Evaluating High Flow Humidification Therapy in Patients With Cystic Fibrosis
Phase: NA
Conditions: Cystic Fibrosis
Sponsor: Virginia Commonwealth University

 
 
Title: Evaluating High Flow Humidification Therapy in Patients with Cystic Fibrosis 
 
NCT #: NCT02129803 
 
Document date: May 25, 2016 
 
Document Type: Protocol and Statistical Analysis Plan 
 
 
 

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Evaluating High Flow Humidification Therapy  
in Patients with Cystic Fibrosis 
Protocol Number:   HM20002205 
  
 
 
NCT02129803 
 
Sponsor: 
 
Virginia Commonwealth University 
 
Funding Support: 
Fisher & Paykel Healthcare  
 
Investigators:  
Bruce K. Rubin, MEngr, MD,MBA, FRCPC (Principal Investigator) 
  
H. Joel Schmidt, MD (Co-Principal Investigator) 
  
Michael S. Schechter, MD, MPH (Sub-Investigator) 
    
Nauman A. Chaudary, MD (Sub-Investigator) 
 
 
Ronald W. Williams, Jr., MD (Sub-Investigator) 
 
Sites:    
 
Children’s Hospital of Richmond at VCU/VCU Medical Center 
   
 
Main Hospital, 7th Floor – Pediatric Services 
  
 
1250 East Marshall Street 
   
 
Richmond, Virginia 23298-5051, United States 
 
Children’s Hospital of Richmond at VCU 
   
 
Children’s Pavilion  
  
 
1000 East Broad Street 
  
 
Richmond, Virginia 23298-0270, United States 
 
  
 
VCU Medical Center 
  
 
Critical Care Hospital, 3rd Floor 
  
 
1213 East Clay Street 
  
 
Richmond, Virginia 23298-5071, United States 
 
  
 
VCU Health Systems 
  
 
3470 Mayland Court 
  
 
Henrico, Virginia 23233-1468, United States 
 
INTRODUCTION 
Mucus secretion and clearance is the primary physical defence of the airway epithelium.1 Although mucus plays 
a defensive role, secretion retention is a common but serious problem in patients with chronic lung disease such 
as cystic fibrosis (CF).3  Poor ion transport and rapid respiratory rate are thought to play a role in secretion 
hypohydration in the CF airway and this is thought to contribute to poor mucus clearance, increasing pulmonary 
symptoms (pulmonary exacerbation), poor sleep quality and a reduction in quality of life (QoL).4 We have 
recently shown that high-flow, heated and humidified air delivered by a nasal cannula (HHNC) improves 
mucociliary clearance and clinical outcomes in young children requiring chronic mechanical ventilation.5 To date, 
nocturnal HHNC (without supplemental oxygen) therapy has not been studied in individuals diagnosed with CF 
but previous laboratory research suggests that this could be safe and beneficial.6  

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HYPOTHESIS 
It is hypothesized that HHNC delivered at 20 liters per minute (LPM) via Optiflow™ cannula and AIRVO™2 
device may favorably affect the physical properties of the sputum and improve the subject’s ability to clear 
secretions, resulting in beneficial clinical effects and improved quality of life. 
 
STUDY OBJECTIVES AND ENDPOINTS 
 
Primary Objectives 
• 
To evaluate the effectiveness of 20 LPM HHNC therapy (Optiflow™ cannula and AIRVO™2 device) – 
experimental therapy versus 5 LPM HHNC therapy (Optiflow™ cannula and AIRVO™2 device) – control 
therapy on physiological outcomes in hospitalized subjects with cystic fibrosis during an acute 
exacerbation.   
 
Secondary Objectives 
 
• 
To determine if the experimental therapy has an effect on Quality of Life as measured by the Cystic 
Fibrosis Questionnaire - Revised (CFQ-R) compared to control therapy 
• 
To determine the effect of the experimental therapy on sleep duration using actigraphy (Actiwatch® 2) 
and subjective sleep quality measured by the Leeds Sleep Evaluation Questionnaire (LSEQ) compared to 
control therapy 
• 
To determine the effect of the experimental therapy on Quality of Life in respect to nasal dysfunction as 
measured by the Sino-Nasal Outcome Test (SNOT-20) compared to control therapy 
• 
To determine the effect of the experimental therapy on comfort and ease of use using the non-validated 
comfort survey (VAS score) compared to control therapy 
Primary Endpoints 
• 
Change in sputum volume, cough transportability and hydration (% solids) 
• 
Change in FEV1 % predicted from admission to end of study.  
STUDY DESIGN 
The study is a single-center, randomized pilot study to evaluate the clinical effectiveness 20 LPM HHNC 
(Optiflow™ cannula and AIRVO™2 device) experimental therapy, versus 5 LPM HHNC (Optiflow™ cannula 
and AIRVO™2 device) control therapy, on specified outcomes in hospitalized subjects with cystic fibrosis during 
acute exacerbation.  
Potential subjects will be identified in clinic before admission to the Children’s Hospital of Richmond at VCU 
(CHoR) or Virginia Commonwealth University Medical. If potential subjects are not identified in clinic, they will 
be introduced to and informed of the study by a member of the study team within 24 hours of hospital admission.   
Assent from a subject will be obtained if they are aged 10 to 17 years along with informed consent from the 
eligible subject’s parent or legal guardian. Informed consent will be obtained from subjects aged 18 years or older. 
All informed consent/assent discussions will take place in a private room and be documented according to the 
Pediatric Research Office’s ‘Informed Consent Process Cover Sheet’. Potential subjects and family members will 
be given as much time as necessary to determine if they would like to participate in the study. No study team 
member will be present during this period to minimize any possible coercion.  

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After informed consent is obtained the subject will be assigned a unique ‘Subject Identification Number.’  This 
number will consist of ‘VCUFP##’, where the first subject will be ‘VCUFP01’, the second ‘VCUFP02’, and so 
forth. This unique identifier will be used instead of the subject’s name, birth date, etc., to identify the subject for 
all study records and data.   
After Subject Identification Number assignment is performed, randomization will occur. The study team will use 
the website www.randomization.com to randomize 30 study conditions (15 experimental and 15 control). The 
Study Coordinator will follow the randomization table chronologically as new subjects are consented. 
This study is designed to accommodate 30 subjects (15 subjects per group) (Table 1). The study population will 
be determined from previously diagnosed CF patients who receive their CF care at CHoR and Virginia 
Commonwealth University. Subjects will be aged 10 years and older who are experiencing a CF exacerbation 
that requires hospital admission and therapy. 
 
Table 1 
STUDY DESIGN 
 
Study Group 
Assigned Intervention 
Total Number of Subjects 
 Control Therapy 
 
Low-Flow, 5 LPM  
(via Optiflow™ cannula) 
Heated (34°C), humidified air 
15 
Experimental Therapy 
High-Flow, 20 LPM  
(via Optiflow™ cannula) 
Heated (34°C), humidified air 
15 
 
If a subject requests to withdraw from the study at any point, they are asked to inform the study doctor.  
Withdrawal from the study will not affect standard treatment the subject will receive for their CF exacerbation or 
ongoing treatment they may require. Upon withdrawal, the subject will forfeit any compensation for study 
participation. 
Study subjects may be involuntarily removed from the study if the study doctor believes that they are not 
complying with the study protocol and/or the study doctor believes it is in the best interest of the subject to stop 
participation.   
Study devices/equipment 
The experimental therapy will be administered using Optiflow™ nasal cannula with the AIRVO™2 humidifier.  
The AIRVO™2 device will heat and humidify ambient air and the Optiflow™ nasal cannula will deliver the 
heated (approximately 34°C) and humidified air via the nares at a flow of 20 LPM. 
Fisher & Paykel Healthcare manufactures the Optiflow™ nasal cannula and the AIRVO™2 device. The 
Optiflow™ nasal cannula and AIRVO™2 device are being provided by Fisher & Paykel Healthcare for the study 
with no cost to the study subject. In addition, the subject will not be subjected to any further costs associated with 
the study. The study devices will only be able available for use by the subjects that are enrolled in the study. The 
subject will be required to return the study device at the conclusion of the subject’s study involvement, or when 
the subject is discharged from the hospital (whichever occurs first). 
The control therapy will be administered using Optiflow™ nasal cannula with the AIRVO™2 device.  The nasal 
cannula will deliver heated (approximately 34°C) and humidified air into the subject’s nares at a flow of 5 LPM. 
This aims to mask the experimental and control therapy from the subjects and investigators. 

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Subjects will be educated by the study coordinator on how the device works and how to set up the nasal cannula 
appropriately. Subjects will be instructed to sleep with the designated nasal cannula and device as instructed 
during their hospitalization, for a maximum of five nights. The time the device is placed in the subject’s nares 
and the time when the device is turned on will be recorded regardless of the intervention group to which the 
subject is assigned.  The nursing staff will be instructed to check that the individual is wearing the device (either 
experimental or control) appropriately throughout the entire night. Should the nursing staff notice the nasal 
cannula being worn incorrectly the nurse will attempt to correctly reposition without disturbing the subject or if 
this is not successful the subject will be awakened to ensure correct cannula placement. Following the overnight 
intervention, the nasal cannula will be removed from the device and washed with warm water and mild dish 
washing detergent. After rinsing with clean water the nasal cannula will be stored in a clean zip locked bag taped 
to the device during periods of non-use.  
At study conclusion for each subject (Table 2. Study Procedures), the device will be cleaned and sanitized per 
manufacturer’s guidelines. While not in use, the devices will remain clean/sanitized and stored appropriately 
within in the hospital facility. 
Eligibility Criteria   
Individuals must meet all of the inclusion criteria listed below in order to be considered as a potential study 
subject. 
Inclusion Criteria: 
• 
Confirmed diagnosis of CF 
• 
Hospital admission for acute pulmonary exacerbation of CF 
• 
10 years of age or older 
• 
Is able to comply with the procedures scheduled within the protocol 
• 
Provide informed consent/assent 
If an individual is eligible as defined by the inclusion criteria but is found to meet any of the exclusion criteria 
listed below, they will not be permitted to enroll in the study. 
Exclusion Criteria: 
• 
Receipt of any aerosolized experimental or investigational drugs within 1 month of enrollment 
• 
History of ENT surgery, nasal bleeding or nasal polyps within 6 months of starting study 
• 
Requires supplemental oxygen 
• 
History of obstructive sleep apnea 
• 
History of pressure headaches requiring therapy within 1 month of enrollment 
• 
Other medical or psychological conditions in which the study doctor(s) believe(s) would inhibit the  
  
individual from being an appropriate study subject. 
• 
Has any contraindications to HHNC as listed below: 
Maxillofacial trauma 
 
 
Complete nasal obstruction 
 
 
Presence of suspected base of skull fracture 
• 
Any contraindication that applies to CPAP/ NIV therapy 
 
 
 
 
 

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STUDY PROCEDURES 
The study requires clinical observations and overnight intervention therapy for/up to the first 5 nights of 
hospitalization. The study procedures to be performed on/by each subject enrolled in the study are outlined in 
Table 2.  
 
 
Table 2 
STUDY PROCEDURES 
 
Time point 
Procedure/Assessment 
SCREENING 
(Day 0) 
(In CF Clinic or 
within 24 hours of 
hospital admission) 
• 
Admission into the Children’s Hospital of Richmond or MCV Hospital for adult 
subjects (hospital). 
• 
Introduction to study and review the study procedures/study device with the study 
coordinator and/or study doctor 
• 
Verification of inclusion/exclusion criteria and signing of Informed Consent 
Document. 
• 
Assignment of the unique Subject Identification Number 
• 
Review of medical history and treatment records 
• 
Baseline tests (as part of standard of care as medically indicated) 
• 
Completion of the Leeds Sleep Evaluation Questionnaire (LSEQ) by subject. 
• 
Completion of the CF-specific health related quality of life survey (Cystic Fibrosis 
Questionnaire – Revised (CFQ-R) by subject. 
• 
Completion of the Sino-Nasal Outcome Test (SNOT-20) by subject. 
• 
Sputum sample collection (if possible) 
• 
Randomization to intervention - either: ‘Control Therapy’ (Low Flow, heated and 
humidified air delivered at 5 LPM via Optiflow™ cannula and AIRVO™2 device)) or 
‘Experimental Therapy’ (High-Flow, heated and humidified air delivered at 20 LPM via 
Optiflow™ cannula and AIRVO™2  device)  
 
BASELINE 
Day 1  
(Approximately 
9:00 AM) 
• 
The device will be turned off (unless the subject has awakened earlier, in which case 
the subject can turn off the device when they wake). 
• 
Sputum sample will be collected (where possible) or collection of previously 
produced sputum to research laboratory by study coordinator by 10:00 AM. 
• 
Study coordinator will ensure that the nasal cannula is removed from the device and 
washed with warm water and mild dish washing detergent and rinsed thoroughly 
with clean water. The study coordinator will then place the nasal cannula in a clean 
zip locked bag taped to the device until required.  
• 
Completion of the Leeds Sleep Evaluation Questionnaire (LSEQ) 
• 
Completion of the device comfort survey (VAS Score). 
• 
The study coordinator will collect the device log, and review the previous night’s 
medical records (including any test results or medication dispensed). 
 
TREATMENT 
PHASE 
Day 2 – 5 (PM) 
• 
There will be no collection of produced sputum during this time.   
• 
There will be no surveys completed during this time. 
• 
The study coordinator and/or the study doctor will continue to review the subject’s 
treatment and medication records.   

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Table 2 
STUDY PROCEDURES 
 
Time point 
Procedure/Assessment 
• 
Subjects will be allowed to go to sleep at whatever time they choose but must turn 
on the device before sleep onset and leave it on throughout the sleep period. 
• 
The nursing staff will be instructed to ensure the subject continues to wear the device 
during the night. If for some reason the device comes off, or is turned off, the nurse 
will record the event and will attempt to correctly reposition without disturbing the 
subject or if this is not successful the subject will be awakened to ensure correct 
cannula placement. If the subject is discharged between Day 2 – Day 5, then the date of 
discharge will follow the ‘Discharge’ study procedure in place of the ‘Treatment Phase’ study 
procedure 
 
DISCHARGE 
Day 6 (AM)* 
(*or earlier if 
discharged prior to 5 
days of treatment) 
• 
The device will be turned off (unless the subject has wakened earlier), in which case 
the subject can turn off the device when they wake. 
• 
Sputum sample will be collected (where possible) or collection of previously 
produced sputum to research laboratory by study coordinator by 10:00 AM. 
• 
Subject will remove Actiwatch® 2 and Study Coordinator will download 
Actiwatch® 2 data 
• 
Completion of the Leeds Sleep Evaluation Questionnaire (LSEQ) by subject 
• 
Completion of the CF-specific health related quality of life survey (Cystic Fibrosis 
Questionnaire – Revised (CFQ-R) by subject 
• 
Completion of the Sino-Nasal Outcome Test (SNOT-20) by subject 
• 
Completion of the device comfort survey (VAS Score) by subject. 
• 
The study coordinator will collect the device log, and review the previous night’s 
medical records (including any test results or medication dispensed). 
• 
A follow-up appointment in the CF clinic will be scheduled according to the study 
doctor’s recommendations (as part of standard care).   
• 
The subject will be reminded to call the study coordinator or the study doctor if there 
are any new problems, questions or concerns once discharged from the hospital.    
 
Clinical Follow-
up Appointment 
• 
The study coordinator and/or the study doctor will review the medical history and 
treatment records. 
• 
Baseline tests (as part of standard of care as medically indicated) 
• 
Completion of the Leeds Sleep Evaluation Questionnaire (LSEQ) by subject 
• 
Completion of the CF-specific health related quality of life survey (Cystic Fibrosis 
Questionnaire – Revised (CFQ-R) by subject 
• 
Completion of the Sino-Nasal Outcome Test (SNOT-20) by subject 
• 
Sputum sample collection (if possible).  The sputum will be delivered to the research 
laboratory by the Study Coordinator 
• 
Study compensation 
 
 
 
 

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DATA HANDLING AND RECORD KEEPING 
Power Calculation 
No studies have evaluated the effect of high-flow HHNC therapy to improve sinopulmonary symptoms in CF. 
Thus, the current study is designed as a pilot study that is likely to be underpowered to reach significance. 
Electronic Database Capture  
Study data will be collected and managed using REDCap (Research Electronic Data Capture). REDCap is a secure 
web application designed to support data capture for research studies, providing user-friendly web-based case 
report forms, real-time data entry validation (e.g. for data types and range checks), audit trails and a de-identified 
data export mechanism to common statistical packages (JMP, SAS). REDCap also includes a powerful tool for 
building and managing online surveys. The database is hosted by VCU under award number UL1RR031990 from 
the National Center for Research Resources and NIH Roadmap for Medical Research, National Institutes of 
Health. 
Only the study coordinators and the research assistants will have access to this password protected database.   
With the exception of the ‘Informed Consent/Assent’ pages in the REDCap database, all subsequent pages will 
only identify the subject by the Subject Identification Number.   
All hard copies of the signed Informed Consent/Assent documents will be kept in locked cabinet which is located 
in the study coordinator’s locked office.  A copy of the signed Informed Consent/Assent will be scanned into the 
subject’s electronic medical record.  Any other paper records that may be generated during the course of the study 
will be de-identified and labeled with the individuals Subject Identification Number and kept separated from the 
consent forms and locked in a cabinet in the study coordinator’s locked office.   
OnCore 
OnCore is a clinical trial management systems (CTMS) which will be used for recording and tracking regulatory 
approvals, staff training and safety management (SAE tracking and IRB reporting). The CTMS system was 
developed by Forte Research and widely used across academic research universities nationwide. The program is 
a secure web-based system hosted by both the VCU and MCV health systems.  Only fully-trained, credentialed 
employees of VCU have access to this database.  The study coordinator will be the only individual (besides 
individuals that manage OnCore) with access to data entered for this study into the OnCore database. 
SPUTUM SAMPLE COLLECTION AND PROCESSING 
Sputum collection is needed for evaluation of biophysical properties. 
The study coordinator will ask the study subject to cough sputum into a provided, sterile sample cup at 9:00 AM 
according to the schedule of events outlined in Table 2. Study Procedures. If the subject is able to produce sputum 
before this time, they will be provided the sterile sample cup and the sputum collected. All sputum samples will 
be transported on ice to the research laboratory as soon as possible on the day of screening and at follow-up. At 
baseline, intervention, and discharge, sputum will be delivered to the research laboratory on ice by 10:00 AM.    
All sputum samples will be identified by the Subject Identification Number and the applicable time-point only.   
 
 
 

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SPUTUM SAMPLE ANALYSIS 
All collected sputum samples will be used for cough transport and mucus hydration measurements. 
In vitro cough transportability 
A simulated cough machine is used to measure the airflow-dependent clearability of sputum. A model Plexiglas 
"trachea", rectangular in cross section (1.2 x 2 cm) is connected to an 8 L tank containing air pressurized to 8 psi 
giving a flow of about 11 L/s. A solenoid controls air release through a flow constrictive element used to mimic 
the airflow pattern of a natural cough. A sinusoidal constriction (length 7.7 cm and height 8 mm) is used to 
decrease the airway diameter while minimizing the turbulence (Reynolds number) of the system. A sample, 40 
µl in volume and 0.5 mm in depth, is placed in a thin line across the base of the Plexiglas trachea. The bulk 
transport of the sample is measured in mm after a single cough maneuver. Three successive measurements are 
made and the results averaged (3). 
Mucus hydration (% solids), and mucus density 
A mucus sample is weighed in a microbalance and dried for 4 hours in a lyophilizer. The dried sample is then 
reweighed in order to calculate the percent solids composition. The density of the mucus is also calculated by 
dividing the weight of the sample by the volume. As the density of mucus should be 1.00 ± 0.15, this measurement 
is used as a check on the validity of the hydration measurement. 
SLEEP DURATION ANALYSIS 
Actigraphy provides a precise measurement of the motion of the part of the body to which a device is attached. 
Sleep/wake patterns will be recorded using the Actiwatch® 2. The data collected by the Actiwatch® 2 will provide 
objective and reliable data of the subject’s sleep/wake patterns during the study period without influence. The 
unique Subject Identification Number assigned at Day 0 will be the only identifier linking the subject and the 
actigraphy data. The device is similar in size to a wrist watch and is well-suited for use with younger subjects or 
those sensitive to wrist-worn devices. The data collected will be downloaded into a software program “Actiware”.  
This software will be located on the Coordinator’s password protected computer.  The data will then be scored 
and analyzed into predetermined intervals that will identify the epoch as either periods of wake or sleep. Statistics 
including Time in Bed (TIB), Total Sleep Time (TST), Wake After Sleep Onset (WASO), Sleep Efficiency (SE), 
Number of Wake Bouts (NWB) and Sleep Onset Latency (SOL) can be tracked over the study period.  
Data Analysis 
Statistical analysis of data will be performed using the JMP Pro 10 statistics package (SAS Institute, Cary, NC). 
Normality of data distribution will be visually checked and normally distributed data will be compared using 
two-tailed t-test and ANOVA. A p< 0.05 will be considered statistically significant. All results will be presented 
as means + the standard error of the mean.  
QUALITATIVE EVALUATION 
 
One sleep and three separate quality of life evaluations will be administered at various time-points according to 
Table 2 - Study Procedures. The information provided by the questionnaires will be transposed into the REDCap 
database by the study coordinator. All paper documents will be de-identified, the only identifier is the Subject 
Identification Number, which is kept in a locked cabinet, in the study coordinator’s locked office.   
 
 

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Leeds Sleep Evaluation Questionnaire (LSEQ) 
The Leeds Sleep Evaluation Questionnaire (LSEQ) is a 10-item, subjective, self-report, 5-10 minute paper and 
pencil measure designed to assess changes in sleep quality over the course of a psychopharmacological treatment 
intervention. The scale evaluates four domains: ease of initiating sleep, quality of sleep, ease of waking and 
behavior following wakefulness using paper and pencil. Developers initially validated the LSEQ in individuals 
aged 18-49 years. In the evaluation "initiating sleep" and the "quality of sleep" factors were correlated with one 
another while "awakening from sleep" and "behavior following wakefulness" factors were also correlated. Of the 
validated scales available to use for this study the LSEQ appears to be the most appropriate given the study being 
conducted.  
Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
The Cystic Fibrosis Questionnaire-Revised (CFQ-R) is health-related quality of life (HRQoL) measure for 
children, adolescents and adults with CF. Initially it was developed through interviews with CF patients and 
healthcare providers and various focus groups and has since undergone comprehensive reliability and validity 
testing. This revised questionnaire is one of the most widely used HRQoL tests for CF. The CFQ-R measures 
how well an individual functions in a variety of domains, including Physical Functioning, Vitality, Health 
Perceptions, Respiratory Symptoms, Treatment Burden, Role Functioning, Emotional Functioning, and Social 
Functioning. This questionnaire is written for the intended age group in regards to language and length of 
questionnaire.    
The Sino-Nasal Outcome Test (SNOT-20)  
The Sino-Nasal Outcome Test 20 (SNOT-20) is a validated, health-related quality of life (HRQoL) questionnaire 
designed to determine the impact of nasal dysfunction on an individual’s social/emotional health. This test 
consists of 20 questions and asks patients to assess nasal symptoms, emotion, and activity on a scale of worsening 
symptoms scored 1 through 7 to provide a quantifiable score capable of disease severity.1,2  
Non-validated device comfort survey (VAS score) 
The non-validated device comfort survey used for this study will be conducted using a VAS score. The VAS 
(visual analog scale) will be used to measured characteristics, such as pain, that cannot be directly measured. The 
subject will be asked to point to a face depicting various levels of pain on a VAS that corresponds to the associated 
pain level when on HHNC and high-flow therapies. 
ETHICS 
Institutional Review Board 
This protocol and any accompanying material to be provided to a potential subject (such as advertisements, 
information sheets, or descriptions of the study used to obtain informed consent) will be submitted to an IRB by 
the investigators and approval from the IRB must be obtained prior to starting the study. This approval will be 
documented in a letter to the investigator specifying the protocol number, protocol version, protocol date, 
documents reviewed, and the date on which the committee met and granted the approval. 
Any amendments made to the protocol after receipt of IRB approval must also be submitted to the IRB for 
approval prior to implementation, if appropriate or the study must be paused and no further recruitment made 
until approval of the amendments has been granted.  All related correspondence and IRB approved documents 
will be retained in a regulatory binder located in a locked cabinet in the study coordinator’s locked office.   
 

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Code of Conduct 
This study will be conducted in accordance with legal and regulatory requirements, as well as the general 
principles set forth in the International Ethical Guidelines for Biomedical Research Involving Human Subjects 
(Council for International Organizations for Medical Sciences 2002), Guidelines for Good Clinical Practice 
(International Conference on Harmonization 1996), and the Declaration of Helsinki (World Medical Association 
2008).  In addition, the study will be conducted in accordance with the protocol, the International Conference on 
Harmonization guideline on Good Clinical Practice, and applicable local regulatory requirements and laws. 
All members of the study team have completed the necessary Collaborative Institutional Training Initiative at the 
University of Miami (CITI) training.  This program also includes Good Clinical Practice training.  All copies of 
the study team member’s certificates of completion as well as their current medical license and Curriculum Vitae 
will be maintained in the study regulatory binder.     
 
LITERATURE CITED 
1. 
Pynnonen MA, Kim HM, Terrell JE. Validation of the Sino-Nasal Outcome Test 20 (SNOT-20)  
  
domains in nonsurgical patients. Am J Rhinology & Allergy. 2009 Jan-Feb;23(1):40-5 
2. 
Rudnick EF, Mitchell RB. Long-term improvements in quality-of-life after surgical therapy for pediatric  
  
sinonasal disease. OTO HNS 2007;6:873-877. 
3. 
Agarwal M, King M, Rubin BK, Shukla JB. Mucus transport in a miniaturized simulated cough  
  
machine: Effect of constriction and serous layer simulant.  Biorheology. 1989; 26:977-88 
4. 
Rubin BK. Mucus, phlegm, and sputum in cystic fibrosis. Resp Care, 2009;54:726-32. 
5.  
McNamara DG, Asher MI, Rubin BK, Stewart A, Byrnes CA. Heated humidification improves clinical  
  
outcomes compared to a heat-and-moisture exchanger in children with tracheostomies. Respir Care.  
  
2014;59:46-53. 
6. 
Voynow JA, Rubin BK. Mucus, mucins, and sputum. CHEST 2009;135:505-512.