Comparison of High Flow Nasal Cannula and Standard Face Mask Oxygen Therapy in Children With Moderate and Severe Bronchiolitis; a Randomized Controlled Trial
Phase: NA
Conditions: Acute Bronchiolitis
Sponsor: Ege University

Protocol No 1 
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Comparison of high-flow nasal cannula and standard face mask 
oxygen therapy in children with moderate and severe bronchiolitis 
requiring oxygen therapy: A randomized controlled trial 
 
 
 
 
 
Trial Registry 
NCT04245202 
 
Date: 10/03/2017 
Revised 1: 10/03/2020 
Revised 2:14/02/2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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CLINICAL STUDY PROTOCOL 
 
Protocol Title 
Comparison of high-flow nasal cannula and standard face mask oxygen 
therapy in children with moderate and severe bronchiolitis requiring 
oxygen therapy: A randomized controlled trial 
Trial Registry 
NCT04245202 
Ethics Approval 
17-2.1/18 by the Human Research Ethics Committee of EUMF 
Co-ordinating center 
Ege University Medical Faculty Pediatric Hospital 
 
Principal investigator 
Aykut Eşki1 
Department 
 
Pediatric Pulmonology 
Research Institution  
Ege University Medical Faculty Pediatric Hospital 
Address 
 
Kazımdirik street, 35040, Bornova, Izmir 
Telephone (+90) 0232 390 12 17 
Fax (+90) 0232 390 13 57 
Co-investigator 
 
 
Esen Demir, MD, Professor1 Department of Pediatric Pulmonology 
Ege University Medical Faculty Pediatric Hospital 
Kazımdirik street, 35040, Bornova, Izmir 
Telephone (+90) 0232 390 12 17 
Fax (+90) 0232 390 13 57 
Gökçen Kartal Öztürk, MD1 Department of Pediatric Pulmonology 
Ege University Medical Faculty Pediatric Hospital 
Kazımdirik street, 35040, Bornova, Izmir 
Telephone (+90) 0232 390 12 17 
Fax (+90) 0232 390 13 57 
Caner Turan, MD2 
 
Department of Pediatric Emergency 
Ege University Medical Faculty Pediatric Hospital 
Kazımdirik street, 35040, Bornova, Izmir 
Telephone (+90) 0232 390 12 17 
Fax (+90) 0232 390 13 57 
Semiha Özgül3 
 
Department of Biostatistics and Medical Informatics 

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Ege University Medical Faculty 
Kazımdirik street, 35040, Bornova, Izmir 
Telephone (+90) 0232 390 12 17 
Fax (+90) 0232 390 13 57 
Figen Gülen, MD, Professor1 Department of Pediatric Pulmonology 
Ege University Medical Faculty Pediatric Hospital 
Kazımdirik street, 35040, Bornova, Izmir 
Telephone (+90) 0232 390 12 17 
Fax (+90) 0232 390 13 57 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL SIGNATURE PAGE 
INVESTIGATORS 
I admit to conducting this clinical study following the design and specific provisions of this 
protocol. 
I understand that I may cease or suspend the study's enrolment at any time if it becomes 
necessary to protect the best interests of the study subjects. This study may be terminated by Ege 
University Medical Faculty, with or without cause. 
I admit to manage or supervise this investigation directly and to ensure that all associates, 
colleagues, and employees assisting in the conduct of this study are informed about their obligations 
in meeting these commitments. 
I will conduct the study under Good Clinical Practice, the Declaration of Helsinki, and the 
moral, ethical, and scientific principles that justify medical research. The study will be conducted 
under all relevant laws and regulations relating to clinical studies and protecting patients. 
I will ensure that the requirements relating to HREC review and approval are met. I will 
provide EUMF with any material which is supplied to the HREC for Ethical approval. 
I admit to maintain adequate and accurate records and make those records available for 
inspection and audit according to relevant regulatory requirements. 
I admit to directly disclose to the HREC any developments in the research activity and all 
unanticipated problems involving risks to human subjects or others. Additionally, I will not make any 
modifications in the research without HREC approval, except where needed to provide study 
participants' safety. 
 
Esen Demir, MD 
 
 
 
Signature 
 
 
 
Date 
Aykut Eşki, MD 
 
 
 
Signature 
 
 
 
Date 
Gökçen Kartal Öztürk, MD  
 
Signature 
 
 
 
Date 
Caner Turan, MD 
 
 
 
Signature 
 
 
 
Date 
 
Semiha Özgül  
 
 
 
Signature 
 
 
 
Date 
 
Figen Gülen, MD 
 
 
 
Signature 
 
 
 
Date 
 
 
 
 

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TABLE OF CONTENTS 
ABBREVIATIONS.............................................................................................................................7 
DEFINITIONS....................................................................................................................................8 
STUDY SYNOPSIS............................................................................................................................9  
SCHEDULE OF OBSERVATIONS AND PROCEDURES..........................................................11 
INTRODUCTION............................................................................................................................13 
1.1 Background................................................................................................................................13 
1.2 High-Flow Nasal Cannula Delivery...........................................................................................13 
1.3 Study Design Rationale..............................................................................................................14 
2. STUDY OBJECTIVE...................................................................................................................14 
2.1 Study Question...........................................................................................................................14 
2.2 Primary Objectives.....................................................................................................................14 
2.3 Secondary Objectives.................................................................................................................15 
2.4 Safety Objectives.......................................................................................................................15 
3. PATIENT POPULATION...........................................................................................................15 
3.1 Sample Size................................................................................................................................15 
3.2 Inclusion Criteria.......................................................................................................................15 
3.3 Exclusion Criteria......................................................................................................................15 
3.4 Withdrawal Criteria....................................................................................................................16 
3.5 Participant Selection..................................................................................................................16 
3.6 Enrolment/Randomization.........................................................................................................16 
3.7 Study Schema.............................................................................................................................17 
4. STUDY PROCEDURES..............................................................................................................18 
4.1 Duration of Treatments..............................................................................................................18 
4.2 Follow up...................................................................................................................................18 
5. STUDY TREATMENT PLAN.....................................................................................................18 
5.1 Investigational Treatments.........................................................................................................18 
5.2 Treatment Failure and Escalation of Care...................................................................................19 
5.3 Accountability of Investigational Products................................................................................19 
5.4 Concomitant Medications and Medical Treatments...................................................................19 
6. SAFETY and ADVERSE EVENT...............................................................................................19 
6.1 Definitions and Classification....................................................................................................20 

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6.2 Follow-up 30-day safety assessment..........................................................................................21 
7. STATISTICAL METHODS........................................................................................................21 
7.1 Sample Size................................................................................................................................21 
7.2 Data Analysis Methods..............................................................................................................21 
7.3 Statistical Analysis Plan.............................................................................................................21 
8. REGULATORY CONSIDERATIONS......................................................................................21 
8.1 Participant Consent....................................................................................................................22 
8.2 Ethical Review...........................................................................................................................22 
8.3 Sponsor......................................................................................................................................22 
9. STUDY ADMINISTRATION......................................................................................................22 
9.1 Protocol Deviations....................................................................................................................22 
9.2 Monitoring and Auditing............................................................................................................23 
9.3 Study Documentation and Records Retention............................................................................23 
9.4 Publication and Use of Study Findings.......................................................................................24 
10. APPENDICES.............................................................................................................................25 
11. REFERENCES............................................................................................................................33 

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ABBREVIATIONS 
AE 
 
 
 
 
Adverse event 
CI  
 
 
 
 
Confidence interval 
CPAP  
 
 
 
Continue positive airway pressure 
CRF 
 
 
 
 
Case report form 
CRS 
 
 
 
 
Clinical respiratory score 
ED 
 
 
 
 
Emergency department 
EUMF  
 
 
 
Ege University Medical Faculty 
FiO2 
 
 
 
 
Fraction of inspired oxygen 
FLUA  
 
 
 
Influenza A 
HR 
 
 
 
 
Heart rete 
HREC  
 
 
 
Human Research Ethics Committee 
HFNCOT 
 
 
 
High-flow nasal cannula oxygen treatment 
HRV  
 
 
 
Human rhinovirus 
IMV 
 
 
 
 
Invasive mechanical ventilation 
IND 
 
 
 
 
Investigational new drug 
IPPV  
 
 
 
Intermittent positive pressure ventilation 
LOS 
 
 
 
 
Length of hospital stay 
LOOT  
 
 
 
Length of oxygen treatment 
MD 
 
 
 
 
Mean difference 
NICE  
 
 
 
National Institute for Health and Clinical Excellence 
mPCR  
 
 
 
Multiplex polymerase chain reaction 
PEEP  
 
 
 
Positive end-expiratory pressure 
PEWS  
 
 
 
Pediatric early warning score 
ICU 
 
 
 
 
Intensive care unit 
PPU 
 
 
 
 
Pediatric Pulmonology Unit 
RCT 
 
 
 
 
Randomised controlled study 
RR 
 
 
 
 
Respiratory rate 
RSV A/B 
 
 
 
Respiratory syncytial virus 
SO2 
 
 
 
 
Peripheral oxygen saturation 
SOT 
 
 
 
 
Standard oxygen treatment 
St-FMOT 
 
 
 
Standard face mask oxygen treatment 
USA  
 
 
 
United State of America 
VBG  
 
 
 
Venous blood gases 

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DEFINITIONS 
Children 
✓ In this study, is a child under the age of 24 months 
Moderate and Severe bronchiolitis 
✓ Defined as per CRS reported by Liu and colleagues (Appendices 1) 
✓ Mild bronchiolitis: 0-4 point 
✓ Moderate bronchiolitis: 5-8 point 
✓ Severe bronchiolitis: 9-12 points 
Supplemental Oxygen Requirement 
✓ Peripheral capillary oxygen saturation (SpO2) <92% while breathing room air 
Standard Face Mask Oxygen Treatment (St-FMOT) 
✓ The gas flow between 6.0 and 10.0 L/min 
Rescue Treatment for St-FMOT 
✓ First-tier, HFNCOT (2 L*kg/min) in the general ward 
✓ Second-tier, admission to ICU for IMV 
High-Flow Nasal Cannula Oxygen Treatment (HFNCOT) 
✓ The gas flow at 2 L*kg/min or maximum 25 L/min 
Rescue Treatment for HFNCOT 
✓ Admission to ICU for IMV

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STUDY SYNOPSIS 
Title  
Comparison of high-flow nasal cannula and standard face mask oxygen 
therapy in children with moderate and severe bronchiolitis: A randomized 
controlled trial. 
Trial Registry  
NCT04245202 
Study Objectives 
A. Primary Objectives 
✓ To evaluate the effect on HR, RR, and CRS 
1. The time it takes for HR to reach its normal range for age (hour) 
2. The time it takes for RR to reach its normal range for age (hour) 
3. The time it takes for CRS to regress from severe [scores of 9-12] to moderate [scores of 5-8] 
bronchiolitis, or from moderate [scores of 5-8] to mild [scores of 0-4] bronchiolitis (hour) 
B. Secondary Objectives 
✓ The decrease in HR compared with the baseline value 
✓ The decrease in RR compared with the baseline value 
✓ The decrease in CRS compared with the baseline score 
✓ The effect on LOS and LOOT 
C. Safety Objectives 
1. The proportion of treatment failure at 4 hours or escalation of care 
2. The proportion of admission to ICU for IMV 
3. The proportion of adverse event 
Rationale      
✓ There has been insufficient RCT conducted on children with moderate and severe 
bronchiolitis requiring oxygen therapy in the general ward. 
Study Population 
A. Inclusion Criteria 
✓ Children aged between 1 and 24 months with moderate and severe bronchiolitis requiring 
oxygen supplement. 
B. Exclusion Criteria 
✓ Children with mild bronchiolitis 
✓ Those with not requiring oxygen therapy 
✓ Those admitted to ICU for urgent IMV 
✓ Those who received supplemental oxygen or HFNCOT at other facilities before arrival 

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✓ Those with known comorbidity (such as congenital heart disease, chronic lung disease, 
neuromuscular disease, metabolic disease, and immunocompromised) 
✓ Those with a craniofacial malformation, an upper airway obstruction, pneumothorax, or nasal 
trauma 
Study Design 
✓ Open-label, two-arm, phase 4 randomized controlled trial 
Sample size (each group) 
✓ 55 in each group (HFNCOT and St-FMOT) 
Investigational treatment: 
✓ Fisher & Paykel MR850 with Optiflow™ Junior Nasal Cannula System 
Control Group 
✓ St-FMOT 
Duration of Treatment 
✓ From admission to EUMF Pediatric Hospital to at 15 days of post-discharge 
Centre/s 
✓ Single-center – EUMF/Pediatric Hospital 
Statistical Methods 
✓ Chi-Squared Test, Fisher's Exact Test, Mann-Whitney-U Test, Linear Mixed Model, Bruner 
Langer Method

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SCHEDULE OF OBSERVATIONS AND PROCEDURES 
Diagnosis bronchiolitis 
Screening ED or PPU 
1h 
2h 
4h 
12h 
24h 
48h 
72h 
96h 
Phone follow-up 
Inclusion/Exclusion criteria 
X 
 
 
 
 
 
 
 
 
X** 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Bodyweight and length 
X 
 
 
 
 
 
 
 
 
 
Body temperature (℃) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Heart rate (beat per min)† 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Respiratory rate (breath per min)† 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Arterial blood pressure (mmHg)† 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical respiratory score† 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PCR 
X 
 
 
 
 
 
 
 
 
 
Blood sample* 
X 
 
 
 
 
 
 
 
 
 
VBG* 
X 
 
 
X 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Medical treatment‡ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse event record 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
If the patient was not discharged after 96 hours, the procedures mentioned above were continued. 
†All parameters were measured during the resting of children. 
*Samples were performed at any time if the clinician deemed it necessary. 

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**All children included in the study were phoned after 15 days post-discharge. 
‡The clinician decides to use medical treatments such as beta2 agonist, systemic steroid, and hypertonic saline.

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1. INTRODUCTION 
1.1 Background 
Acute bronchiolitis is globally one of the most considerable health burdens for children. It is 
estimated that approximately 34 million children under five years suffer from lower respiratory tract 
infection, with 3.4 million admissions to hospital and about 199,000 deaths per year, especially in 
developing countries.1 In the seminar conducted by Florin and colleagues,2 they reported that the role 
of medical therapies in children with bronchiolitis was investigated many times. Still, none of these 
treatments has shown efficacy. The NICE and AAP guidelines3 recommend supportive therapies, 
including oxygen supplementation, respiratory support, and hydration. There are currently three ways 
of delivering oxygen to pediatric patients; 
✓ Invasive mechanical ventilation, e.g., IPPV in critical care settings, or 
✓ Non-invasive ventilation, e.g., CPAP predominantly in critical care settings, or 
✓ Via nasal cannulae, mask, or head-box in ward settings. 
High-flow nasal cannula oxygen treatment (HFNCOT) has become an increasingly 
widespread practice for managing bronchiolitis in recent years. Still, it is not recommended for 
treating bronchiolitis, according to the current NICE guidelines.3 Although HFNCOT has been 
performed extensively for many years in the neonatal population, support for its safety and efficacy 
in children is still somewhat limited.4 Previous observational and physiological studies suggested that 
HFNCOT may decrease respiratory effort, reduce intubation rates, and improve gas exchange.5,6 
Conversely, other reports showed that HFNCOT results in no significant changes in the RR, LOS, 
and the quality of ICU admission for IMV.7–9 Although these reports represent an excellent 
progression in the daily clinical management of bronchiolitis and contribute valuable information to 
the literature, the major problem in this area is the lack of an adequate number of RCTs. 
 
1.2 High-Flow Nasal Cannula Oxygen Delivery 
Warmed humidified titrated medical air/oxygen is delivered through a non-sealing nasal 
cannula. The Optiflow™ system manufactured by Fisher & Paykel allows humidified flows of up to 
25 L/min to be given. There is wide variation in the flows used and methods used to calculate them; 
however, flows are more remarkable than the standard maximum of 2 L/min. Those who exceed the 
patient's tidal volume are usually described as high flow. The effective delivery of high-flow oxygen 
at optimal humidity with dead space flushing and an element of positive airway pressure is expected 
to be beneficial in managing acute bronchiolitis.5 Previously published studies showed that HFNCOT 
notably decreases in HR and RR relative to St-FMOT.10–12 In contrast, it was illustrated that children 

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treated with HFNCOT had identical results in reducing the HR and RR compared with those treated 
with St-FMOT.4,13 Otherwise, there are conflicting results in the literature regarding whether 
HFNCOT decreases CRS compared with SOT. Some prospective trials14,15 did not show a 
considerable reduction when comparing between HFNCOT and SOT. 
In contrast, others showed that HFNCOT is more effective in reducing CRS than SOT.16,17 
High-flow oxygen has been found to lower intubation rates and decrease the LOS for children in ICU 
settings.6,13 The Schibler et al.6 study followed the introduction of high-flow oxygen for bronchiolitis 
and found intubation rates dropped from 37% to 7% over four years as usage increased from use in 
13% of patients to 66% by 2009. This RCT aims to address the gap in knowledge by studying the 
Fisher & Paykel® humidification system with Optiflow nasal prongs used in the care of children aged 
between 1 and 24 months with moderate and severe bronchiolitis requiring oxygen supplementation. 
Bronchiolitis was selected as there is a significant disease burden in this age group due to a variety 
of viral causative organisms, and no other effective medical treatment may confound results. 
 
1.3 Study Design Rationale 
This study includes a single site longitudinal observational cohort study [HREC 
(03.14.2017/No: 17-2.1/18)] nested within an open, two-arm randomized control trial HFNCOT 
compared to St-FMOT in the management of moderate and severe bronchiolitis requiring oxygen 
supplementation in children aged between 1 and 24 months. 
 
2. STUDY OBJECTIVE 
2.1 Study Question 
In children aged between 1 and 24 months with moderate and severe bronchiolitis requiring 
oxygen supplementation, does HFNCOT delivered via a Fisher & Paykel MR850 humidifier with 
Optiflow Junior prongs compared to St-FMOT decrease HR, RR, and CRS during the acute 
admission? 
 
2.2 Primary Objectives 
✓ The median time it takes for HR to reach its normal range for age (hour) 
✓ The median time it takes for RR to reach its normal range for age (hour) 
✓ The median time it takes for CRS to regress from severe [scores of 9-12] to moderate [scores 
of 5-8] bronchiolitis, or from moderate [scores of 5-8] to mild [scores of 0-4] bronchiolitis 
(hour) 

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2.3 Secondary Objectives 
✓ The mean difference in HR decreased compared with the baseline value from randomization 
to 96 hours (or to discharge) 
✓ The mean difference in RR decreased compared with the baseline value from randomization 
to 96 hours (or to discharge) 
✓ The mean difference in CRS regress compared with the baseline value from randomization to 
96 hours (or to discharge) 
✓ The length of hospital stays [from admission to discharge (hour)] 
✓ The length of oxygen treatment [from admission to weaning to room air (hour)] 
 
2.4 Safety Objectives 
✓ The proportion of the treatment failure at 4 hours and escalation of care 
✓ The proportion of the admission of ICU for IMV 
✓ The proportion of adverse events 
 
3. PATIENT POPULATION 
3.1 Sample Size 
Sample size calculations were done using a t-test on the primary outcome. Based on our pilot 
trial to obtain a power of 80% and alpha of 0.05 with a 1:1 proportion of control to intervention 
groups, the sample size yielded a total of 100 participants for CRS, 38 for RR, and 43 for HR. Given 
these sample sizes, we chose to recruit a minimum of 100 subjects. However, the final sample size 
was 110 patients, considering the study's longitudinal aspect (with a 10% attrition rate) 
 
3.2 Inclusion Criteria 
✓ Consented children aged between 1 and 24 months with a clinical diagnosis of moderate and 
severe bronchiolitis requiring oxygen supplementation presenting to the EUMF ED or PPU 
 
3.3 Exclusion Criteria 
✓ Children with mild bronchiolitis 
✓ Those with not requiring oxygen supplement 
✓ Those admitted to ICU for IMV 
✓ Those who received supplemental oxygen or HFNCOT at other facilities before arrival 

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✓ Those with known comorbidity (such as congenital heart disease, chronic lung disease, 
neuromuscular disease, metabolic disease, and immunocompromised) 
✓ Those with a craniofacial malformation, an upper airway obstruction, pneumothorax, or nasal 
trauma 
 
3.4 Withdrawal Criteria 
Consenting parents/legal guardians will be informed that they have the opportunity of 
withdrawing their infant/s from the study at any time with no explanation. Data generated by the 
drawn infant/s will be censored at the time of withdrawal. They will remain part of the study and will 
be analyzed by intention to treat and per-protocol approach for adherent patients to their protocol. 
Withdrawn children who require ongoing supplemental oxygen will receive the standard care for 
bronchiolitis, and no additional data will be collected after withdrawal. 
 
3.5 Participant selection 
Children aged between 1 and 24 months with moderate and severe bronchiolitis requiring 
oxygen supplementation presenting to the EUMF ED or PPU with parents/legal guardians' informed 
consent will be randomized to experimental (HFNCOT) or standard oxygen therapy (St-FMOT). 
 
3.6 Enrolment/Randomisation 
During the clinical and eligibility assessment, and after obtaining written informed consent, 
we will apply nasal cannula wall oxygen at 2 L/min if a child needs supplemental oxygen. After 
written informed consent, the physician assigned the participants to either St-FMOT or HFNCOT by 
using simple randomization. On even-numbered days, patients received the St-FMOT, while on odd-
numbered days received the HFNCOT. This trial is an open study because of the inability to blind 
clinicians, parents, or investigators to the two interventions. 
 
 
 
 
 
 
 
 

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3.7 
Study Schema 
 
 
Randomisation
Post-discharge
Eligible for study
+
Obtained informed consent
St-FMOT
Success
Failure
HFNCOT
Success
ICU/IMV
Recovery
Follow-up 15-days
Death
HFNCOT
Success
Failure
ICU/IMV
Recovery
Follow-up 15-days
Death

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4. STUDY PROCEDURES 
4.1 Duration of Treatment 
Treatment will continue from presentation in the ED or PPU to the transfer of care home to 
the parents/legal guardians. 
 
4.2 Follow up 
An investigator will attend telephone follow-up on the first working day after the infant is 15 
days post-discharge. The parent/legal guardian will be contacted and asked 7 set survey questions to 
determine whether an adverse event under therapeutic goods administration requirements, and the 
treatment has been successful post-discharge (Appendix 2). The investigator will record any 
identified adverse events relating to the study devices, and the infant will be followed up further if it 
is clinically indicated. 
 
5. STUDY TREATMENT PLAN 
Study procedures will be individually documented in the case report form, available in ED 
and PPU. This trial will not introduce any invasive procedure or investigation not usually attended as 
standard care. 
 
5.1 Investigational Treatments 
Children will receive maximum therapy for 4 hours, which means that children receive at a 
flow rate of 2 L*kg/min, but we will let the FiO2 reduce if children give an excellent response to the 
treatment. For children on St-FMOT, the FiO2 will be reduced at any time if children provide a 
suitable response to the treatment, and the oxygen requirement will be controlled by turning off the 
flow every hour. Reducing the flow rate should be considered after 4 hours if the children's 
observations for HR, RR, retraction, SpO2, feeding ability and tolerability, CRS, and PEWS stabilize 
or decrease. 
➢ Control Arm: Children in the standard-therapy group received supplemental oxygen via a simple 
face mask, a range of 6-10 L/min, to maintain a SpO2 level between 92-98%. Those who sustained 
the SpO2 >92% in the ambient oxygen concentration were weaned off St-FMOT. 
 
5.2 Experimental Arm: Children in the high-flow group received heated and humidified high-flow 
oxygen at a rate of 2 L*kg/min (maximum 25 L/min), using an age-appropriate Optiflow Junior 
cannula and Airvo 2 high-flow system (Fisher and Paykel Healthcare). The initial FiO2 was set at 

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40%. The starting flow rate continued for a minimum of 4 hours. According to the patients' clinical 
response, the flow rate was decreased by 0.5 L*kg/min per hour. The FiO2 was adjusted to obtain 
the SpO2 levels between 92-98%. When the flow rate was at 0.5 L*kg/min, and the FiO2 was 
equal to the ambient oxygen concentration, HFNCOT was stopped. 
 
5.3 Treatment Failure and Escalation of Care  
✓ The clinician will decide on the escalation of care at any time if the Pediatric Early Warning 
Score (PEWS) is ≥7 points (Appendices 3). 
✓ Treatment failure at 4 hours is considered when at least three of the following five criteria are 
present for both groups.  
1. No change or an increase in HR relative to baseline 
2. No change or an increase in RR relative to baseline 
3. Persistence of low SpO2 (<92%) in the three near independent measurements despite 
receiving FiO2 >40% for HFNCOT and at a maximum 10 L/min for St-FMOT 
4. No change or an increase in CRS relative to baseline 
5. Blood pressure of carbon dioxide >60 mm/Hg 
✓ Children with treatment failure at 4 hours or who need escalation of care will be treated as 
follows: 
➢ Control Arm: Children who deteriorate on the St-FMOT will receive HFNCOT (at 2 L*kg/min) 
as a rescue treatment in the ward or be transferred to the ICU for IMV. 
➢ Experimental Arm: Children who deteriorate on HFNCOT are admitted to the ICU for IMV as 
a rescue treatment. 
 
5.4 Accountability of Investigational Products 
Fisher & Paykel® will provide technical and educational support for the duration of the trial. 
 
5.5 Concomitant Medications and Medical Treatments 
Patients on asthma prevention or treatment medications are excluded from this trial due to the 
confounding effects of existing asthma and its required management. The clinician will use medical 
treatments such as beta-2 agonist, systemic steroid, and hypertonic saline. 
 
6. SAFETY AND ADVERSE EVENT(S) 

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During the study, AEs, regardless of relatedness to the study device, will be reported on the 
AE page of the CRF (Appendices 4). All adverse reactions will be recorded in CRF and registered in 
the manuscript and clinicaltrial.gov. Open disclosure is paramount to the ongoing efficacy and ethical 
conduct of the trial, so parents/ legal guardians of participants experiencing AE are to be entirely 
briefed about the nature and effect of the AE. They are to be informed of likely consequences and 
alternative facts considered relevant following the standard disclosure duty. 
 
6.1 Definitions and Classification 
✓ Adverse Event (AE) 
Any untoward medical occurrence in a patient who is administered a pharmaceutical product 
or device does not necessarily have a causal relationship with this treatment. An AE is any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of an investigational product. 
✓ Suspected Adverse Reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For IND safety reporting purposes, 'reasonable possibility' 
means there is evidence to suggest a causal relationship between the drug and the adverse event. A 
suspected adverse reaction implies less certainty about causality than an adverse reaction, which 
means any adverse event caused by a drug. 
✓ Adverse Reaction 
An adverse reaction means any adverse event caused by a drug. Adverse reactions are a subset 
of all suspected adverse reactions where there is reason to conclude that the drug caused the event. 
✓ Unexpected Adverse Reaction 
An adverse event or suspected adverse reaction is considered as unexpected; 
✓ Not listed in the investigator brochure or is not listed at the specificity or severity that 
has been observed 
✓ An investigator brochure is not required or available 
✓ Not consistent with the risk information described in the general research plan or 
elsewhere in the current application, as amended. 
▪ For example, under this definition, hepatic necrosis would be unexpected 
(under greater severity) if the investigator brochure referred only to elevated 
hepatic enzymes or hepatitis. 

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▪ Similarly, cerebral thromboembolism and cerebral vasculitis would be 
unexpected (under greater specificity) if the investigator brochure listed only 
cerebral vascular accidents. 
✓ Unexpected as used in this definition, it also refers to adverse events or suspected 
adverse reactions mentioned in the investigator brochure as occurring with a class of 
drugs or as anticipated from the drug's pharmacological properties, but are not 
explicitly mentioned with the drug under investigation. 
✓ Serious Adverse Reaction 
An adverse event 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, a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions, or a 
congenital anomaly/congenital disability. 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 patient or subject and may require medical or surgical 
intervention to prevent one outcome listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
✓ Life-Threatening Adverse Reaction 
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view 
of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. 
 
6.2 Follow-up 15 days safety assessment 
On the initial business day after 15 days, post-discharge an investigator will contact the 
parent/legal guardian to ask about any AE which may have occurred following the infant's return 
home under any medical administrations' requirements. 
 
7. STATISTICAL METHODS 
7.1 Sample Size 

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Sample size calculations were done using a t-test on the primary outcome. Based on our pilot 
trial to obtain a power of 80% and alpha of 0.05 with a 1:1 proportion of control to intervention 
groups, the sample size yielded a total of 100 participants for CRS, 38 for RR, and 43 for HR. Given 
these sample sizes, we chose to recruit a minimum of 100 subjects. However, the final sample size 
was 110 patients, considering the study's longitudinal aspect (with a 10% attrition rate). 
 
7.2 Data Analysis Methods 
Categorical and continuous variables will be expressed as frequency (percentage) and median 
(IQR). Between groups, we will use the Mann-Whitney-U test for comparing the time of success for 
HR, RR, and CRS (SPSS Inc., version 25.0, Chicago, IL, USA). The longitudinal analysis part of the 
study will be performed non-parametrically with the Brunner Langer model for CRS conducted with 
a linear mixed model in a parametric way for HR and RR. Brunner Langer model (F1-LD-F1) is 
applied using web-based software (R software, version 3.5.2, package: nparLD, R Foundation for 
Statistical Computing, Vienna, Austria; http://r-project.org). The PROC MIXED procedure in the 
SAS software is used (Version 9.3; SAS Institute, Cary, NC, USA) to perform linear mixed models 
in which subjects will be included as random effects. When there is a significant interaction effect in 
the longitudinal analysis (P < .1), the time effect will be analyzed in each group, and groups will be 
compared at baseline and following time points (the baseline was subtracted from these time points). 
The proportions of the treatment failure at 4 hours, rescued patient, ICU admission, and AE are 
analyzed using Fisher's Exact test and given with odds ratio (OR) and 95% Confidence Interval (CI). 
We will perform intention-to-treat and per-protocol approaches for all outcomes. The time of success 
for HR, RR, and CRS outcomes will be analyzed using the PP approach. A 2-sided P < .05 defines 
statistical significance. 
 
Statistical Analysis Plan 
The biostatistician in the study, which has blinded to allocation, will perform the analysis. An 
interim analysis will not be performed. If substantial evidence of increased risk of harms (p <0.001) 
observed in both groups, stopping rules will be used with the biostatistician's advice. Intention to treat 
and per-protocol approaches will be conducted if necessary. 
 
8. REGULATORY CONSIDERATIONS 
8.1 Participant Consent 

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We will describe the study's nature and identified risks to the parents/legal guardians of 
possible recruits in a written document (Informed Volunteer Consent Form) and verbally. An 
Investigator will obtain written informed consent from each participant's parent/legal guardian before 
participation in the study under regulatory requirements. 
 
8.2 Ethical Review 
Before the study's commencement, the protocol and any amendment(s), Informed Consent 
Form, and Study Information Letter will be referred to the HREC of EUMF, and the Principal 
Investigator will keep the written approval. The approval will submit to the study by title, protocol 
number, and version date and provide details of the documents reviewed by the HREC. During the 
course, the Principal Investigator will submit to the HREC: amendments to the protocol, adverse 
event data, outcome, and administrative changes to the protocol. At the end of the study, the Principal 
Investigator will inform the HREC in writing that the course has ended. No further activities regarding 
this protocol will be conducted at the site. The Investigators will perform the above responsibilities 
under the Note for Guidance on Good Clinical Practice annotated with any adverse events comments 
and the National Health and Medical Research Council National Statement on Ethical Conduct in 
Human Research, 2008. 
 
8.3 Sponsor 
The Director of the Scientific Research Projects of Ege University will approve the study. 
There is no other sponsor. Material for the trial is supplied under the Ministry of Health contract 
arrangements and loan items from Fisher and Paykel®. 
 
9. STUDY ADMINISTRATION 
9.1 Protocol Deviations 
Protocol deviations will be reported in the publication of the results (CONSORT, 2010). 
 
9.2 Monitoring and Auditing 
Researchers will meet periodically to discuss the trial progress and review processes. The 
team will analyze adverse events as they are notified. 
 
9.3 Study Documentation and Records Retention 

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Pediatric study documentation will be kept for a minimum of 22 years. Participant files and 
other essential documents (study protocol, signed informed consent forms, correspondence, and other 
documents relating to the study) will be securely archived in HREC of EUMF to meet these 
conditions. He or she must notify the Study Approver if the Researcher should want to assign the 
investigation documentation to another party or transfer to another position. 
 
9.4 Publication and Use of Study Findings 
Study findings will be submitted to various peer-reviewed, high impact journals depending 
on the report's focus, e.g., pediatric diagnostics, pathology, and respiratory disease.

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10. Appendices 
Appendices 1: Initial Assessment of Children According to CRS Reported by Liu and Colleagues. 
 
0 point 
1 point 
2 point 
3 point 
Respiratory rate 
<2 months 
2-12 months 
1-2 years 
2-3 years 
4-5 years 
6-12 years 
>12 years 
 
 
≤60 
≤50 
≤40 
≤34 
≤30 
≤26 
≤23 
 
61–69 
51–59 
41–44 
35–39 
31–35 
27–30 
24–27 
 
≥70 
≥60 
≥45 
≥40 
≥36 
≥31 
≥28 
Retraction 
None 
IC 
IC and SS 
IC, SS, and SC 
Dyspnea 
0-2 years 
 
 
 
2-4 years 
 
 
 
 
Normal feeding, vocalizations, 
and activity 
 
 
Normal feeding, vocalizations, 
and play 
 
 
 
1 of the following: difficulty 
feeding; decreased 
vocalization; or agitated 
 
1 of the following: 
decreased appetite, 
increased coughing after 
play, hyperactivity 
 
2 of the following: difficulty 
feeding; decreased vocalization; 
or agitated 
 
2 of the following: decreased 
appetite, increased coughing 
after play, hyperactivity 
 
 
Stops feeding, no 
vocalizations, or drowsy 
or confused 
 
Stops eating or drinking, 
stops playing, or drowsy 
or confused 
 

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≥5 years 
 
Counts to ≥10 in one breath 
 
Counts to 7–9 one breath 
 
Counts to 4–6 in one breath 
 
Counts to ≤3 in one breath 
Wheeze 
Normal breathing; no  
wheezing present 
End-expiratory wheeze only 
Expiratory wheeze only (greater 
than end-expiratory wheeze) 
Inspiratory and expiratory 
wheeze or diminished 
breath sounds or both 
 

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Appendices 2: Parent Follow up Questionnaire 
Infant's name 
 
Parent's name 
 
Study device 
□ St-FMOT                          □ HFNCOT 
Has your child returned to his former health state? If the answer is no, give detail. 
□ Yes                                     □ No 
Was there any need for medical treatment after discharge? If the answer is no, give detail. □ Yes                                     □ No 
Are there any of the complaints as followed? 
□ Fever                                  □ Respiratory distress      
□ Wheeze                              □ Shortness of breath 
□ Cough                                □ Fast breathing        
□ Central cyanosis 
Has your child's nutritional status returned to the state it was in before hospitalization? 
If the answer is no, give detail. 
□ Yes                                     □ No 
……………………. 
Did you re-hospitalized after discharge? 
If the answer is yes, give details about why? 
□ Yes                                     □ No 
…………………. 
Is there anything else you would like to tell us about your child's health status? 
Open-ended answer ………………….. 

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Appendices 3: Pediatric Early Warning Score 
 
Age groups 
0 
1 
2 
4 
Heart rate (bpm) 
0 to < 3 months 
3 to < 12 months 
1-4 years 
>4-12 years 
>12 years 
> 110 and < 150 
> 100 and < 150 
> 90 and < 120 
> 70 and < 110 
>60 and < 100 
≥ 150 or ≤ 110 
≥ 150 or ≤ 100 
≥ 120 or ≤ 90 
≥ 110 or ≤ 70 
≥ 100 or ≤ 60 
≥ 180 or ≤ 90 
≥ 170 or ≤ 80 
≥ 150 or ≤ 70 
≥ 130 or ≤ 60 
≥ 120 or ≤ 70 
≥ 190 or ≤ 80 
≥ 180 or ≤ 70 
≥ 170 or ≤ 60 
≥ 150 or ≤ 50 
≥ 140 or ≤ 40 
Systolic blood pressure 
(mmHg) 
0 to < 3 months 
3 to < 12 months 
1-4 years 
>4-12 years 
>12 years 
> 60 and < 80 
> 80 and < 100 
> 90 and < 110 
> 90 and < 120 
> 100 and < 130 
≥ 80 or ≤ 60 
≥ 100 or ≤ 80 
≥ 110 or ≤ 90 
≥ 120 or ≤ 90 
≥ 130 or ≤ 100 
≥ 100 or ≤ 50 
≥ 120 or ≤ 70 
≥ 125 or ≤ 75 
≥ 140 or ≤ 80 
≥ 150 or ≤ 85 
≥ 130 or ≤ 45 
≥ 150 or ≤ 60 
≥ 160 or ≤ 65 
≥ 170 or ≤ 70 
≥ 190 or ≤ 75 
Capillary refill time 
 
< 3 seconds 
 
 
≥ 3 seconds 
Respiratory rate  
(breaths/minute) 
0 to < 3 months 
3 to < 12 months 
1-4 years 
>4-12 years 
>12 years 
> 29 and < 61 
> 24 and < 51 
> 19 and < 41 
> 19 and < 31 
> 11 and < 17 
≥ 61 or ≤ 29 
≥ 51 or ≤ 24 
≥ 41 or ≤ 19 
≥ 31 or ≤ 19 
≥ 17 or ≤ 11 
≥ 81 or ≤ 19 
≥ 71 or ≤ 19 
≥ 61 or ≤ 15 
≥ 41 or ≤ 14 
≥ 23 or ≤ 10 
≥ 91 or ≤ 15 
≥ 81 or ≤ 15 
≥ 71 or ≤ 12 
≥ 51 or ≤ 10 
≥ 30 or ≤ 9 
Respiratory effort 
 
Normal 
Mild increase 
Moderate increase 
Severe 
increase/any 
apnea 
Oxygen saturation (%) 
 
> 94 
91 to 94 
≤ 90 
 

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Oxygen therapy 
 
Room air 
 
Any to < 4 L/minute or < 
50% 
≥ 4 L/minute or ≥ 50% 

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Appendices 4. Case report form 
Case No and date 
 
Age (months) 
 
Gender 
□ Male                                □ Female 
Gestational age 
 
Body weight (gr/kg) 
 
Virus detected in RT-PCR 
□ Yes                                  □ No 
If yes, which virus was detected 
 
Number of bronchiolitis 
□ 1        □ 2       □ 3+ 
Season 
□ Winter                               □ Autumn                               □ Spring                               □ Summer 
Study device 
□ St-FMOT                         □ HFNCOT 
VARIABLES 
Body 
temperature (℃) 
Heart rate 
(bpm) 
Respiratory 
rate 
(/min) 
Arterial tension 
(mm/Hg) 
SpO2 (%) Venous 
blood 
gases 
Ph-PCO2 
CRS 
At first admission 
 
 
 
 
 
 
 
1 h 
 
 
 
 
 
 
 
2 h 
 
 
 
 
 
 
 
4 h 
 
 
 
 
 
 
 
12 h 
 
 
 
 
 
 
 
24 h 
 
 
 
 
 
 
 

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2 d 
 
 
 
 
 
 
 
3 d 
 
 
 
 
 
 
 
4 d 
 
 
 
 
 
 
 
5 d 
 
 
 
 
 
 
 
6 d 
 
 
 
 
 
 
 
7 d 
 
 
 
 
 
 
 
8 d 
 
 
 
 
 
 
 
9 d 
 
 
 
 
 
 
 
10 d 
 
 
 
 
 
 
 
Length of oxygen requirement (h) 
 
Length of hospital stay (d) 
 
Beta2 mimetic use? 
□ Yes                                  □ No 
If yes, how many days did it use? (d)  
Inhaler corticosteroid use? 
□ Yes                                  □ No 
If yes, how many days did it use? (d)  
IV corticosteroid use? 
□ Yes                                  □ No 
If yes, how many days did it use? (d)  
Inhaler hypertonic saline use? 
□ Yes                                  □ No 
If yes, how many days did it use? (d)  
Did any complications occur? 
□ Yes                                  □ No 

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Which complications occurred? 
 
Transfer to ICU 
□ Yes                                  □ No 
Did the treatment fail at the 4th 
hour? 
□ Yes                                  □ No 
Laboratory 
findings 
at 
first 
admission 
WBC:                                  ANC:                                        ALC:                                   CRP:                   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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