver H, Lavallee D, Dalal AA, Mapel D. Adherence to 
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21.    Foster JM, Usherwood T, Smith L, et al. Inhaler reminders improve adherence with 
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Appendix 1 
Table A 
Pressurized metered dose inhaler (pMDI) compatible with the BreatheSmart HeroTracker 
 
 
Daily Control  
Advair Diskus (100/50 mg), (250/50 mcg), 
(500/50 mcg) 
Dulera 100/5 mcg and 200/5 mcg 
Advair HFA (45/21 mcg), (115/21 mcg), 
Duolin HFA 20 mcg 

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(230/21 mcg) 
AeroSpan 80 mcg (60 count) and (120 count) 
Flovent 44 mcg, 110 mcg and 220 mcg 
Alvesco 80 mcg and 160 mcg 
Flovent Diskus 50 mcg, 100 mcg and 250 
mcg 
Asmanex HFA 
Foratec HFA 12 mcg 
Asthavent 100 mcg 
Foster 100/6 mcg 
Atimos 12 mcg (50 count), (100 count) and 
(120 count) 
Ipvent HFA 40 mcg 
Beclate HFA 50 mcg, 100 mcg, 200 mcg  
QVAR 40 mcg, 80 mcg 
Budeflam 100 mcg 
Serevent Diskus 
Ciclovent 160 mcg 
Seroflo 50 mcg,125 mcg, 250 mcg  
Clenil 50 mcg, 100 mcg, 200 mcg, 250 mcg 
Symbicort 80/4.5 mcg, 160/4.5 mcg, 400/12 
mcg 
Rescue  
Atrovent HFA 
ProAir HFA 
Proventil HFA 
Ventolin HFA 60 count, 200 count 
Xopenex HFA 80 count, 200 count