BMJ Open › content › bmjopen › 7 › 6 › e016746...For peer review only 4 Strengths and limitations of this study • This is the first study to compare nasal high-flow with

For peer review only

A multicentre, randomised controlled, non-inferiority trial, comparing nasal high-flow with nasal continuous positive

airway pressure as primary support for newborn infants with early respiratory distress born in Australian non-

tertiary special care nurseries (The HUNTER Trial): study protocol

Journal: BMJ Open

Manuscript ID bmjopen-2017-016746

Article Type: Protocol

Date Submitted by the Author: 07-Mar-2017

Complete List of Authors: Manley, Brett; The Royal Women's Hospital, Newborn Research Centre

Roberts, Calum; The Royal Women's Hospital, Newborn Research Centre Arnolda, Gaston; University of New South Wales, New South Wales, Australia, Department of Public Health and Community Medicine Wright, Ian; University of Wollongong, Owen, Louise; The Royal Women's Hospital, Newborn Research Centre; Murdoch Children's Research Institute, Critical Care and Neurosciences Division Dalziel, Kim; The University of Melbourne, School of Population and Global Health Foster, Jann; Western Sydney University, New South Wales, Australia, School of Nursing and Midwifery

Davis, Peter; The Royal Women's Hospital, Newborn Research Buckmaster, Adam; Central Coast Local Health District, Gosford, New South Wales, Australia

<b>Primary Subject Heading</b>:

Paediatrics

Secondary Subject Heading: Intensive care, Respiratory medicine

Keywords: NEONATOLOGY, Paediatric intensive & critical care < PAEDIATRICS, PERINATOLOGY

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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A multicentre, randomised controlled, non-inferiority trial,

comparing nasal high-flow with nasal continuous positive

airway pressure as primary support for newborn infants with

early respiratory distress born in Australian non-tertiary

special care nurseries (The HUNTER Trial): study protocol

Brett J. Manley, PhD1,2, Calum T. Roberts, MBChB1,2, Gaston R.B. Arnolda, PhD3,

Ian M.R. Wright, MB BS4-6, Louise S. Owen, MD1,2,7, Kim M. Dalziel, PhD8, Jann P.

Foster, PhD9-11, Peter G. Davis, MD1,2,7, and Adam G. Buckmaster, PhD6,12.

1. Neonatal Services and Newborn Research Centre, The Royal Women’s

Hospital, Victoria, Australia

2. Department of Obstetrics and Gynaecology, The University of Melbourne,

Victoria, Australia

3. Department of Public Health and Community Medicine, University of New

South Wales, New South Wales, Australia

4. Illawarra Health and Medical Research Institute and Graduate Medicine,

University of Wollongong, New South Wales, Australia 5. Department of Paediatrics, The Wollongong Hospital, Wollongong, New South

Wales, Australia

6. University of Newcastle, New South Wales, Australia

7. Murdoch Childrens Research Institute, Victoria, Australia

8. Centre for Health Policy, Melbourne School of Global and Population Health, The

University of Melbourne, Victoria, Australia

9. School of Nursing and Midwifery, Western Sydney University, New South Wales,

Australia

10. Sydney Nursing School/Sydney Medical School, University of Sydney, New

South Wales, Australia

11. Ingham Institute, Liverpool, New South Wales, Australia

12. Central Coast Local Health District, Gosford, New South Wales, Australia

Trial Contact:

Dr. Brett Manley

Newborn Research Centre

The Royal Women’s Hospital

Level 7, 20 Flemington Road

Parkville, Victoria 3032

Australia

Email: [email protected]

Trial Steering Committee:

Brett Manley, Adam Buckmaster, Gaston Arnolda, Louise Owen, Ian Wright, Jann

Foster, and Peter Davis.

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Trial Sponsor:


20 Flemington Road


Australia

Acknowledgements:

The HUNTER Trial Investigators: Amy Brett and Bernice Mills (Victorian trial

coordinators), The Royal Women’s Hospital, Victoria, Australia; Jane Wardle

(NSW trial coordinator), Gosford Hospital, New South Wales, Australia; Wei Qi

Fan, Northern Hospital, Victoria, Australia; Isaac Marshall, Geelong Hospital,

Victoria, Australia; Rosalynn Pszczola, Sunshine Hospital, Victoria, Australia;

Alice Fang, Box Hill Hospital (Eastern Health), Victoria, Australia; Tracey Clark,

Dandenong Hospital (Monash Health), Victoria, Australia; Alex Aldis, NICU

parent and Life’s Little Treasures Foundation, Victoria, Australia. Data

Monitoring and Safety Committee: David Cartwright (Chair), Royal Brisbane and

Women’s Hospital, Queensland, Australia; Chris McKinlay, Liggins Institute,

University of Auckland, New Zealand; Stuart Dalziel, Starship Children’s Hospital,

Auckland, New Zealand; Susan Donath, Murdoch Childrens Research Institute,

Victoria, Australia.

Author contributions: BJM conceived and designed the trial protocol, co-wrote the

first draft and revised the manuscript for intellectual content. CTR co-wrote the first

draft and revised the manuscript for intellectual content. GA, AB, IMRW, LSO, JF

and PGD conceived and designed the trial protocol and revised the manuscript for

important intellectual content. GA designed the statistical analysis. KD designed the

cost-effectiveness analysis and revised the manuscript for important intellectual

content. All the authors have read and approved the final manuscript, and are

accountable for its accuracy.

Competing interests: None declared.

Word count: 4787

Abstract word count: 271

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ABSTRACT

Introduction

Nasal high-flow (nHF) therapy is a popular mode of respiratory support for newborn

infants. Evidence for nHF use is predominantly from neonatal intensive care units

(NICUs). There are no randomised trials of nHF use in non-tertiary special care

nurseries (SCNs). We hypothesise that nHF is non-inferior to nasal continuous

positive airway pressure (CPAP) as primary support for newborn infants with

respiratory distress, in the population cared for in non-tertiary SCNs.

Methods and analysis The HUNTER trial is an unblinded Australian multicentre randomised non-inferiority

trial. Infants are eligible if born at a gestational age ≥31 weeks with birth weight

≥1200 g and admitted to a participating non-tertiary SCN, are <24 hours old at

randomisation, and require non-invasive respiratory support or supplemental oxygen

for >1 hour. Infants are randomised to treatment with either nHF or CPAP. The

primary outcome is treatment failure within 72 hours of randomisation, as determined

by objective oxygenation, apnoea, or blood gas criteria, or by a clinical decision that

urgent intubation and mechanical ventilation, or transfer to a tertiary NICU, is

required. Secondary outcomes include incidence of pneumothorax requiring drainage,

duration of respiratory support, supplemental oxygen and hospitalisation, costs

associated with hospital care, cost-effectiveness, parental stress and satisfaction, and

nursing workload.

Ethics and dissemination

Multi-site ethical approval for the study has been granted by The Royal Children’s

Hospital, Melbourne, Australia (Trial Reference No. 34222), and by each

participating site. The trial is currently recruiting in 8 centres in Victoria and New

South Wales, Australia, with one previous site no longer recruiting. The trial results

will be published in a peer-reviewed journal, and presented at national and

international conferences.

Trial registration

Australian and New Zealand Clinical Trials Registry (ANZCTR):

ACTRN12614001203640

Funding statement

Funded by the National Health and Medical Research Council, Australia (Project

Grant 1098790, Early Career Fellowship 1088279 – Brett Manley). The funder had no

input into the study design; collection, management, analysis, or interpretation of

data; writing of the report; or the decision to submit the report for publication.

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Strengths and limitations of this study

• This is the first study to compare nasal high-flow with nasal continuous

positive airway pressure as respiratory support for newborn infants in non-

tertiary settings

• The study is well powered to detect non-inferiority of nasal high-flow with a

non-inferiority margin of 10%; the use of a non-inferiority study design is

appropriate given the advantages of nasal high-flow over nasal continuous

positive airway pressure

• The study includes assessment of parental stress, nursing workload, and

financial costs

• Blinding of the allocated respiratory support modes is not possible, so

objective criteria were specified for the primary outcome of treatment failure

• Some infants in the nasal high-flow group will have received a brief period of

nasal continuous positive airway pressure prior to randomisation

INTRODUCTION

Background

Preterm birth, at <37 weeks’ gestational age (GA), affecting about 15 million infants

annually, is a major cause of morbidity and mortality worldwide. About one million

infants die from complications of prematurity every year.1 In Australia, about 9% of

all births are preterm.2 A major contributor to mortality and morbidity in preterm

infants is respiratory distress syndrome (RDS) due to surfactant deficiency in the

lungs, which leads to many preterm infants requiring respiratory support soon after

birth; the proportion of infants who develop RDS increases with lower GA. However,

about 80% of preterm infants are born moderate- to late-preterm (32–36 weeks’ GA),2

where RDS is less common. Respiratory symptoms in this more mature preterm

population, and in term infants, may be due to conditions such as transient tachypnoea

of the newborn, or infection.

It is estimated that 2.5-5% of all newborn infants have respiratory distress.3 In

Australia, most of these infants are born in a non-tertiary hospital and cared for in a

special care nursery (SCN), where they may be treated with supplemental oxygen and

‘non-invasive’ respiratory support from nasal continuous positive airway pressure

(CPAP). However, if these treatments are not available, not successful, or if an infant

is born very preterm (<32 weeks’ gestation) or very small (<1250 g), then the infant

usually needs to be transferred to a tertiary-level neonatal intensive care unit (NICU).

In Australia, neonatal intensive care is centralised in large metropolitan centres, and

maternal and infant transfers often involve large distances and significant costs.

The standard non-invasive respiratory support: CPAP

CPAP uses large prongs in the nose, or a mask over the nose, fitted firmly to the

infant’s face. The prongs or mask deliver heated and humidified air and oxygen under

pressure. CPAP can be used effectively as the primary mode of respiratory support

(the first mode of respiratory support applied after admission to the neonatal unit soon

after birth) in infants with respiratory distress, even those born at 25-30 weeks’

gestation.4,5

When used in Australian non-tertiary SCNs to treat late preterm and term

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infants with respiratory distress, CPAP reduces the need for transfer to a tertiary

NICU, and reduces costs in comparison to the use of supplemental oxygen alone.6

However, CPAP has been associated with an increased risk of pneumothorax

compared to supplemental oxygen alone.6,7

CPAP is a widely-used method of respiratory support in Australian SCNs,8,9

but has

some disadvantages. CPAP fixation devices are bulky and cover much of the infant’s

face, interfering with parental interaction and feeding; trauma to the nasal skin or

septum is a commonly reported complication.10

Nursing vigilance is required to

ensure that an adequate seal (and hence pressure) is maintained without causing nasal

injury. For these reasons, and others including limits on staff and equipment, CPAP

may not be a feasible therapy in smaller SCNs.

The new therapy: nasal high-flow

In recent years, nasal high-flow (nHF) therapy, a newer form of non-invasive

respiratory support, has become popular as an alternative to CPAP around the world,

including in Australasian SCNs.9,11-13

Nasal HF therapy delivers heated, humidified,

blended oxygen and air via small bi-nasal prongs, using gas flows of at least 1 Litre

per minute (L/min).14

Whilst nHF therapy has been adopted by many NICUs around

the world, there has until recently been relatively little evidence to support this

practice. The increasing popularity of nHF seems to be due to its reported advantages

over CPAP: it is easier to apply and maintain, more comfortable for infants,

associated with less nasal trauma, and preferred by parents and nursing staff.15-18

If

nHF was demonstrated to be an effective mode of respiratory support in non-tertiary

SCNs, these factors would make it the preferred interface in this setting.

Clinical trials of nHF in newborn infants

Preventing extubation failure in NICUs

The majority of published randomised controlled trials (RCTs) of nHF have evaluated

its use as an alternative to CPAP, as post-extubation respiratory support. An updated

Cochrane Review18

of these trials, published in 2016, found no difference in rates of

treatment failure or reintubation in infants treated with post-extubation nHF,

compared to those treated with CPAP. The nHF infants were noted to have lower

rates of nasal trauma, and a small reduction in the risk of pneumothorax.

Primary Respiratory Support for Newborn Infants

Prior to the HUNTER trial commencing, there was little evidence from RCTs to

support the use of nHF as primary support for newborn infants. Yoder and

colleagues19

conducted an RCT in 432 infants, of whom about one-third were

included in an ‘early support’ arm. There was no difference between the nHF and

CPAP groups in need for intubation, or in other neonatal morbidities. Studies by

Iranpour20

and Kugelman,21

each including approximately 70 infants, compared nHF

with CPAP, and nasal intermittent positive airway pressure (NIPPV), respectively, as

early respiratory support for preterm infants; they found no difference between groups

in rates of treatment failure or other important outcomes.

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Within the past year, two larger RCTs evaluating nHF as primary respiratory support

in NICUs have been published. The HIPSTER trial22

included 564 preterm infants of

mean 32 weeks’ GA, and 1.7 kg in birth weight, not previously treated with

surfactant, in nine NICUs in Australia and Norway. Nasal HF use resulted in a higher

rate of treatment failure (based on objective clinical criteria) than CPAP (25.5% vs.

13.3%, P<0.01), but no greater risk of intubation, likely due to the use of ‘rescue’

CPAP in infants with nHF failure. Lavizzari et al23

studied 316 infants of mean 33

weeks’ GA and 1.9 kg in birth weight in an Italian NICU. They found no difference in

rates of treatment failure (mechanical ventilation within 72 hours) between infants

treated with nHF and those treated with CPAP and/or biphasic positive airway

pressure (10.8% vs. 9.5%, P=0.71). However, it is notable that infants in this study

could be intubated, treated with surfactant, and extubated (‘INSURE’ treatment),

without being classed as having treatment failure. Surfactant use was common,

occurring in >40% of infants in both treatment groups.

While providing important guidance on the use of primary nHF in NICUs, it is

important to recognise that the results of these studies cannot be directly applied to

use in non-tertiary SCNs, where there is currently no high-quality evidence to guide

practice. Staffing in SCNs is different to that in tertiary NICUs, and infants in SCNs

have different antenatal exposures, gestational ages, and pathologies.

Summary and Rationale

The reported advantages of nHF – easier nursing care, improved feeding and parental

interaction, reduced nasal trauma and greater infant comfort – have led to widespread

adoption of this new therapy. While there are now a number of studies assessing nHF

use in the NICU, there are no published trials that study the efficacy and safety of

nHF compared with CPAP as early respiratory support for newborn infants in SCNs.

The reference treatment against which non-inferiority is being assessed, CPAP, has

been shown to be effective in SCNs in a study with similar inclusion criteria and

CPAP treatment protocols.6 If proven to be effective and safe, the ease of use of nHF

would mean that it could be widely applied to infants with respiratory distress in non-

tertiary SCNs, both in Australia and around the world, potentially reducing the need

for transfer to a tertiary NICU – reducing costs and keeping mothers and their babies

together. Conversely, if nHF is shown to be unsafe or significantly less effective than

CPAP, this will guide clinicians to avoid nHF treatment of newborn infants outside

NICUs. The above considerations led to the adoption of a non-inferiority trial design.

METHODS AND ANALYSIS

Study design

HUNTER is a multicentre, randomised, non-inferiority trial, including newborn

infants cared for in non-tertiary SCNs, who require early non-invasive respiratory

support in the first 24 hours of life.

Aim

The aim of the HUNTER trial is to determine whether nHF is non-inferior to CPAP in

avoiding treatment failure when used as early non-invasive respiratory support for

newborn infants cared for in Australian non-tertiary SCNs.

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Blinding

Blinding of the allocated treatment is not feasible, as the mode of respiratory support

is clearly apparent to medical and nursing staff and parents/guardians. We have

therefore defined objective criteria for the primary outcome to minimise potential

bias, and provided guidance to clinicians considering the need to escalate respiratory

support and/or arrange transfer to a tertiary NICU.

Outcomes

The primary outcome will be assessed on a hypothesis of non-inferiority. Outcomes,

eligibility criteria, and the CPAP treatment protocol are similar to those of a study in

Australian SCNs that demonstrated the efficacy of CPAP in comparison to passive

oxygen for preventing treatment failure.6 The major change from that study is a

reduction in the fraction of inspired oxygen (FiO2) threshold for treatment failure

from 0.50 to 0.40, in line with current international practice to reduce neonatal

oxygen exposure.

Primary outcome: The primary outcome is treatment failure within 72 hours of

randomisation. Treatment failure occurs when an infant has reached maximal therapy

for their allocated treatment (nHF 8 L/min or CPAP 8 cm H2O), and one or more of

the following criteria are satisfied:

1. Sustained increase in oxygen requirement: fraction of inspired oxygen (FiO2)

≥0.40 for more than one hour to maintain peripheral oxygen saturation (SpO2) 91-

95%

2. Respiratory acidosis: both pH <7.20 and pCO2 >60 millimetres of mercury (mm

Hg) on two blood gas samples (which can be capillary, venous or arterial), with

the first sample collected at least one hour after initiation of the assigned

treatment, and the second sample taken at least one hour after the first.

3. Frequent or severe apnoea: more than one apnoea receiving positive pressure

ventilation within any 24-hour period, or six or more apnoeas in any six hour

period receiving intervention (stimulation or increased oxygen)

4. The treating paediatrician determines that urgent intubation and mechanical

ventilation is required

5. The treating paediatrician determines that the infant requires transfer to a tertiary

NICU, through consultation with the local neonatal transport service.

Secondary outcomes: The secondary outcomes are:

1. Cost: Estimated differences between the interventions based on the costs of

equipment, care in SCNs and NICUs, costs associated with hospital stay, costs to

the family, and the costs of transfer (both infant and maternal)

2. Mortality (specified as a significant adverse event)

3. Pneumothorax requiring drainage via needle thoracocentesis or intercostal

catheter insertion (specified as a significant adverse event)

4. Duration of supplemental oxygen (hours)

5. Oxygen supplementation at 28 days of age, or at 36 weeks’ corrected GA for

infants born <32 weeks’ gestation

6. Mechanical ventilation via an endotracheal tube in the first 72 hours after

randomisation, and at any time prior to discharge home

7. Duration of respiratory support (hours): including hours of nHF, CPAP, and

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mechanical ventilation.

8. Duration of hospital admission, duration of admission to a tertiary NICU (days)

9. Incidence of nasal trauma

10. Weight gain and feeding performance, including weight gain from birth to

hospital discharge, proportion of infants fully breastfed at discharge, number of

days receiving any intravenous fluids, and number of days to reach full suck feeds

(defined as tolerating suck feeds without any requirement for intravenous fluids or

naso/orogastric feeds for >24 hours)

11. Parental stress and satisfaction, measured using a modified version of the

validated Parental Stressor Scale: NICU,24

assessed as soon as possible after

treatment has ceased, or prior to transfer to a NICU

12. Nursing workload and treatment preference, measured using the Professional

Assessment of Optimal Nursing Care Intensity Scale tool25

, and by questionnaire

Setting

The trial has been enrolling infants in nine non-tertiary SCNs in Victoria and New

South Wales, Australia. All participating SCNs routinely care for newborn infants

with respiratory distress, using CPAP as the standard non-invasive support mode.

Participating centres did not previously use nHF to treat newborn infants. These SCNs

have 24-hour on-site junior paediatric staff, and a designated consultant paediatrician

available to advise management and/or attend as required.

Eligibility criteria

Infants are eligible for inclusion in the trial if:

1. They are born at ≥31 weeks’ GA by best obstetric estimate, and have birth weight

≥1200 g; and

2. They are admitted to the SCN of a participating centre and are <24 hours old at

the time of randomisation; and

3. They require non-invasive respiratory support after admission to the SCN, or

require any supplemental oxygen to maintain SpO2 91-95% for more than one

hour

Infants are excluded from the trial if:

1. They have received more than two hours of CPAP prior to randomisation; or

2. They have previously been intubated (including intubation for suctioning below

the cords in the delivery room), or immediately need intubation, as determined by

the attending paediatrician; or

3. They have a known major congenital abnormality that may impact upon the

infant’s condition after birth (eg. complex congenital cardiac disease, upper

airway obstruction, gastrointestinal malformation); or

4. They are judged by their paediatrician to require transfer to another hospital for

ongoing care (the reason for this decision will be clearly documented)

Randomisation

Randomisation will be pre-stratified by centre, and according to GA at birth: <34

weeks’ GA and ≥34 weeks’ GA. Within each stratum, a 1:1 allocation ratio and block

randomisation with variable block sizes (4, 6, or 8) will be used. Multiple births with

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more than one eligible infant will be randomised individually. Each participating

centre will be provided with consecutively numbered, sealed opaque randomisation

envelopes containing the assigned treatment allocation. The appropriate envelope will

be opened after written consent has been obtained and the infant has become eligible

for the trial; the assigned treatment will then immediately be applied to the infant.

Random sequences were generated in SAS v9.4 by author Arnolda.

Clinical management

Eligible and consented infants will be randomised to treatment with either nHF or

CPAP; allocated treatment will be applied immediately after randomisation. Infants in

both groups will receive standard supportive care as per local policies, e.g. blood

tests, X-rays, antibiotics, intravenous fluids/nutrition, and enteral feeds. In both

groups, supplemental oxygen will be adjusted to maintain SpO2 91-95%.

Interventions

nHF therapy is defined as heated, humidified gas (blended air/oxygen) delivered at

gas flows of 5-8 L/min via the Fisher & Paykel (F&P) ‘Optiflow Junior’ circuit and

prongs.

CPAP is defined as the use of short binasal prongs or nasal mask to deliver heated,

humidified gas (blended air/oxygen) using a “bubble” CPAP device (any brand may

be used) with set pressures of 5-8 cm H2O.

Intervention group: nHF

1. A nasal cannula size should be selected that maintains a leak at the nares

2. The starting flow will be 6 L/min for all infants

3. Increasing nHF support: Gas flow may be increased to a maximum of 8 L/min

4. If treatment failure criteria are satisfied, infants should receive CPAP 8 cm H2O,

and then be managed as per the CPAP group protocol

a. if treatment failure criteria are again satisfied when the infant is receiving

CPAP 8 cm H2O, it is recommended that the treating paediatrician

consider referral to the local neonatal transport service for advice and/or

transfer of the infant to a tertiary NICU, and surfactant may be

administered at the paediatrician’s discretion according to the unit’s

individual policy

b. if the infant’s condition is improving, the CPAP pressure should be

weaned, and nHF may be re-instituted at the paediatrician’s discretion

5. Decreasing and ceasing nHF support:

a. gas flow may be decreased (in decrements of 1 L/min) or ceased if there is

no supplemental oxygen requirement (infant is receiving air), or if the

infant has required FiO2 <0.25 for >24 hours

b. nHF should be ceased when the gas flow is 5 L/min, and there is no

supplemental oxygen requirement, or the infant has required FiO2 <0.25

for >24 hours:

c. if nHF is ceased, infants may receive ongoing oxygen supplementation via

‘low-flow’ nasal cannulae, cot oxygen, or head-box oxygen

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d. After ceasing nHF, if non-invasive breathing support is again required,

nHF should be recommenced at ≥5 L/min, and managed as above

6. Infants randomised to nHF will not receive CPAP after randomisation, unless

treatment failure criteria are met.

Standard care group: CPAP

1. The starting set pressure will be 6 cm H2O for all infants

2. Increasing CPAP support: the set CPAP pressure may be increased to a maximum

of 8 cm H2O

3. If treatment failure criteria are satisfied, it is recommended that the treating

paediatrician consider referral to the local neonatal transport service for advice

and/or transfer of the infant to a tertiary NICU, and surfactant may be

administered at the paediatrician’s discretion according to the unit’s individual

policy

4. Decreasing and ceasing CPAP support:

a. the set pressure may be decreased (in decrements of 1 cm H2O) or ceased

if there is no supplemental oxygen requirement (infant is receiving air), or

if the infant has required FiO2 <0.25 for >24 hours

b. CPAP should be ceased when the set pressure is 5 cm H2O, and there is no


for >24 hours:

c. If CPAP is ceased, infants may receive ongoing oxygen supplementation

via ‘low-flow’ nasal cannulae, cot oxygen, or head-box oxygen

d. After ceasing CPAP, if non-invasive breathing support is again required,

CPAP should be recommenced at ≥5 cm H2O, and managed as above

5. Infants randomised to CPAP will not receive nHF at any stage of their admission.

Sample size calculation

Non-inferiority of nHF will be determined using the absolute risk difference (RD) and

95% confidence interval (CI) for the primary outcome of treatment failure within 72

hours of randomisation. We have set the margin of non-inferiority at 10%. Thus, for

nHF to be non-inferior to CPAP, the upper limit of the two-sided 95% CI of the RD

must be <10%. This margin was adopted after agreement between the site

investigators and our parent representative; it is equivalent to the smallest margin

chosen in previously published non-inferiority trials of neonatal respiratory

support,23,26

and is narrower than in most non-inferiority trials published in the adult

medical literature.

Based on pre-trial data from six non-tertiary SCNs, we estimate the rate of the

primary outcome in the CPAP group will be 17%. A sample size of 750 infants (375

infants in each group) is required to demonstrate non-inferiority of nHF with 90%

power: i.e. to be 90% sure that the upper limit of a two-sided 95% CI will exclude a

difference in favour of CPAP or more than 10%

(www.sealedenvelope.com/power/binary-noninferior).

Statistical analysis and economic evaluation plan

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Statistical analysis will be performed by the principal investigator (BJM) with

assistance from the trial Steering Committee. Data will be exported from an electronic

database to an electronic statistical package for analysis. The primary analysis will be

by intention-to-treat. A secondary per protocol analysis will also be performed for the

primary outcome and any important differences reported, as is recommended for non-

inferiority trials.27

The difference between the groups in the incidence of the primary outcome will be

reported using RD with two-sided 95% CI. Subgroup analysis by GA at birth will be

performed for the primary outcome and selected secondary outcomes. Dichotomous

secondary outcomes will be compared with a RD (two-sided 95% CI) and a Chi

squared test. Continuous secondary outcomes will be compared by the appropriate

parametric (t-test) or non-parametric (Mann-Whitney U) test. The primary outcome

will be assessed on a hypothesis of non-inferiority; all secondary outcomes will be

assessed against a hypothesis of superiority.

Cost-effectiveness analysis will incorporate the costs of the device and of hospital

care split into NICU, SCN and general hospital costs. A decision analysis will be

constructed based on the primary outcome and associated hospital costs. Cost-

effectiveness will be reported as a cost per additional treatment failure avoided for

nHF versus CPAP, and univariate and probabilistic sensitivity analyses will be

conducted.

Nursing workload measures will be analysed using longitudinal methods, as these are

provided by the nurse primarily responsible for the infant at the hospital of birth, for

each shift in the first 72 hours of care after randomisation.

ETHICS AND DISSEMINATION

Research ethics approval


Hospital, Melbourne, Australia (No. 34222, current approved protocol version 5, 9th

September 2016), and by each participating site.

Recruitment and consent

In all cases, prospective, written consent will be obtained from a parent or guardian.

Consent may be either antenatal or postnatal.

For postnatal consent, eligible infants will be identified after birth and their parents or

guardians approached as soon as possible for prospective consent. Parents or

guardians of infants who are not yet eligible, but are likely to become eligible (e.g.

infants requiring supplemental oxygen who are likely to continue on this treatment)

may also be approached. In some cases, antenatal consent may be obtained (e.g. when

a preterm birth is planned). Written consent will be recorded on the trial patient

information and consent form.

Consent will be obtained by a doctor or nurse who has been trained in obtaining

consent for the trial and who has received education regarding the trial protocol.

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Wherever possible, consent will be obtained by someone not directly involved in the

clinical care of the infant at the time.

Data collection and storage

Data will be sourced from the infant’s bedside observation chart, medical and nursing

notes, pathology results, electronic monitors, the mother’s medical chart, and verbally

and by questionnaire from parents/guardians and nursing staff. Data will be de-

identified and entered onto a paper case record form, and subsequently entered into a

secure, web-based electronic database.

Monitoring and safety

An independent data safety and monitoring committee (DSMC) has been convened,

consisting of two neonatologists, a paediatric emergency specialist, and a statistician.

An early safety review was undertaken after 150 infants were recruited to the trial,

and further safety reviews are planned approximately six monthly. A single review of

the primary outcome and its components was planned, after the primary outcome was

known for 375 participants.

Defined significant adverse events (SAEs) for the study are:

• Air leak from the lung (pneumothorax) requiring drainage via needle

thoracocentesis or intercostal catheter insertion

• Death before discharge from hospital

All SAEs are reported to the lead Human Research Ethics Committee and to

committees at the relevant site.

The DSMC may make a recommendation to the Steering Committee to temporarily or

permanently stop the trial. Although no formal stopping rule will be used, such a

decision may be based on:

• A difference in the primary outcome such that the committee considers the trial

should no longer continue

• An increase in the rate of SAEs in the nHF group

• Equipment failure or unforeseen complications pertaining to the equipment or its

manufacture

• New information such as other trial results which make it ethically impossible to

continue the trial

The primary outcome review was completed in December 2016, and on the basis of

this, and on safety reviews conducted to date, the DSMC has recommended that the

trial continue without modification.

Dissemination of results

The results of the trial will be published in a peer-reviewed journal, and presented at

national and international conferences.

Current status and study duration

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The trial began recruiting in April 2015, with additional sites joining subsequently. It

is currently recruiting in eight centres, with one previous site ceasing recruitment due

to a change in its level of care classification, meaning that it could no longer care for

infants requiring prolonged non-invasive respiratory support. It is expected that

recruitment for the study will be completed in 2018.

Funding

The trial is funded by the National Health and Medical Research Council (NHMRC),

Australia (Project grant 1098790). Brett Manley is the recipient of an NHMRC Early

Career Fellowship (1088279).

Trial registration


ACTRN12614001203640.

DISCUSSION

Nasal HF therapy has been widely adopted in neonatal practice due to its desirable

qualities such as ease of use, reduced nasal trauma, and parental and nursing

preference.15-18

Recently, the HIPSTER trial demonstrated that in NICUs, rates of

treatment failure with nHF are higher than with CPAP in preterm infants born ≥28

weeks’ GA, although with ‘rescue’ CPAP available there is no difference in rates of

intubation.22

The HIPSTER results suggest that CPAP should be favoured over nHF if

only one treatment is available, however these findings cannot be directly applied to

environments other than the NICU. The other recently published trial of primary nHF

was also performed in a NICU, and included a high rate of surfactant treatment, an

intervention which may not be feasible in SCNs, and has not been shown to provide

an advantage over routine CPAP treatment, particularly in the population relevant to

SCNs (infants ≥31 weeks’ GA).28

There has traditionally been a lack of clinical research in newborn infants cared for in

non-tertiary SCNs, and only one previous RCT of respiratory support in this setting.6

Research in SCNs is important, because care of infants in these units incorporates a

number of factors distinct from tertiary NICUs. Non-tertiary SCNs do not care for

large numbers of very preterm or very low birth weight infants, and often need to treat

term infants with respiratory distress. The resources and staffing available in non-

tertiary SCNs are different from those in NICUs, and whilst capable of intubation and

mechanical ventilation as a stabilisation measure, SCNs are not equipped to provide

this level of treatment for longer periods. The implications for failure of non-invasive

support are therefore greater in SCNs: transfer of the infant to a NICU, and separation

from his or her parents. Furthermore, there are potentially important financial

implications of treatment failure: retrieval by specialist neonatal transport services,

particularly when over long distances, as would apply in many areas of Australia, bear

a significant cost. Transfers from SCNs also have an impact on staffing and resource

allocation in receiving tertiary NICUs.

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There has never been a randomised trial of nHF in non-tertiary SCNs. Nasal HF may

be an effective mode of support in this setting, and, due to its ease of use, would be

preferable to CPAP if shown to be non-inferior. However, it is equally important to

determine if nHF is unsafe or significantly inferior to CPAP, so that clinicians may be

guided to avoid nHF use in non-tertiary SCNs. If nHF use was associated with a

reduction in nursing workload, it may prove to be more economically cost-effective

than CPAP, or may result in a greater capacity to manage infants requiring non-

invasive support in SCNs. CPAP is associated with an increased risk of pneumothorax

in comparison with oxygen treatment.6 A Cochrane Review noted nHF treatment to

be associated with a small reduction in pneumothorax rate compared with CPAP.18

If

a lower rate of this complication was seen in our trial with nHF, in conjunction with

non-inferiority in treatment efficacy, nHF could be the preferred mode of treatment.

The HUNTER trial is a well-powered, carefully designed randomised clinical trial,

which will determine whether nHF is an appropriate mode of early respiratory support

for newborn infants in the non-tertiary setting. The non-inferiority design used in the

HUNTER trial was until recently quite rare, but has been used recently in similar

trials by our group.22,29

The choice of non-inferiority margin of 10% was made in

view of the fact that the primary outcome was treatment failure and not a more critical

outcome, such as death, and that infants who have treatment failure on nHF will be

offered CPAP, which may ‘rescue’ them from intubation and/or transfer to a NICU,

as seen in previous NICU trials of nHF.22,29,30

A potential limitation to this trial is that blinding of treatment allocation is not

possible. We have attempted to minimise this by setting objective treatment failure

criteria, which were agreed upon by all participating centres. Some infants allocated

to nHF will receive a brief period of CPAP before randomisation, which conceivably

could affect interpretation of the results. However, we have aimed to restrict the

impact of this by excluding infants who have received two or more hours of CPAP

from the trial, which we felt to be the shortest window in which seeking parental

consent would be feasible.

The use of nHF in NICU practice is well established, and supported by evidence from

multiple RCTs. However, nHF use is also being adopted in non-tertiary SCNs,9,13,31,32

a setting in which there is little evidence of its efficacy and safety. If this trial

demonstrates that nHF is non-inferior to CPAP as primary support for newborn

infants in non-tertiary SCNs, then many units worldwide are likely to incorporate nHF

into their routine practice. However, if nHF is inferior to CPAP, the results of this

study will ensure that this treatment is not applied inappropriately, and infants in non-

tertiary SCNs with respiratory distress will continue to receive evidence-based care.

REFERENCES

1. Blencowe H, Cousens S, Oestergaard MZ, et al. National, regional, and

worldwide estimates of preterm birth rates in the year 2010 with time trends

since 1990 for selected countries: a systematic analysis and implications.

Lancet.2012;379(9832):2162-72.

2. Australian Institute of Health and Welfare 2016. Australia’s mothers and

babies 2014—in brief. Perinatal statistics series no. 32. Cat no. PER 87. Canberra:

AIHW; 2016.

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3. Buckmaster A, Arnolda G, Wright I, et al. Targeted oxygen therapy in

special care nurseries: is uniformity a good thing? J Paediatr Child

Health.2012;48(6):476-82.

4. Dunn MS, Kaempf J, de Klerk A, et al. Randomized trial comparing 3

approaches to the initial respiratory management of preterm neonates.

Pediatrics.2011;128(5):e1069-76.

5. Morley CJ, Davis PG, Doyle LW, et al. Nasal CPAP or intubation at birth for

very preterm infants. The New England journal of medicine.2008;358(7):700-8.

6. Buckmaster AG, Arnolda G, Wright IM, et al. Continuous positive airway

pressure therapy for infants with respiratory distress in non tertiary care

centers: a randomized, controlled trial. Pediatrics.2007;120(3):509-18.

7. Ho JJ, Subramaniam P, Davis PG. Continuous distending pressure for

respiratory distress in preterm infants. Cochrane Database Syst

Rev.2015(7):CD002271.

8. Roberts CL, Badgery-Parker T, Algert CS, et al. Trends in use of neonatal

CPAP: a population-based study. BMC pediatrics.2011;11:89.

9. Manley BJ, Owen L, Doyle LW, et al. High-flow nasal cannulae and nasal

continuous positive airway pressure use in non-tertiary special care nurseries in

Australia and New Zealand. Journal of paediatrics and child

health.2012;48(1):16-21.

10. Robertson NJ, McCarthy LS, Hamilton PA, et al. Nasal deformities resulting

from flow driver continuous positive airway pressure. Archives of disease in

childhood Fetal and neonatal edition.1996;75(3):F209-12.

11. Hochwald O, Osiovich H. The use of high flow nasal cannulae in neonatal

intensive care units: Is clinical practice consistent with the evidence? Journal of

Neonatal-Perinatal Medicine.2010;3 (3):187-91.

12. Hough JL, Shearman AD, Jardine LA, et al. Humidified high flow nasal

cannulae: current practice in Australasian nurseries, a survey. Journal of

paediatrics and child health.2012;48(2):106-13.

13. Roberts CT, Owen LS, Manley BJ, et al. High-flow support in very preterm

infants in Australia and New Zealand. Archives of disease in childhood Fetal and

neonatal edition.2015.

14. Wilkinson D, Andersen C, O'Donnell CP, et al. High flow nasal cannula for

respiratory support in preterm infants. Cochrane Database Syst

Rev.2011(5):CD006405.

15. Klingenberg C, Pettersen M, Hansen EA, et al. Patient comfort during

treatment with heated humidified high flow nasal cannulae versus nasal

continuous positive airway pressure: a randomised cross-over trial. Arch Dis

Child Fetal Neonatal Ed.2014;99(2):F134-7.

16. Osman M, Elsharkawy A, Abdel-Hady H. Assessment of pain during

application of nasal-continuous positive airway pressure and heated, humidified

high-flow nasal cannulae in preterm infants. J Perinatol.2015;35(4):263-7.

17. Roberts CT, Manley BJ, Dawson JA, et al. Nursing perceptions of high-flow

nasal cannulae treatment for very preterm infants. Journal of paediatrics and

child health.2014;50(10):806-10.


respiratory support in preterm infants. Cochrane Database Syst

Rev.2016;2:CD006405.

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19. Yoder BA, Stoddard RA, Li M, et al. Heated, humidified high-flow nasal

cannula versus nasal CPAP for respiratory support in neonates.

Pediatrics.2013;131(5):e1482-90.

20. Iranpour R, Sadeghnia A, Hesaraki M. High-flow nasal cannula versus

nasal continuous positive airway pressure in the management of respiratory

distress syndrome. J Isfahan Med School.2011;29:761-71.

21. Kugelman A, Riskin A, Said W, et al. A randomized pilot study comparing

heated humidified high-flow nasal cannulae with NIPPV for RDS. Pediatr

Pulmonol.2014.

22. Roberts CT, Owen LS, Manley BJ, et al. Nasal High-Flow Therapy for

Primary Respiratory Support in Preterm Infants. The New England journal of

medicine.2016;375(12):1142-51.

23. Lavizzari A, Colnaghi M, Ciuffini F, et al. Heated, Humidified High-Flow

Nasal Cannula vs Nasal Continuous Positive Airway Pressure for Respiratory

Distress Syndrome of Prematurity: A Randomized Clinical Noninferiority Trial.

JAMA Pediatr.2016.

24. Miles MS, Funk SG, Carlson J. Parental Stressor Scale: neonatal intensive

care unit. Nursing research.1993;42(3):148-52.

25. Fagerstrom L, Rainio AK, Rauhala A, et al. Validation of a new method for

patient classification, the Oulu Patient Classification. J Adv Nurs.2000;31(2):481-

90.


Primary Respiratory Support in Preterm Infants. N Engl J

Med.2016;375(12):1142-51.

27. Piaggio G, Elbourne DR, Pocock SJ, et al. Reporting of noninferiority and

equivalence randomized trials: extension of the CONSORT 2010 statement. JAMA

: the journal of the American Medical Association.2012;308(24):2594-604.

28. Isayama T, Chai-Adisaksopha C, McDonald SD. Noninvasive Ventilation

With vs Without Early Surfactant to Prevent Chronic Lung Disease in Preterm

Infants: A Systematic Review and Meta-analysis. JAMA Pediatr.2015;169(8):731-

9.

29. Manley BJ, Owen LS, Doyle LW, et al. High-Flow Nasal Cannulae in Very

Preterm Infants after Extubation. The New England journal of

medicine.2013;369(15):1425-33.

30. Collins CL, Holberton JR, Barfield C, et al. A randomized controlled trial to

compare heated humidified high-flow nasal cannulae with nasal continuous

positive airway pressure postextubation in premature infants. J

Pediatr.2013;162(5):949-54 e1.

31. Ojha S, Gridley E, Dorling J. Use of heated humidified high-flow nasal

cannula oxygen in neonates: a UK wide survey. Acta Paediatr.2013;102(3):249-

53.

32. Shetty S, Sundaresan A, Hunt K, et al. Changes in the use of humidified

high flow nasal cannula oxygen. Archives of disease in childhood Fetal and

neonatal edition.2016.

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SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*

Section/item Item No

Description Addressed on page number

Administrative information

Title 1 Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym ___________1

Trial registration 2a Trial identifier and registry name. If not yet registered, name of intended registry ___________3

2b All items from the World Health Organization Trial Registration Data Set __ Throughout

Protocol version 3 Date and version identifier __________13

Funding 4 Sources and types of financial, material, and other support ___________3

Roles and

responsibilities

5a Names, affiliations, and roles of protocol contributors ___________2

5b Name and contact information for the trial sponsor ___________2

5c Role of study sponsor and funders, if any, in study design; collection, management, analysis, and

interpretation of data; writing of the report; and the decision to submit the report for publication, including

whether they will have ultimate authority over any of these activities

___________3

5d Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint

adjudication committee, data management team, and other individuals or groups overseeing the trial, if

applicable (see Item 21a for data monitoring committee)

___________1

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2

Introduction

Background and

rationale

6a Description of research question and justification for undertaking the trial, including summary of relevant

studies (published and unpublished) examining benefits and harms for each intervention

__________4-6

6b Explanation for choice of comparators __________4-6

Objectives 7 Specific objectives or hypotheses ___________7

Trial design 8 Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group),

allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory)

__________6-7

Methods: Participants, interventions, and outcomes

Study setting 9 Description of study settings (eg, community clinic, academic hospital) and list of countries where data will

be collected. Reference to where list of study sites can be obtained

___________8

Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and

individuals who will perform the interventions (eg, surgeons, psychotherapists)

_________8-9

Interventions 11a Interventions for each group with sufficient detail to allow replication, including how and when they will be

administered

_________ 9-10

11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose

change in response to harms, participant request, or improving/worsening disease)

_________9-10

11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence

(eg, drug tablet return, laboratory tests)

__________N/A

11d Relevant concomitant care and interventions that are permitted or prohibited during the trial __________9-10

Outcomes 12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood

pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg,

median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen

efficacy and harm outcomes is strongly recommended

__________7-8

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Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for

participants. A schematic diagram is highly recommended (see Figure)

_____See Figure

Sample size 14 Estimated number of participants needed to achieve study objectives and how it was determined, including

clinical and statistical assumptions supporting any sample size calculations

__________11

Recruitment 15 Strategies for achieving adequate participant enrolment to reach target sample size __________11

Methods: Assignment of interventions (for controlled trials)

Allocation:

Sequence

generation

16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any

factors for stratification. To reduce predictability of a random sequence, details of any planned restriction

(eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants

or assign interventions

__________9

Allocation

concealment

mechanism

16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered,

opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned

___________9

Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to

interventions

___________9

Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome

assessors, data analysts), and how

__________7

17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s

allocated intervention during the trial

_________N/A__

Methods: Data collection, management, and analysis

Data collection

methods

18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related

processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of

study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known.

Reference to where data collection forms can be found, if not in the protocol

________7,12

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18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be

collected for participants who discontinue or deviate from intervention protocols

_________N/A__

Data management 19 Plans for data entry, coding, security, and storage, including any related processes to promote data quality

(eg, double data entry; range checks for data values). Reference to where details of data management

procedures can be found, if not in the protocol

_________12__

Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the

statistical analysis plan can be found, if not in the protocol

_________11__

20b Methods for any additional analyses (eg, subgroup and adjusted analyses) _________11__

20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any

statistical methods to handle missing data (eg, multiple imputation)

_________11__

Methods: Monitoring

Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of

whether it is independent from the sponsor and competing interests; and reference to where further details

about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not

needed

________12-13__

21b Description of any interim analyses and stopping guidelines, including who will have access to these interim

results and make the final decision to terminate the trial

________12-13__

Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse

events and other unintended effects of trial interventions or trial conduct

________12-13__

Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent

from investigators and the sponsor

_______12-13___


Research ethics

approval

24 Plans for seeking research ethics committee/institutional review board (REC/IRB) approval ________12___

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5

Protocol

amendments

25 Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes,

analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals,

regulators)

________N/A__

Consent or assent 26a Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and

how (see Item 32)

_________12__

26b Additional consent provisions for collection and use of participant data and biological specimens in ancillary

studies, if applicable

________N/A__

Confidentiality 27 How personal information about potential and enrolled participants will be collected, shared, and maintained

in order to protect confidentiality before, during, and after the trial

_________12__

Declaration of

interests

28 Financial and other competing interests for principal investigators for the overall trial and each study site _________2__

Access to data 29 Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that

limit such access for investigators

________N/A___

Ancillary and post-

trial care

30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial

participation

________N/A__

Dissemination policy 31a Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals,

the public, and other relevant groups (eg, via publication, reporting in results databases, or other data

sharing arrangements), including any publication restrictions

_________13__

31b Authorship eligibility guidelines and any intended use of professional writers _________N/A__

31c Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code _________N/A_

Appendices

Informed consent

materials

32 Model consent form and other related documentation given to participants and authorised surrogates __Not included_

Biological

specimens

33 Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular

analysis in the current trial and for future use in ancillary studies, if applicable

_________N/A__

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*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for important clarification on the items.

Amendments to the protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the Creative Commons

“Attribution-NonCommercial-NoDerivs 3.0 Unported” license.

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Figure. Schedule of enrolment, interventions, and assessments: The HUNTER Trial.

STUDY PERIOD

Enrolment Allocation Post-allocation Close-out

TIMEPOINT** -t1 0 t1 t2 tx

ENROLMENT:

Eligibility screen X

Informed consent X

Allocation X

INTERVENTIONS:

Nasal HF X

CPAP X

ASSESSMENTS:

Baseline variables X X

Primary outcome X

Other outcomes

X X

t1 Immediately after randomisation t2 72 hours after randomisation tx First hospital discharge

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A multicentre, randomised controlled, non-inferiority trial, comparing nasal high-flow with nasal continuous positive

airway pressure as primary support for newborn infants with early respiratory distress born in Australian non-

tertiary special care nurseries (The HUNTER Trial): study protocol

Journal: BMJ Open

Manuscript ID bmjopen-2017-016746.R1

Article Type: Protocol

Date Submitted by the Author: 18-Apr-2017

Complete List of Authors: Manley, Brett; The Royal Women's Hospital, Newborn Research Centre

Roberts, Calum; The Royal Women's Hospital, Newborn Research Centre Arnolda, Gaston; University of New South Wales, New South Wales, Australia, Department of Public Health and Community Medicine Wright, Ian; University of Wollongong, Owen, Louise; The Royal Women's Hospital, Newborn Research Centre; Murdoch Children's Research Institute, Critical Care and Neurosciences Division Dalziel, Kim; The University of Melbourne, School of Population and Global Health Foster, Jann; Western Sydney University, New South Wales, Australia, School of Nursing and Midwifery

Davis, Peter; The Royal Women's Hospital, Newborn Research Buckmaster, Adam; Central Coast Local Health District, Gosford, New South Wales, Australia

<b>Primary Subject Heading</b>:

Paediatrics

Secondary Subject Heading: Intensive care, Respiratory medicine

Keywords: NEONATOLOGY, Paediatric intensive & critical care < PAEDIATRICS, PERINATOLOGY


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A multicentre, randomised controlled, non-inferiority trial,

comparing nasal high-flow with nasal continuous positive

airway pressure as primary support for newborn infants with

early respiratory distress born in Australian non-tertiary

special care nurseries (The HUNTER Trial): study protocol

Brett J. Manley, PhD1,2, Calum T. Roberts, MBChB1,2, Gaston R.B. Arnolda, PhD3,

Ian M.R. Wright, MB BS4-6, Louise S. Owen, MD1,2,7, Kim M. Dalziel, PhD8, Jann P.

Foster, PhD9-11, Peter G. Davis, MD1,2,7, and Adam G. Buckmaster, PhD6,12.

1. Neonatal Services and Newborn Research Centre, The Royal Women’s

Hospital, Victoria, Australia

2. Department of Obstetrics and Gynaecology, The University of Melbourne,

Victoria, Australia

3. Department of Public Health and Community Medicine, University of New

South Wales, New South Wales, Australia

4. Illawarra Health and Medical Research Institute and Graduate Medicine,

University of Wollongong, New South Wales, Australia 5. Department of Paediatrics, The Wollongong Hospital, Wollongong, New South

Wales, Australia

6. University of Newcastle, New South Wales, Australia

7. Murdoch Childrens Research Institute, Victoria, Australia

8. Centre for Health Policy, Melbourne School of Global and Population Health, The

University of Melbourne, Victoria, Australia

9. School of Nursing and Midwifery, Western Sydney University, New South Wales,

Australia

10. Sydney Nursing School/Sydney Medical School, University of Sydney, New

South Wales, Australia

11. Ingham Institute, Liverpool, New South Wales, Australia

12. Central Coast Local Health District, Gosford, New South Wales, Australia

Trial Contact:

Dr. Brett Manley

Newborn Research Centre


Level 7, 20 Flemington Road


Australia

Email: [email protected]

Trial Steering Committee:

Brett Manley, Adam Buckmaster, Gaston Arnolda, Louise Owen, Ian Wright, Jann

Foster, and Peter Davis.

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Trial Sponsor:


20 Flemington Road


Australia

Acknowledgements:

The HUNTER Trial Investigators: Amy Brett and Bernice Mills (Victorian trial

coordinators), The Royal Women’s Hospital, Victoria, Australia; Jane Wardle

(NSW trial coordinator), Gosford Hospital, New South Wales, Australia; Wei Qi

Fan, Northern Hospital, Victoria, Australia; Isaac Marshall, Geelong Hospital,

Victoria, Australia; Rosalynn Pszczola, Sunshine Hospital, Victoria, Australia;

Alice Fang, Box Hill Hospital (Eastern Health), Victoria, Australia; Tracey Clark,

Dandenong Hospital (Monash Health), Victoria, Australia; Alex Aldis, NICU

parent and Life’s Little Treasures Foundation, Victoria, Australia. Data

Monitoring and Safety Committee: David Cartwright (Chair), Royal Brisbane and

Women’s Hospital, Queensland, Australia; Chris McKinlay, Liggins Institute,

University of Auckland, New Zealand; Stuart Dalziel, Starship Children’s Hospital,

Auckland, New Zealand; Susan Donath, Murdoch Childrens Research Institute,

Victoria, Australia. Health Economics: Li Huang, The University of Melbourne.

Author contributions: BJM conceived and designed the trial protocol, co-wrote the

first draft and revised the manuscript for intellectual content. CTR co-wrote the first

draft and revised the manuscript for intellectual content. GA, AB, IMRW, LSO, JF

and PGD conceived and designed the trial protocol and revised the manuscript for

important intellectual content. GA designed the statistical analysis. KD designed the

cost-effectiveness analysis and revised the manuscript for important intellectual

content. All the authors have read and approved the final manuscript, and are

accountable for its accuracy.

Competing interests: None declared.

Word count: 5175

Abstract word count: 271

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ABSTRACT

Introduction

Nasal high-flow (nHF) therapy is a popular mode of respiratory support for newborn

infants. Evidence for nHF use is predominantly from neonatal intensive care units

(NICUs). There are no randomised trials of nHF use in non-tertiary special care

nurseries (SCNs). We hypothesise that nHF is non-inferior to nasal continuous

positive airway pressure (CPAP) as primary support for newborn infants with

respiratory distress, in the population cared for in non-tertiary SCNs.

Methods and analysis The HUNTER trial is an unblinded Australian multicentre randomised non-inferiority

trial. Infants are eligible if born at a gestational age ≥31 weeks with birth weight

≥1200 g and admitted to a participating non-tertiary SCN, are <24 hours old at

randomisation, and require non-invasive respiratory support or supplemental oxygen

for >1 hour. Infants are randomised to treatment with either nHF or CPAP. The

primary outcome is treatment failure within 72 hours of randomisation, as determined

by objective oxygenation, apnoea, or blood gas criteria, or by a clinical decision that

urgent intubation and mechanical ventilation, or transfer to a tertiary NICU, is

required. Secondary outcomes include incidence of pneumothorax requiring drainage,

duration of respiratory support, supplemental oxygen and hospitalisation, costs

associated with hospital care, cost-effectiveness, parental stress and satisfaction, and

nursing workload.



Hospital, Melbourne, Australia (Trial Reference No. 34222), and by each

participating site. The trial is currently recruiting in 8 centres in Victoria and New

South Wales, Australia, with one previous site no longer recruiting. The trial results

will be published in a peer-reviewed journal, and presented at national and

international conferences.

Trial registration


ACTRN12614001203640

Funding statement

Funded by the National Health and Medical Research Council, Australia (Project

Grant 1098790, Early Career Fellowship 1088279 – Brett Manley). The funder had no

input into the study design; collection, management, analysis, or interpretation of

data; writing of the report; or the decision to submit the report for publication.

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Strengths and limitations of this study

• This is the first study to compare nasal high-flow with nasal continuous

positive airway pressure as respiratory support for newborn infants in non-

tertiary settings

• The study is well powered to detect non-inferiority of nasal high-flow with a

non-inferiority margin of 10%; the use of a non-inferiority study design is

appropriate given the advantages of nasal high-flow over nasal continuous

positive airway pressure

• The study includes assessment of parental stress, nursing workload, and

financial costs

• Blinding of the allocated respiratory support modes is not possible, so

objective criteria were specified for the primary outcome of treatment failure

• Some infants in the nasal high-flow group will have received a brief period of

nasal continuous positive airway pressure prior to randomisation

INTRODUCTION

Background

Preterm birth, at <37 weeks’ gestational age (GA), affecting about 15 million infants

annually, is a major cause of morbidity and mortality worldwide. About one million

infants die from complications of prematurity every year.1 In Australia, about 9% of

all births are preterm.2 A major contributor to mortality and morbidity in preterm

infants is respiratory distress syndrome (RDS) due to surfactant deficiency in the

lungs, which leads to many preterm infants requiring respiratory support soon after

birth; the proportion of infants who develop RDS increases with lower GA. However,

about 80% of preterm infants are born moderate- to late-preterm (32–36 weeks’ GA),2

where RDS is less common. Respiratory symptoms in this more mature preterm

population, and in term infants, may be due to conditions such as transient tachypnoea

of the newborn, or infection.

It is estimated that 2.5-5% of all newborn infants have respiratory distress.3 In

Australia, most of these infants are born in a non-tertiary hospital and cared for in a

special care nursery (SCN), where (depending on the level of neonatal care available)

they may be treated with supplemental oxygen and/or ‘non-invasive’ respiratory

support from nasal continuous positive airway pressure (CPAP). However, if these

treatments are not available such as in some smaller SCNs, or not successful, or if an

infant is born very preterm (<32 weeks’ gestation) or very small (<1250 g), then the

infant usually needs to be transferred to a tertiary-level neonatal intensive care unit

(NICU). In Australia, neonatal intensive care is centralised in large metropolitan

centres, and maternal and infant transfers from regional or rural centres involve large

distances and significant costs.

The standard non-invasive respiratory support: CPAP

CPAP uses large prongs in the nose, or a mask over the nose, fitted firmly to the

infant’s face. The prongs or mask deliver heated and humidified air and oxygen under

pressure. CPAP can be used effectively as the primary mode of respiratory support

(the first mode of respiratory support applied after admission to the neonatal unit soon

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after birth) in infants with respiratory distress, even those born at 25-30 weeks’

gestation.4,5

When used in Australian non-tertiary SCNs to treat late preterm and term

infants with respiratory distress, CPAP reduces the need for transfer to a tertiary

NICU, and reduces costs in comparison to the use of supplemental oxygen alone.6

However, CPAP has been associated with an increased risk of pneumothorax

compared to supplemental oxygen alone.6,7

CPAP is a widely-used method of respiratory support in larger Australian SCNs,8,9

but has some disadvantages. CPAP fixation devices are bulky and cover much of the

infant’s face, interfering with parental interaction and feeding; trauma to the nasal

skin or septum is a commonly reported complication.10

Nursing vigilance is required

to ensure that an adequate seal (and hence pressure) is maintained without causing

nasal injury. For these reasons, and others including limits on staff and equipment,

CPAP is not currently a feasible therapy in smaller Australian SCNs (with birth rates

mostly <1500/year) that infrequently care for infants who require respiratory support.

The new therapy: nasal high-flow

In recent years, nasal high-flow (nHF) therapy, a newer form of non-invasive

respiratory support, has become popular as an alternative to CPAP around the world,

including in Australasian SCNs.9,11-15

Nasal HF therapy delivers heated, humidified,

blended oxygen and air via small bi-nasal prongs, using gas flows of at least 1 Litre

per minute (L/min).16

Whilst nHF therapy has been adopted by many NICUs around

the world, there has until recently been relatively little evidence to support this

practice. The increasing popularity of nHF seems to be due to its reported advantages

over CPAP: it is easier to apply and maintain, more comfortable for infants,

associated with less nasal trauma, and preferred by parents and nursing staff.17-20

If

nHF was demonstrated to be an effective mode of respiratory support in non-tertiary

SCNs, these factors would make it the preferred interface in this setting.

Clinical trials of nHF in newborn infants

Preventing extubation failure in NICUs

The majority of published randomised controlled trials (RCTs) of nHF have evaluated

its use as an alternative to CPAP, as post-extubation respiratory support. An updated

Cochrane Review20

of these trials, published in 2016, found no difference in rates of

treatment failure or reintubation in infants treated with post-extubation nHF,

compared to those treated with CPAP. The nHF infants were noted to have lower

rates of nasal trauma, and a small reduction in the risk of pneumothorax.

Primary Respiratory Support for Newborn Infants

Prior to the HUNTER trial commencing, there was little evidence from RCTs to

support the use of nHF as primary support for newborn infants. Yoder and

colleagues21

conducted an RCT in 432 infants, of whom about one-third were

included in an ‘early support’ arm. There was no difference between the nHF and

CPAP groups in need for intubation, or in other neonatal morbidities. Studies by

Iranpour22

and Kugelman,23

each including approximately 70 infants, compared nHF

with CPAP, and nasal intermittent positive airway pressure (NIPPV), respectively, as

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early respiratory support for preterm infants; they found no difference between groups

in rates of treatment failure or other important outcomes.

Within the past year, two larger RCTs evaluating nHF as primary respiratory support

in NICUs have been published. The HIPSTER trial24

included 564 preterm infants of

mean 32 weeks’ GA, and 1.7 kg in birth weight, not previously treated with

surfactant, in nine NICUs in Australia and Norway. Nasal HF use resulted in a higher

rate of treatment failure (based on objective clinical criteria) than CPAP (25.5% vs.

13.3%, P<0.01), but no greater risk of intubation, likely due to the use of ‘rescue’

CPAP in infants with nHF failure. Lavizzari et al25 studied 316 infants of mean 33

weeks’ GA and 1.9 kg in birth weight in an Italian NICU. They found no difference in

rates of treatment failure (mechanical ventilation within 72 hours) between infants

treated with nHF and those treated with CPAP and/or biphasic positive airway

pressure (10.8% vs. 9.5%, P=0.71). However, it is notable that infants in this study

could be intubated, treated with surfactant, and extubated (‘INSURE’ treatment),

without being classed as having treatment failure. Surfactant use was common,

occurring in >40% of infants in both treatment groups.

While providing important guidance on the use of primary nHF in NICUs, it is

important to recognise that the results of these studies cannot be directly applied to

use in non-tertiary SCNs, where there is currently no high-quality evidence to guide

practice. Staffing in SCNs is different to that in tertiary NICUs, and infants in SCNs

have different antenatal exposures, gestational ages, and pathologies.

Summary and Rationale

The reported advantages of nHF – easier nursing care, improved feeding and parental

interaction, reduced nasal trauma and greater infant comfort – have led to widespread

adoption of this new therapy. While there are now a number of studies assessing nHF

use in the NICU, there are no published trials that study the efficacy and safety of

nHF compared with CPAP as early respiratory support for newborn infants in SCNs.

The reference treatment against which non-inferiority is being assessed, CPAP, has

been shown to be effective in SCNs in a study with similar inclusion criteria and

CPAP treatment protocols.6 If proven to be effective and safe, the ease of use of nHF

would mean that it could be widely applied to infants with respiratory distress in non-

tertiary SCNs, both in Australia and around the world, potentially reducing the need

for transfer to a tertiary NICU – reducing costs and keeping mothers and their babies

together. Conversely, if nHF is shown to be unsafe or significantly less effective than

CPAP, this will guide clinicians to avoid nHF treatment of newborn infants outside

NICUs. The above considerations led to the adoption of a non-inferiority trial design.

METHODS AND ANALYSIS

Study design

HUNTER is a multicentre, randomised, non-inferiority trial, including newborn

infants cared for in Australian non-tertiary SCNs, who require early non-invasive

respiratory support in the first 24 hours of life. A schedule of enrolment,

interventions, and assessments is shown in the FIGURE.

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Aim

The aim of the HUNTER trial is to determine whether nHF is non-inferior to CPAP in

avoiding treatment failure when used as early non-invasive respiratory support for

newborn infants cared for in Australian non-tertiary SCNs.

Blinding

Blinding of the allocated treatment is not feasible, as the mode of respiratory support

is clearly apparent to medical and nursing staff and parents/guardians. We have

therefore defined objective criteria for the primary outcome to minimise potential

bias, and provided guidance to clinicians considering the need to escalate respiratory

support and/or arrange transfer to a tertiary NICU.

Outcomes

The primary outcome will be assessed on a hypothesis of non-inferiority. Outcomes,

eligibility criteria, and the CPAP treatment protocol are similar to those of a study in

Australian SCNs that demonstrated the efficacy of CPAP in comparison to passive

oxygen for preventing treatment failure.6 The major change from that study is a

reduction in the fraction of inspired oxygen (FiO2) threshold for treatment failure

from 0.50 to 0.40, in line with current international practice to reduce neonatal

oxygen exposure.

Primary outcome: The primary outcome is treatment failure within 72 hours of

randomisation. Treatment failure occurs when an infant has reached maximal therapy

for their allocated treatment (nHF 8 L/min or CPAP 8 cm H2O), and one or more of

the following criteria are satisfied:

1. Sustained increase in oxygen requirement: fraction of inspired oxygen (FiO2)

≥0.40 for more than one hour to maintain peripheral oxygen saturation (SpO2) 91-

95%

2. Respiratory acidosis: both pH <7.20 and pCO2 >60 millimetres of mercury (mm

Hg) on two blood gas samples (which can be capillary, venous or arterial), with

the first sample collected at least one hour after initiation of the assigned

treatment, and the second sample taken at least one hour after the first.

3. Frequent or severe apnoea: more than one apnoea receiving positive pressure

ventilation within any 24-hour period, or six or more apnoeas in any six hour

period receiving intervention (stimulation or increased oxygen)

4. The treating paediatrician determines that urgent intubation and mechanical

ventilation is required

5. The treating paediatrician determines that the infant requires transfer to a tertiary

NICU, through consultation with the local neonatal transport service.

Secondary outcomes: The secondary outcomes are:

1. Cost: Estimated differences between the interventions based on the costs of

equipment, care in SCNs and NICUs, costs associated with hospital stay, costs to

the family, and the costs of transfer (both infant and maternal)

2. Mortality (specified as a significant adverse event)

3. Pneumothorax requiring drainage via needle thoracocentesis or intercostal

catheter insertion (specified as a significant adverse event)

4. Duration of supplemental oxygen (hours)

5. Oxygen supplementation at 28 days of age, or at 36 weeks’ corrected GA for

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infants born <32 weeks’ gestation

6. Mechanical ventilation via an endotracheal tube in the first 72 hours after

randomisation, and at any time prior to discharge home

7. Duration of respiratory support (hours): including hours of nHF, CPAP, and

mechanical ventilation.

8. Duration of hospital admission, duration of admission to a tertiary NICU (days)

9. Incidence of nasal trauma

10. Weight gain and feeding performance, including weight gain from birth to

hospital discharge, proportion of infants fully breastfed at discharge, number of

days receiving any intravenous fluids, and number of days to reach full suck feeds

(defined as tolerating suck feeds without any requirement for intravenous fluids or

naso/orogastric feeds for >24 hours)

11. Parental stress and satisfaction, measured using a modified version of the

validated Parental Stressor Scale: NICU,26

assessed as soon as possible after

treatment has ceased, or prior to transfer to a NICU

12. Nursing workload and treatment preference, measured using the Professional

Assessment of Optimal Nursing Care Intensity Scale tool27

, and by questionnaire

Setting

The trial has been enrolling infants in nine non-tertiary SCNs in Victoria and New

South Wales, Australia. All participating SCNs routinely care for newborn infants

with respiratory distress, using CPAP as the standard non-invasive support mode;

participating centres did not previously use nHF to treat newborn infants. No

Australian SCNs provide ongoing mechanical ventilation; this is only provided whilst

awaiting transfer of the infant to a tertiary NICU. All participating centres administer

exogenous surfactant if the infant requires intubation for RDS prior to retrieval by the

neonatal transport team; the standard of care is that all these infants are transferred to

a tertiary NICU. Two participating centres have some experience using the ‘INSURE’

(Intubate, Surfactant, Extubate) procedure28

in select infants with the support of the

neonatal transport service (after which NICU transfer could potentially be avoided),

but this is an infrequent practice that is staff-dependent. The participating SCNs have

24-hour on-site junior paediatric staff, and a designated on-call consultant

paediatrician available to advise management and/or attend as required. Some

participating centres have one or two consultant staff with specialist neonatal training,

but most Australian SCNs do not.

Eligibility criteria

Infants are eligible for inclusion in the trial if:

1. They are born at ≥31 weeks’ GA by best obstetric estimate, and have birth weight

≥1200 g; and

2. They are admitted to the SCN of a participating centre and are <24 hours old at

the time of randomisation; and

3. They require non-invasive respiratory support after admission to the SCN (at

clinician discretion), or require any supplemental oxygen to maintain SpO2 91-

95% for more than one hour

Infants are excluded from the trial if:

1. They have received more than two hours of CPAP prior to randomisation; or

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2. They have previously been intubated (including intubation for suctioning below

the cords in the delivery room), or immediately need intubation, as determined by

the attending paediatrician; or

3. They have a known major congenital abnormality that may impact upon the

infant’s condition after birth (eg. complex congenital cardiac disease, upper

airway obstruction, gastrointestinal malformation); or

4. They are judged by their paediatrician to require transfer to another hospital for

ongoing care (the reason for this decision will be clearly documented)

Randomisation

Randomisation will be pre-stratified by centre, and according to GA at birth: <34

weeks’ GA and ≥34 weeks’ GA. Within each stratum, a 1:1 allocation ratio and block

randomisation with variable block sizes (4, 6, or 8) will be used. Multiple births with

more than one eligible infant will be randomised individually. Each participating

centre will be provided with consecutively numbered, sealed opaque randomisation

envelopes containing the assigned treatment allocation. The appropriate envelope will

be opened after written consent has been obtained and the infant has become eligible

for the trial; the assigned treatment will then immediately be applied to the infant.

Random sequences were generated in SAS v9.4 by author Arnolda.

Clinical management

Eligible and consented infants will be randomised to treatment with either nHF or

CPAP; allocated treatment will be applied immediately after randomisation. Infants in

both groups will receive standard supportive care as per local policies, e.g. blood

tests, antibiotics, intravenous fluids/nutrition, and enteral feeds. In both groups,

supplemental oxygen will be adjusted to maintain SpO2 91-95%. Chest X-rays and

blood gas analyses are not mandated prior to randomisation, and the timing of these

investigations will be a physician discretion in keeping with the pragmatic trial

design, however it is expected that most enrolled infants will have these investigations

performed as per local guidelines.

Interventions

nHF therapy is defined as heated, humidified gas (blended air/oxygen) delivered at

gas flows of 5-8 L/min via the Fisher & Paykel (F&P) ‘Optiflow Junior’ circuit and

prongs.

CPAP is defined as the use of short binasal prongs or nasal mask to deliver heated,

humidified gas (blended air/oxygen) using a “bubble” CPAP device (any brand may

be used) with set pressures of 5-8 cm H2O.

Intervention group: nHF

1. A nasal cannula size should be selected that maintains a leak at the nares

2. The starting flow will be 6 L/min for all infants

3. Increasing nHF support: Gas flow may be increased to a maximum of 8 L/min

4. If treatment failure criteria are satisfied, infants should receive CPAP 8 cm H2O,

and then be managed as per the CPAP group protocol

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a. if treatment failure criteria are again satisfied when the infant is receiving

CPAP 8 cm H2O, it is recommended that the treating paediatrician

consider referral to the local neonatal transport service for advice and/or

transfer of the infant to a tertiary NICU, and surfactant may be

administered at the paediatrician’s discretion according to the unit’s

individual policy

b. if the infant’s condition is improving, the CPAP pressure should be

weaned, and nHF may be re-instituted at the paediatrician’s discretion

5. Decreasing and ceasing nHF support:

a. gas flow may be decreased (in decrements of 1 L/min) or ceased if there is

no supplemental oxygen requirement (infant is receiving air), or if the

infant has required FiO2 <0.25 for >24 hours

b. nHF should be ceased when the gas flow is 5 L/min, and there is no


for >24 hours:

c. if nHF is ceased, infants may receive ongoing oxygen supplementation via

‘low-flow’ nasal cannulae, cot oxygen, or head-box oxygen

d. After ceasing nHF, if non-invasive breathing support is again required,

nHF should be recommenced at ≥5 L/min, and managed as above

6. Infants randomised to nHF will not receive CPAP after randomisation, unless

treatment failure criteria are met.

Standard care group: CPAP

1. The starting set pressure will be 6 cm H2O for all infants

2. Increasing CPAP support: the set CPAP pressure may be increased to a maximum

of 8 cm H2O

3. If treatment failure criteria are satisfied, it is recommended that the treating

paediatrician consider referral to the local neonatal transport service for advice

and/or transfer of the infant to a tertiary NICU, and surfactant may be

administered at the paediatrician’s discretion according to the unit’s individual

policy

4. Decreasing and ceasing CPAP support:

a. the set pressure may be decreased (in decrements of 1 cm H2O) or ceased

if there is no supplemental oxygen requirement (infant is receiving air), or

if the infant has required FiO2 <0.25 for >24 hours

b. CPAP should be ceased when the set pressure is 5 cm H2O, and there is no


for >24 hours:

c. If CPAP is ceased, infants may receive ongoing oxygen supplementation

via ‘low-flow’ nasal cannulae, cot oxygen, or head-box oxygen

d. After ceasing CPAP, if non-invasive breathing support is again required,

CPAP should be recommenced at ≥5 cm H2O, and managed as above

5. Infants randomised to CPAP will not receive nHF at any stage of their admission.

Sample size calculation

Non-inferiority of nHF will be determined using the absolute risk difference (RD) and

95% confidence interval (CI) for the primary outcome of treatment failure within 72

hours of randomisation. We have set the margin of non-inferiority at 10%. Thus, for

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nHF to be non-inferior to CPAP, the upper limit of the two-sided 95% CI of the RD

must be <10%. This margin was adopted after agreement between the site

investigators and our parent representative; it is equivalent to the smallest margin

chosen in previously published non-inferiority trials of neonatal respiratory

support,25,29

and is narrower than in most non-inferiority trials published in the adult

medical literature.

Based on pre-trial data from six non-tertiary SCNs, we estimate the rate of the

primary outcome in the CPAP group will be 17%. A sample size of 750 infants (375

infants in each group) is required to demonstrate non-inferiority of nHF with 90%

power: i.e. to be 90% sure that the upper limit of a two-sided 95% CI will exclude a

difference in favour of CPAP or more than 10%

(www.sealedenvelope.com/power/binary-noninferior).

Statistical analysis and economic evaluation plan

Statistical analysis will be performed by the principal investigator (BJM) with

assistance from the trial Steering Committee. Data will be exported from an electronic

database to an electronic statistical package for analysis. The primary analysis will be

by intention-to-treat. A secondary per protocol analysis will also be performed for the

primary outcome and any important differences reported, as is recommended for non-

inferiority trials.30

The difference between the groups in the incidence of the primary outcome will be

reported using RD with two-sided 95% CI. Subgroup analysis by GA at birth will be

performed for the primary outcome and selected secondary outcomes. Dichotomous

secondary outcomes will be compared with a RD (two-sided 95% CI) and a Chi

squared test. Continuous secondary outcomes will be compared by the appropriate

parametric (t-test) or non-parametric (Mann-Whitney U) test. The primary outcome

will be assessed on a hypothesis of non-inferiority; all secondary outcomes will be

assessed against a hypothesis of superiority.

Cost-effectiveness analysis will be conducted from the healthcare system perspective,

incorporating the costs of inpatient stay including the associated device and patient

transfer costs. Routinely available costs of inpatient stay will be sourced from the

hospital costing units. To inform whether it is cost-effective to incorporate nHF or

CPAP into the existing health system, decision analysis will be constructed based on

the primary outcome and associated hospital costs. Univariate and probabilistic

sensitivity analyses will be conducted to test the impact of uncertainty in data.

Nursing workload measures will be analysed using longitudinal methods, as these are

provided by the nurse primarily responsible for the infant at the hospital of birth, for

each shift in the first 72 hours of care after randomisation.

ETHICS AND DISSEMINATION



Hospital, Melbourne, Australia (No. 34222, current approved protocol version 5, 9th

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September 2016). Site-specific governance approval has been granted by the

following human research ethics committees: Victoria, Australia: Western Health,

Northern Health, Eastern Health, Barwon Health, and Monash Health; New South

Wales, Australia: Central Coast Local Health District, Illawarra Shoalhaven Local

Health District.

Recruitment and consent

In all cases, prospective, written consent will be obtained from a parent or guardian.

Consent may be either antenatal or postnatal.

For postnatal consent, eligible infants will be identified after birth and their parents or

guardians approached as soon as possible for prospective consent. Parents or

guardians of infants who are not yet eligible, but are likely to become eligible (e.g.

infants requiring supplemental oxygen who are likely to continue on this treatment)

may also be approached. In some cases, antenatal consent may be obtained (e.g. when

a preterm birth is planned). Written consent will be recorded on the trial patient

information and consent form.

Consent will be obtained by a doctor or nurse who has been trained in obtaining

consent for the trial and who has received education regarding the trial protocol.

Wherever possible, consent will be obtained by someone not directly involved in the

clinical care of the infant at the time.

Data collection, storage and access

Data will be sourced from the infant’s bedside observation chart, medical and nursing

notes, pathology results, electronic monitors, the mother’s medical chart, and verbally

and by questionnaire from parents/guardians and nursing staff. Data will be de-

identified and entered onto a paper case record form, and subsequently entered into a

secure, web-based electronic database. Only the members of the Trial Steering

Committee will have access to the final dataset.

Monitoring and safety

An independent data safety and monitoring committee (DSMC) has been convened,

consisting of two neonatologists, a paediatric emergency specialist, and a statistician.

An early safety review was undertaken after 150 infants were recruited to the trial,

and further safety reviews are planned approximately six monthly. A single review of

the primary outcome and its components was planned, after the primary outcome was

known for 375 participants.

Defined serious adverse events (SAEs) for the study are:

• Air leak from the lung (pneumothorax) requiring drainage via needle

thoracocentesis or intercostal catheter insertion

• Death before discharge from hospital

All incidences of these SAEs are reported to the lead Human Research Ethics

Committee and to committees at the relevant site.

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The DSMC may make a recommendation to the Steering Committee to temporarily or

permanently stop the trial. Although no formal stopping rule will be used, such a

decision may be based on:

• A difference in the primary outcome such that the committee considers the trial

should no longer continue

• An increase in the rate of SAEs in the nHF group

• Equipment failure or unforeseen complications pertaining to the equipment or its

manufacture

• New information such as other trial results which make it ethically impossible to

continue the trial

The primary outcome review was completed in December 2016, and on the basis of

this, and on safety reviews conducted to date, the DSMC has recommended that the

trial continue without modification.

Dissemination of results

The results of the trial will be published in a peer-reviewed journal, and presented at

national and international conferences.

Current status and study duration

The trial began recruiting in April 2015, with additional sites joining subsequently. It

is currently recruiting in eight centres, with one previous site ceasing recruitment due

to a change in its level of care classification, meaning that it could no longer care for

infants requiring prolonged non-invasive respiratory support. To the end of March

2017, over 500 infants have been enrolled in the trial. It is expected that recruitment

for the study will be completed in 2018.

Funding

The trial is funded by the National Health and Medical Research Council (NHMRC),

Australia (Project grant 1098790). Brett Manley is the recipient of an NHMRC Early

Career Fellowship (1088279).

Trial registration


ACTRN12614001203640.

DISCUSSION

Nasal HF therapy has been widely adopted in neonatal practice due to its desirable

qualities such as ease of use, reduced nasal trauma, and parental and nursing

preference.17-20

Recently, the HIPSTER trial demonstrated that in NICUs, rates of

treatment failure with nHF are higher than with CPAP in preterm infants born ≥28

weeks’ GA, although with ‘rescue’ CPAP available there is no difference in rates of

intubation.24

The HIPSTER results suggest that CPAP should be favoured over nHF if

only one treatment is available, however these findings cannot be directly applied to

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environments other than the NICU. The other recently published trial of primary nHF

was also performed in a NICU, and included a high rate of surfactant administration

by the INSURE technique, an intervention which is not currently practiced routinely

in Australian SCNs, and that has not been well-studied in the SCN setting or in the

infant population relevant to SCNs (infants ≥31 weeks’ GA).28

There has traditionally been a lack of clinical research in newborn infants cared for in

non-tertiary SCNs, and only one previous RCT of respiratory support in this setting.6

Research in SCNs is important, because care of infants in these units incorporates a

number of factors distinct from tertiary NICUs. Non-tertiary SCNs do not care for

large numbers of very preterm or very low birth weight infants, and often need to treat

term infants with respiratory distress. The resources and staffing available in non-

tertiary SCNs are different from those in NICUs, and whilst capable of intubation and

mechanical ventilation as a stabilisation measure, SCNs are not equipped to provide

this level of treatment for longer periods. The implications for failure of non-invasive

support are therefore greater in SCNs: transfer of the infant to a NICU, and separation

from his or her parents. Furthermore, there are potentially important financial

implications of treatment failure: retrieval by specialist neonatal transport services,

particularly when over long distances, as would apply in many areas of Australia, bear

a significant cost. Transfers from SCNs also have an impact on staffing and resource

allocation in receiving tertiary NICUs.

There has never been a randomised trial of nHF in non-tertiary SCNs. Nasal HF may

be an effective mode of support in this setting, and, due to its ease of use, would be

preferable to CPAP if shown to be non-inferior. However, it is equally important to

determine if nHF is unsafe or significantly inferior to CPAP, so that clinicians may be

guided to avoid nHF use in non-tertiary SCNs. If nHF use was associated with a

reduction in nursing workload, it may prove to be more economically cost-effective

than CPAP, or may result in a greater capacity to manage infants requiring non-

invasive support in SCNs. CPAP is associated with an increased risk of pneumothorax

in comparison with oxygen treatment.6 A Cochrane Review noted nHF treatment to

be associated with a small reduction in pneumothorax rate compared with CPAP.20

If

a lower rate of this complication was seen in our trial with nHF, in conjunction with

non-inferiority in treatment efficacy, nHF could be the preferred mode of treatment.

The HUNTER trial is a well-powered, carefully designed randomised clinical trial,

which will determine whether nHF is an appropriate mode of early respiratory support

for newborn infants in the non-tertiary setting. The non-inferiority design used in the

HUNTER trial was until recently quite rare, but has been used recently in similar

trials by our group.24,31

The choice of non-inferiority margin of 10% was made in

view of the fact that the primary outcome was treatment failure and not a more critical

outcome, such as death, and that infants who have treatment failure on nHF will be

offered CPAP, which may ‘rescue’ them from intubation and/or transfer to a NICU,

as seen in previous NICU trials of nHF.24,31,32

A potential limitation to this trial is that blinding of treatment allocation is not

possible. We have attempted to minimise this by setting objective treatment failure

criteria, which were agreed upon by all participating centres. Some infants allocated

to nHF will receive a brief period of CPAP before randomisation, which conceivably

could affect interpretation of the results. However, we have aimed to restrict the

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impact of this by excluding infants who have received two or more hours of CPAP

from the trial, which we felt to be the shortest window in which seeking parental

consent would be feasible. The HUNTER trial is a pragmatic trial, designed to assess

whether nHF is non-inferior to CPAP in real-world practice. We have not mandated

the need or timing of investigations such as chest x-rays or blood gas analysis, nor

have we protocolised the decision to treat infants with non-invasive support, which

remains at clinician discretion. We acknowledge that some randomised infants may

have recovered from respiratory distress without the use of non-invasive support, or

may have an unrecognised pneumothorax if randomised prior to a chest x-ray being

performed.

The use of nHF in NICU practice is well established, and supported by evidence from

multiple RCTs. However, nHF use is also being adopted in non-tertiary SCNs,9,13-15

a

setting in which there is little evidence of its efficacy and safety. If this trial

demonstrates that nHF is non-inferior to CPAP as primary support for newborn

infants in non-tertiary SCNs, then many units worldwide are likely to incorporate nHF

into their routine practice. However, if nHF is inferior to CPAP, the results of this

study will ensure that this treatment is not applied inappropriately, and infants in non-

tertiary SCNs with respiratory distress will continue to receive evidence-based care.

REFERENCES

1. Blencowe H, Cousens S, Oestergaard MZ, et al. National, regional, and

worldwide estimates of preterm birth rates in the year 2010 with time trends

since 1990 for selected countries: a systematic analysis and implications. Lancet

2012;379(9832):2162-72.

2. Australian Institute of Health and Welfare 2016. Australia’s mothers and

babies 2014—in brief. Perinatal statistics series no. 32. Cat no. PER 87. Canberra:

AIHW; 2016.

3. Buckmaster A, Arnolda G, Wright I, et al. Targeted oxygen therapy in

special care nurseries: is uniformity a good thing? J Paediatr Child Health

2012;48(6):476-82.

4. Dunn MS, Kaempf J, de Klerk A, et al. Randomized trial comparing 3

approaches to the initial respiratory management of preterm neonates.

Pediatrics 2011;128(5):e1069-76.

5. Morley CJ, Davis PG, Doyle LW, et al. Nasal CPAP or intubation at birth for

very preterm infants. The New England journal of medicine 2008;358(7):700-8.

6. Buckmaster AG, Arnolda G, Wright IM, et al. Continuous positive airway

pressure therapy for infants with respiratory distress in non tertiary care

centers: a randomized, controlled trial. Pediatrics 2007;120(3):509-18.

7. Ho JJ, Subramaniam P, Davis PG. Continuous distending pressure for

respiratory distress in preterm infants. Cochrane Database Syst Rev

2015;7):CD002271.

8. Roberts CL, Badgery-Parker T, Algert CS, et al. Trends in use of neonatal

CPAP: a population-based study. BMC pediatrics 2011;11(89.

9. Manley BJ, Owen L, Doyle LW, et al. High-flow nasal cannulae and nasal

continuous positive airway pressure use in non-tertiary special care nurseries in

Australia and New Zealand. Journal of paediatrics and child health

2012;48(1):16-21.

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10. Robertson NJ, McCarthy LS, Hamilton PA, et al. Nasal deformities resulting

from flow driver continuous positive airway pressure. Archives of disease in

childhood Fetal and neonatal edition 1996;75(3):F209-12.

11. Hochwald O, Osiovich H. The use of high flow nasal cannulae in neonatal

intensive care units: Is clinical practice consistent with the evidence? . Journal of

Neonatal-Perinatal Medicine 2010;3 (3):187-91.

12. Hough JL, Shearman AD, Jardine LA, et al. Humidified high flow nasal

cannulae: current practice in Australasian nurseries, a survey. J Paediatr Child

Health 2012;48(2):106-13.

13. Roberts CT, Owen LS, Manley BJ, et al. High-flow support in very preterm

infants in Australia and New Zealand. Arch Dis Child Fetal Neonatal Ed

2016;101(5):F401-3.

14. Ojha S, Gridley E, Dorling J. Use of heated humidified high-flow nasal

cannula oxygen in neonates: a UK wide survey. Acta Paediatr 2013;102(3):249-

53.

15. Shetty S, Sundaresan A, Hunt K, et al. Changes in the use of humidified

high flow nasal cannula oxygen. Arch Dis Child Fetal Neonatal Ed

2016;101(4):F371-2.


respiratory support in preterm infants. Cochrane Database Syst Rev

2011;5):CD006405.

17. Klingenberg C, Pettersen M, Hansen EA, et al. Patient comfort during

treatment with heated humidified high flow nasal cannulae versus nasal

continuous positive airway pressure: a randomised cross-over trial. Arch Dis

Child Fetal Neonatal Ed 2014;99(2):F134-7.

18. Osman M, Elsharkawy A, Abdel-Hady H. Assessment of pain during

application of nasal-continuous positive airway pressure and heated, humidified

high-flow nasal cannulae in preterm infants. J Perinatol 2015;35(4):263-7.

19. Roberts CT, Manley BJ, Dawson JA, et al. Nursing perceptions of high-flow

nasal cannulae treatment for very preterm infants. Journal of paediatrics and

child health 2014;50(10):806-10.


respiratory support in preterm infants. Cochrane Database Syst Rev

2016;2(CD006405.

21. Yoder BA, Stoddard RA, Li M, et al. Heated, humidified high-flow nasal

cannula versus nasal CPAP for respiratory support in neonates. Pediatrics

2013;131(5):e1482-90.

22. Iranpour R, Sadeghnia A, Hesaraki M. High-flow nasal cannula versus

nasal continuous positive airway pressure in the management of respiratory

distress syndrome. J Isfahan Med School 2011;29(761-71.

23. Kugelman A, Riskin A, Said W, et al. A randomized pilot study comparing

heated humidified high-flow nasal cannulae with NIPPV for RDS. Pediatr

Pulmonol 2015;50(6):576-83.


Primary Respiratory Support in Preterm Infants. The New England journal of

medicine 2016;375(12):1142-51.

25. Lavizzari A, Colnaghi M, Ciuffini F, et al. Heated, Humidified High-Flow

Nasal Cannula vs Nasal Continuous Positive Airway Pressure for Respiratory

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Distress Syndrome of Prematurity: A Randomized Clinical Noninferiority Trial.

JAMA Pediatr 2016; 10.1001/jamapediatrics.2016.1243

26. Miles MS, Funk SG, Carlson J. Parental Stressor Scale: neonatal intensive

care unit. Nursing research 1993;42(3):148-52.

27. Fagerstrom L, Rainio AK, Rauhala A, et al. Validation of a new method for

patient classification, the Oulu Patient Classification. J Adv Nurs 2000;31(2):481-

90.

28. Isayama T, Chai-Adisaksopha C, McDonald SD. Noninvasive Ventilation

With vs Without Early Surfactant to Prevent Chronic Lung Disease in Preterm

Infants: A Systematic Review and Meta-analysis. JAMA Pediatr 2015;169(8):731-

9.


Primary Respiratory Support in Preterm Infants. N Engl J Med

2016;375(12):1142-51.

30. Piaggio G, Elbourne DR, Pocock SJ, et al. Reporting of noninferiority and

equivalence randomized trials: extension of the CONSORT 2010 statement.

JAMA: the journal of the American Medical Association 2012;308(24):2594-604.

31. Manley BJ, Owen LS, Doyle LW, et al. High-Flow Nasal Cannulae in Very

Preterm Infants after Extubation. The New England journal of medicine

2013;369(15):1425-33.

32. Collins CL, Holberton JR, Barfield C, et al. A randomized controlled trial to

compare heated humidified high-flow nasal cannulae with nasal continuous

positive airway pressure postextubation in premature infants. J Pediatr

2013;162(5):949-54 e1.

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FIGURE LEGEND

FIGURE. Schedule of enrolment, interventions, and assessments: The HUNTER

Trial.

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FIGURE. Schedule of enrolment, interventions, and assessments: The HUNTER Trial.

255x205mm (96 x 96 DPI)

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SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*

Section/item Item No

Description Addressed on page number

Administrative information

Title 1 Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym ___________1

Trial registration 2a Trial identifier and registry name. If not yet registered, name of intended registry ___________3

2b All items from the World Health Organization Trial Registration Data Set __ Throughout

Protocol version 3 Date and version identifier __________13

Funding 4 Sources and types of financial, material, and other support ___________3

Roles and responsibilities

5a Names, affiliations, and roles of protocol contributors ___________2

5b Name and contact information for the trial sponsor ___________2

5c Role of study sponsor and funders, if any, in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication, including whether they will have ultimate authority over any of these activities

___________3

5d Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint adjudication committee, data management team, and other individuals or groups overseeing the trial, if applicable (see Item 21a for data monitoring committee)

___________1

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Introduction

Background and rationale

6a Description of research question and justification for undertaking the trial, including summary of relevant studies (published and unpublished) examining benefits and harms for each intervention

__________4-6

6b Explanation for choice of comparators __________4-6

Objectives 7 Specific objectives or hypotheses ___________7

Trial design 8 Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group), allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory)

__________6-7

Methods: Participants, interventions, and outcomes

Study setting 9 Description of study settings (eg, community clinic, academic hospital) and list of countries where data will be collected. Reference to where list of study sites can be obtained

___________8

Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and individuals who will perform the interventions (eg, surgeons, psychotherapists)

_________8-9

Interventions 11a Interventions for each group with sufficient detail to allow replication, including how and when they will be administered

_________ 9-10

11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose change in response to harms, participant request, or improving/worsening disease)

_________9-10

11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence (eg, drug tablet return, laboratory tests)

__________N/A

11d Relevant concomitant care and interventions that are permitted or prohibited during the trial __________9-10

Outcomes 12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg, median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen efficacy and harm outcomes is strongly recommended

__________7-8

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Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for participants. A schematic diagram is highly recommended (see Figure)

_____See Figure

Sample size 14 Estimated number of participants needed to achieve study objectives and how it was determined, including clinical and statistical assumptions supporting any sample size calculations

__________11

Recruitment 15 Strategies for achieving adequate participant enrolment to reach target sample size __________11

Methods: Assignment of interventions (for controlled trials)

Allocation:

Sequence generation

16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions

__________9

Allocation concealment mechanism

16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned

___________9

Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions

___________9

Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data analysts), and how

__________7

17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s allocated intervention during the trial

_________N/A__

Methods: Data collection, management, and analysis

Data collection methods

18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known. Reference to where data collection forms can be found, if not in the protocol

________7,12

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18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for participants who discontinue or deviate from intervention protocols

_________N/A__

Data management 19 Plans for data entry, coding, security, and storage, including any related processes to promote data quality (eg, double data entry; range checks for data values). Reference to where details of data management procedures can be found, if not in the protocol

_________12__

Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the statistical analysis plan can be found, if not in the protocol

_________11__

20b Methods for any additional analyses (eg, subgroup and adjusted analyses) _________11__

20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any statistical methods to handle missing data (eg, multiple imputation)

_________11__

Methods: Monitoring

Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is independent from the sponsor and competing interests; and reference to where further details about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed

________12-13__

21b Description of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial

________12-13__

Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse events and other unintended effects of trial interventions or trial conduct

________12-13__

Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent from investigators and the sponsor

_______12-13___



24 Plans for seeking research ethics committee/institutional review board (REC/IRB) approval ________12___

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Protocol amendments

25 Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes, analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals, regulators)

________N/A__

Consent or assent 26a Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and how (see Item 32)

_________12__

26b Additional consent provisions for collection and use of participant data and biological specimens in ancillary studies, if applicable

________N/A__

Confidentiality 27 How personal information about potential and enrolled participants will be collected, shared, and maintained in order to protect confidentiality before, during, and after the trial

_________12__

Declaration of interests

28 Financial and other competing interests for principal investigators for the overall trial and each study site _________2__

Access to data 29 Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that limit such access for investigators

________12___

Ancillary and post-trial care

30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial participation

________N/A__

Dissemination policy 31a Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals, the public, and other relevant groups (eg, via publication, reporting in results databases, or other data sharing arrangements), including any publication restrictions

_________13__

31b Authorship eligibility guidelines and any intended use of professional writers _________N/A__

31c Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code _________N/A_

Appendices

Informed consent materials

32 Model consent form and other related documentation given to participants and authorised surrogates __Not included_

Biological specimens

33 Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in the current trial and for future use in ancillary studies, if applicable

_________N/A__

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*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for important clarification on the items. Amendments to the protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the Creative Commons “Attribution-NonCommercial-NoDerivs 3.0 Unported” license.

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BMJ Open › content › bmjopen › 7 › 6 › e016746...For peer review only 4 Strengths and limitations of this study • This is the first study to compare nasal high-flow with