ANZCTR - Registration

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers

Trial registered on ANZCTR

Registration number

ACTRN12613000303741

Ethics application status

Approved

Date submitted

18/03/2013

Date registered

19/03/2013

Date last updated

2/03/2021

Date data sharing statement initially provided

2/03/2021

Date results information initially provided

2/03/2021

Type of registration

Prospectively registered

Titles & IDs

Public title

High Flow Nasal Cannulae as Primary Support in the Treatment of Early Respiratory Distress (The HIPSTER Trial)

Scientific title

A multi-centre, randomised, controlled, non-inferiority trial comparing high flow nasal cannulae to nasal continuous positive airway pressure as primary respiratory support, in preterm infants of 28 weeks' gestation and above, with early respiratory distress or apnoea, assessing assigned treatment failure within 72 hours.

Secondary ID [1]

nil

Universal Trial Number (UTN)

Trial acronym

The HIPSTER Trial

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Respiratory distress of the newborn

Condition category

Condition code

Respiratory

Other respiratory disorders / diseases

Reproductive Health and Childbirth

Complications of newborn

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

High flow nasal cannula (HFNC) therapy. Heated, humidified, blended gas (air/oxygen) will be delivered at a flow rate of 4-8 L/minute using either Fisher & Paykel or Vapotherm circuits and nasal prongs. HFNC prong size will be selected as per the manufacturer's recommendations (maintaining a leak at the nares) and there will be no alterations to the manufacturer's recommended set-up of the circuit.

1. Infants randomised to HFNC will commence on flow rates of 6-8 L/min.

2. HFNC limits will be 4-8 L/min from trial entry until discharge home.

3. The attending clinical team will increase/decrease flow rates at their discretion in whole number flow increments (e.g. 4, 5, 6, 7, 8 L/min) and these changes will require a documented medical order. Infants should be reviewed at least every 24 hours and weaning considered if they are clinically improving with FiO2 (fraction of inspired oxygen) <0.30.

4. The flow rate should not exceed 8 L/min in any infant.

5. Infants who are stable on HFNC at 4 L/min, with FiO2 <0.30, for more than 24 hours, may cease HFNC and be tried in air or on low flow nasal cannulae (cessation at this stage is not mandatory; earlier cessation will be at the discretion of the attending clinical team if FiO2 <0.30).

6. Infants who satisfy failure criteria whilst receiving HFNC at 8 L/min will cease HFNC and receive ‘rescue’ NCPAP initially at 7-8 cm H2O (physician discretion). These infants will be deemed to have treatment failure for the primary outcome. Infants who subsequently again satisfy the failure criteria on NCPAP of 8 cm H2O, still within the primary outcome period of 72 hours, will be intubated and mechanically ventilated.

7. Should the decision be taken to recommence non-invasive respiratory support later during their admission (including post-extubation), infants in the HFNC group should again initially receive HFNC, unless they previously experienced treatment failure with HFNC. They may subsequently receive NCPAP at the discretion of the attending clinical team.

Intervention code [1]

Treatment: Devices

Comparator / control treatment

Nasal continuous positive airway pressure (NCPAP). This is defined as the use of short binasal prongs to deliver humidified, blended gas (air/oxygen) with any NCPAP device (including ventilator-generated or ‘bubble’ NCPAP).

1. Infants randomised to NCPAP will commence on pressures of 6-8 cm H2O.

2. NCPAP pressure limits are 5-8 cm H2O during the primary outcome period. After this point set NCPAP pressures are at the discretion of the attending clinician.

3. Changes to NCPAP pressures will be made at the discretion of the attending clinical team, with a documented medical order for any change.

4. Infants randomised to NCPAP will not receive HFNC for 72 hours after trial entry. After this period, HFNC should still not be used unless an infant has moderate to severe nasal trauma, defined as at least three consecutive scores of 2, or any score of 3 or more, on the Trial Nasal Trauma Chart.

5. The attending clinical team will increase or decrease NCPAP pressures at their discretion in whole number increments (e.g. 5, 6, 7, 8 cm H2O), and these changes will require a documented medical order. Infants should be reviewed at least every 24 hours and weaning considered if they are clinically improving with FiO2 <0.30

6. Infants who are stable on NCPAP at 5 cm H2O, with FiO2 <0.30, for more than 24 hours, may cease NCPAP and be tried in air or on low flow nasal cannulae (cessation at this stage is not mandatory; earlier cessation will be at the discretion of the attending clinical team if FiO2 <0.30).

7. Infants who satisfy failure criteria whilst receiving NCPAP 8 cm H2O will be intubated and mechanically ventilated. These infants will be deemed to have treatment failure for the primary outcome.

8. Should the decision be taken to recommence non-invasive respiratory support later during the admission (including post-extubation), infants in the NCPAP group should again receive NCPAP, unless they have already suffered moderate to severe nasal trauma from NCPAP as described above.

Control group

Active

Outcomes

Primary outcome [1]

The primary outcome is treatment failure within 72 hours after initiation of the assigned treatment. To fail the assigned treatment, the infant must be receiving maximal therapy (NCPAP 8 cm H2O or HFNC 8 L/min), plus at least one of:

- Sustained fraction of inspired oxygen (FiO2) requirement 0.40 or more to maintain peripheral oxygen saturation (SpO2) within the specified normal limits of the participating centre
- pH 7.20 or lower and pCO2 >60 mm Hg on free-flowing capillary or arterial blood gas sample, taken at least 1 hour after initiation of assigned treatment
- Six or more apnoeas requiring intervention (not self-resolving) within any 6-hour period, or 2 or more apnoeas requiring positive pressure ventilation within any 24-hour period

Treatment failure will also be adjudged to have occurred in any infant requiring urgent intubation and mechanical ventilation (at medical discretion)

Timepoint [1]

72 hours after initiation of allocated treatment.

Secondary outcome [1]

Treatment failure in the pre-defined gestational age subgroups (less than 32 weeks, and 32 weeks and above)

Timepoint [1]

72 hours after intitiation of allocated treatment

Secondary outcome [2]

Reason for commencing non-invasive respiratory support, which may include one or more of:
- Clinical signs of respiratory distress (tachypnea >60 breaths/minute, audible grunting, intercostal/subcostal recession)
- Oxygen requirement
- Respiratory acidosis on blood gas sampling
- Apnoea

Timepoint [2]

At initiation of allocated treatment

Secondary outcome [3]

Reason(s) for treatment failure if applicable (number of infants who failed for each defined criteria)

Timepoint [3]

72 hours after initiation of allocated treatment

Secondary outcome [4]

Incidence of intubation and mechanical ventilation within the 72 hour primary outcome period, and at any time during the hospital admission; overall and within GA subgroups

Timepoint [4]

At discharge from hospital

Secondary outcome [5]

Incidence of bronchopulmonary dysplasia (BPD), defined as a supplemental oxygen requirement and/or receiving respiratory support at 36 weeks’ post-menstrual age (PMA)

Timepoint [5]

At 36 weeks' post-menstrual age

Secondary outcome [6]

Incidence of pneumothorax or other air leak (e.g. pneumomediastinum, pulmonary interstitial emphysema) while receiving the assigned treatment, and at any point from trial entry until hospital discharge

Timepoint [6]

At hospital discharge

Secondary outcome [7]

Total number of days of any respiratory support, and total number of days of each type of respiratory support (including HFNC, NCPAP, non-synchronised nasal intermittent positive pressure ventilation [nsNIPPV] and mechanical ventilation via an endotracheal tube) received after trial entry until discharge from hospital, with one day defined as a calendar day where a treatment was received for any time period (thus some days may be counted for more than one type of support)

Timepoint [7]

At hospital discharge

Secondary outcome [8]

Last day of supplemental oxygen received, recorded as day of life and also as PMA at final cessation of oxygen

Timepoint [8]

At hospital discharge

Secondary outcome [9]

Number of infants discharged home with oxygen

Timepoint [9]

At hospital discharge

Secondary outcome [10]

Number of infants treated with postnatal corticosteroids for lung disease

Timepoint [10]

At hospital discharge

Secondary outcome [11]

Incidence of significant neonatal morbidities after trial entry until discharge from hospital:
Confirmed sepsis, including
- Septicaemia, defined as any positive blood culture and treatment with IV antibiotics for at least 48 hours
- Meningitis, defined as growth of a single organism from cerebrospinal fluid (CSF) and/or a raised CSF white cell count
(Note that during a single illness episode, an infant may satisfy criteria for more than one of the above)
Patent ductus arteriosus treated with medication and/or surgery
Necrotising enterocolitis (NEC) Bell’s stage 2 or above
Isolated intestinal perforation (not associated with NEC)
Incidence of the following diagnoses on any cranial ultrasound
- Intraventricular haemorrhage grade III or IV
- Cystic periventricular leukomalacia
- Post-haemorrhagic ventricular dilatation and whether it required intervention
Retinopathy of prematurity requiring laser eye surgery in one or both eyes

Timepoint [11]

At hospital discharge

Secondary outcome [12]

Duration of caffeine therapy in days, and PMA at cessation

Timepoint [12]

At hospital discharge

Secondary outcome [13]

Number of days to reach full feeds, defined as tolerating at least 120 ml/kg/day of milk, or demand suck feeding (breast or bottle) with no intravenous fluids.

Timepoint [13]

At hospital discharge

Secondary outcome [14]

Number of days to reach full suck feeds, defined as the first day on which no intravenous fluids or nasogastric/orogastric feeds are given

Timepoint [14]

At hospital discharge

Secondary outcome [15]

Proportion of infants fully breast-fed at discharge home from hospital

Timepoint [15]

At hospital discharge

Secondary outcome [16]

Weight gain, calculated as:
Last weight (g) before discharge home from hospital minus birth weight (g), giving a weight gain in g/day from birth to discharge

Timepoint [16]

At hospital discharge

Secondary outcome [17]

Incidence of nasal trauma stage 2 or above as recorded on the Trial Nasal Trauma Chart, the type of respiratory support the infant was receiving at the time of the first such recorded trauma, and whether a change to the type of respiratory support was required (The same scoring system will be used in all participating centres)

Timepoint [17]

At hospital discharge

Secondary outcome [18]

Duration of hospital admission, including
- Days in any level III (tertiary) hospital, and
- Total number of days in any hospital

Timepoint [18]

At hospital discharge

Secondary outcome [19]

Incidence of transfer to another hospital prior to first discharge home

Timepoint [19]

At hospital discharge

Secondary outcome [20]

Proportion of infants who die before discharge

Timepoint [20]

At hospital discharge

Eligibility

Key inclusion criteria

1. Preterm infants of at least 28 weeks and <37 weeks’ GA at birth by best obstetric estimate
2. Age <24 hours
3. Admitted to the neonatal intensive care unit (NICU) of a participating centre, whether inborn or outborn
4. Prospective parental consent obtained
5. Decision has been made, at or after admission to the NICU, by the attending clinician, to commence or continue non-invasive respiratory support (some infants may have received a brief period of NCPAP prior to admission to the NICU, as part of their standard care during resuscitation/stabilisation at delivery and/or during transfer from the birth centre or theatre)
6. At randomisation, infant has received <4 hours NCPAP support
7. Full intensive care is being offered

Minimum age

No limit

Maximum age

24 Hours

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1. GA <28 weeks, or 37 weeks and above, at birth
2. Previous intubation and mechanical ventilation, or immediate need for intubation and mechanical ventilation, as determined by the attending clinician
3. Any infant who is receiving NCPAP 8 cm H2O and already satisfying the treatment failure criteria, as specified above
4. Any infant who has received 4 hours or more of NCPAP support
5. Participation in a concurrent study that prohibits inclusion in this trial
6. Known major upper airway, lower respiratory tract, cardiac or gastrointestinal tract anomaly
7. Known air leak syndrome

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

There will be pre-randomisation stratification by gestational age (<32 weeks’, and 32 weeks’ gestation and above) and by centre. Multiple births will be randomised individually. The trial statistician will provide sets of consecutively numbered, sealed opaque envelopes containing the assigned treatment, using varying block sizes. The envelope will be opened either prior to the infant arriving on the neonatal unit if he/she is already receiving non-invasive support, or immediately after the a decision has been made to commence or continue non-invasive support in an infant already admitted to the unit.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

The randomisation will be in randomly permuted blocks of variable length, stratified by study centre, and by gestational age.

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

Phase

Not Applicable

Type of endpoint/s

Efficacy

Statistical methods / analysis

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

27/05/2013

Actual

27/05/2013

Date of last participant enrolment

Anticipated

Actual

16/06/2015

Date of last data collection

Anticipated

Actual

31/12/2015

Sample size

Target

750

Accrual to date

Final

564

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

The Royal Women's Hospital - Parkville

Recruitment hospital [2]

Royal Brisbane & Womens Hospital - Herston

Recruitment hospital [3]

Mercy Hospital for Women - Heidelberg

Recruitment hospital [4]

Monash Medical Centre - Clayton campus - Clayton

Recruitment postcode(s) [1]

3052 - Parkville

Recruitment postcode(s) [2]

4006 - Herston

Recruitment postcode(s) [3]

3084 - Heidelberg

Recruitment postcode(s) [4]

3168 - Clayton

Recruitment outside Australia

Country [1]

Norway

State/province [1]

East Norway, North Norway

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council

Address [1]

National Health and Medical Research Council
16 Marcus Clarke Street
Canberra
ACT 2601

Country [1]

Australia

Funding source category [2]

Hospital

Name [2]

The Royal Women's Hospital

Address [2]

The Royal Women's Hospital
Cnr Grattan Street & Flemington Road
Parkville
Victoria 3052

Country [2]

Australia

Primary sponsor type

Individual

Name

Professor Peter Davis

Address

The Royal Women's Hospital
Cnr Grattan Street & Flemington Road
Parkville
Victoria 3052

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

The Royal Women's Hospital Human Research Ethics Committee

Ethics committee address [1]

The Royal Women's Hospital
Cnr Grattan Street & Flemington Road
Parkville
Victoria 3052

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

06/03/2013

Approval date [1]

16/05/2013

Ethics approval number [1]

EC00259

Ethics committee name [2]

The Royal Children's Hospital Human Research Ethics Committee

Ethics committee address [2]

The Royal Children's Hospital
50 Flemington Road
Parkville
VIC 3052

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

05/08/2013

Approval date [2]

22/08/2013

Ethics approval number [2]

EC00238

Ethics committee name [3]

Mercy Hospital for Women Human Research Ethics Committee

Ethics committee address [3]

163 Studley Rd, Heidelberg VIC 3084, Australia

Ethics committee country [3]

Australia

Date submitted for ethics approval [3]

Approval date [3]

27/11/2013

Ethics approval number [3]

R13/34

Ethics committee name [4]

South-Eastern Norway Regional Health Authority Research Ethics Committee

Ethics committee address [4]

Gullhaugveien 1-3, 0484 Oslo

Ethics committee country [4]

Norway

Date submitted for ethics approval [4]

Approval date [4]

01/01/2014

Ethics approval number [4]

2013/1657

Summary

Brief summary

Every year, thousands of babies are born early (premature). Many premature babies need help to breathe for several days after birth, and sometimes for much longer. The most commonly used way of supporting the breathing of premature infants is with a technique called nasal continuous positive airway pressure (NCPAP). NCPAP uses large prongs snugly fitted into the baby’s nostrils, kept in place by a tight-fitting hat. The prongs supply air or oxygen under pressure to help keep the baby’s lungs open, making it easier to breathe. NCPAP is a well-tried and tested method of breathing support, but has some disadvantages: the hat and tubing can be quite bulky and cover most of the baby’s face, and the large prongs can rub on the baby’s nose and sometimes cause damage to the skin.

A newer form of breathing support being used around the world, and in Australia, is called high flow nasal cannulae (HFNC). This method uses smaller prongs in the baby’s nose and does not require a hat to hold the prongs in place. Like NCPAP, HFNC also supplies air or oxygen under pressure to help support the baby’s breathing. Because the prongs are smaller and less bulky, HFNC may be more comfortable for babies than NCPAP, and it is easier to see the baby’s face. For these reasons, HFNC has become very popular as treatment for premature babies, and is being used around the world. However, HFNC has not been widely studied as a way of supporting breathing for babies soon after birth.

The HIPSTER trial will compare the use of these two types of breathing support as treatment for premature babies who have breathing difficulties soon after they have been born. Premature babies born after 28 weeks’ and before 37 weeks’ gestation, who need breathing support in the first 24 hours of life, will be able to join this study. Babies who join the study will be chosen at random to receive either NCPAP or HFNC. The study will include a total of 612 babies, 306 will be treated with each type of breathing support. The main thing we are interested in is whether babies are successfully treated with the type of breathing support they are given. Babies who are given HFNC and are not improving can be switched over to have NCPAP, to see whether that helps. Information will be collected about the babies, such as how long the babies in each group need to carry on with breathing support, whether they need extra breathing help, whether they get any damage to their nose from the prongs, and how well they feed and grow. Basic information will also be collected about the mothers of the babies and the pregnancy.

Trial website

Trial related presentations / publications

Roberts CT, Owen LS, Manley BJ, et al. A multicentre, randomised controlled, non-inferiority trial, comparing high flow therapy with nasal continuous positive airway pressure as primary support for preterm infants with respiratory distress (the HIPSTER trial): study protocol. BMJ Open. 2015;5:e008483 doi: 10.1136/bmjopen-2015-008483 [published Online].

Roberts CT, Owen LS, Manley BJ, Frøisland DH, Donath SM, Dalziel KM, Pritchard MA, Cartwright DW, Collins CL, Malhotra A, Davis PG; HIPSTER Trial Investigators. Nasal High-Flow Therapy for Primary Respiratory Support in Preterm Infants.N Engl J Med. 2016 Sep 22;375(12):1142-51.

Public notes

Contacts

Principal investigator

Name

Dr Calum Roberts

Address

Department of Newborn Research
Level 7
The Royal Women's Hospital
Cnr Grattan Street & Flemington Road
Parkville
Victoria 3052

Country

Australia

Phone

+61383453770

Fax

+61383453789

[email protected]

Contact person for public queries

Name

Dr Calum Roberts

Address

Department of Newborn Research
Level 7
The Royal Women's Hospital
Cnr Grattan Street & Flemington Road
Parkville
Victoria 3052

Country

Australia

Phone

+61383453770

Fax

+61383453789

[email protected]

Contact person for scientific queries

Name

Dr Calum Roberts

Address

Department of Newborn Research
Level 7
The Royal Women's Hospital
Cnr Grattan Street & Flemington Road
Parkville
Victoria 3052

Country

Australia

Phone

+61383453770

Fax

+61383453789

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

Type	Is Peer Reviewed?	DOI	Citations or Other Details	Attachment
Study results article	Yes		Roberts, C. T., et al. (2016). "Nasal High-Flow Th... [More Details]

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Cost-Effectiveness Analysis of Nasal Continuous Positive Airway Pressure Versus Nasal High Flow Therapy as Primary Support for Infants Born Preterm.	2018	https://dx.doi.org/10.1016/j.jpeds.2017.12.072
Embase	Refining the Use of Nasal High-Flow Therapy as Primary Respiratory Support for Preterm Infants.	2018	https://dx.doi.org/10.1016/j.jpeds.2018.01.031
Embase	High-flow nasal cannulae as primary respiratory support for preterm infants-an international, multi-centre, randomised, controlled, non-inferiority trial.	2016	https://dx.doi.org/10.1111/jpc.13194
Embase	Nasal high flowas primary respiratory support for preterm infants.	2016	https://dx.doi.org/10.1007/s00431-016-2785-8
Embase	Nasal high-flow therapy for primary respiratory support in preterm infants.	2016	https://dx.doi.org/10.1056/NEJMoa1603694
Embase	A multicentre, randomised controlled, non-inferiority trial, comparing High flow therapy with nasal continuous positive airway pressure as primary support for preterm infants with respiratory distress (the HIPSTER trial): Study protocol.	2015	https://dx.doi.org/10.1136/bmjopen-2015-008483
Embase	Predictors and Outcomes of Early Intubation in Infants Born at 28-36 Weeks of Gestation Receiving Noninvasive Respiratory Support.	2020	https://dx.doi.org/10.1016/j.jpeds.2019.09.026

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically