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Trial registered on ANZCTR


Registration number
ACTRN12615000077561
Ethics application status
Approved
Date submitted
17/11/2014
Date registered
29/01/2015
Date last updated
8/01/2019
Date data sharing statement initially provided
8/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Weaning preterm infants with a gestational age (GA) of <30 weeks from respiratory support: a comparison of duration of respiratory support with heated humidified high flow nasal cannula (HHHFNC) and continuous positive airway pressure (CPAP).
Scientific title
Duration of respiratory support in preterm infants with a gestational age (GA) of <30 weeks weaned from continuous positive airway pressure (CPAP): a randomized controlled trial comparing heated humidified high flow nasal cannula (HHHFNC) and CPAP.
Secondary ID [1] 283347 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
CHiPS Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Respiratory distress of the newborn 290239 0
Condition category
Condition code
Respiratory 290631 290631 0 0
Other respiratory disorders / diseases
Reproductive Health and Childbirth 290633 290633 0 0
Complications of newborn

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Heated Humidified High Flow Nasal Cannula (HHHFNC) therapy. HHHFNC will be delivered at a flow rate of 2L-6L/min, of blended gas/oxygen, using Fisher & Paykel circuits and nasal prongs. HHHFNC prong size to be selected as per the manufacturer's recommendations, with no alterations to be made to the manufacturer's recommended circuit set-up.

1. Infants randomised to HHHFNC will commence on a flow rate of 6L/min.

2. The attending Senior Medical Officer (SMO) will decrease/increase flow rates at their discretion. These changes will require a documented medical order. Infants will be reviewed at least 24 hourly and flow rates decreased to a minimum flow rate of 2L/min. If SMO deems necessary to increase flow rates, these will not exceed 8L/min in any infant.

3. Infants who are stable on 2L/min, with Fi02 <30% for 24 hours, may cease HHHFNC and be tried in air or on low flow nasal cannula. Trial off HHHFNC is at the discretion of the SMO, and is not mandatory at this time.

4. Infants who satisfy failure criteria whilst receiving HHHFNC at 6L/min will have their flow increased to 8L/min HHHFNC. If continue to meet failure criteria at this time, will be placed on 'rescue' nCPAP at 8cmH20. When these infants once again reach the study inclusion criteria they will be placed back on the HHHFNC arm of the trial.

5. Endpoint of the study will occur at 36 weeks gestational age.
Intervention code [1] 288068 0
Treatment: Devices
Comparator / control treatment
Nasal Continuous Positive Airway Pressure (nCPAP). nCPAP will be delivered at a pressure of 6cmH20 humidified blended gas/oxygen, using Fisher & Paykel binasal bubble circuits.

1. Infants randomised to nCPAP will commence on a pressure of 6cmH20.

2. The attending Senior Medical Officer (SMO) will decrease/increase nCPAP pressure at their discretion. These changes will require a documented medical order. Infants will be reviewed at least 24 hourly and pressures decreased to a minimum pressure of 5cmH20. If SMO deems necessary to increase nCPAP pressure, these will not exceed 6cmH20 in any infant.

3.Infants who are stable on 5cmH20, with Fi02 <30% for 48 hours, may cease nCPAP and be tried off respiratory support or on low flow nasal cannula. Trial off nCPAP is at the discretion of the SMO, and is not mandatory at this time.

4. Infants who satisfy failure criteria whilst receiving nCPAP at 6cmH20 will have their pressure increased to 8cmH20. When these infants once again reach the study inclusion criteria they will be placed back on the nCPAP arm of the trial.

5. Endpoint of the study will occur at 36 weeks gestational age.
Control group
Active

Outcomes
Primary outcome [1] 290645 0
The primary outcome is duration (in hours) of respiratory support from randomisation to achieving at least 72 hours free of respiratory support.

Timepoint [1] 290645 0
36 weeks gestational age.
Secondary outcome [1] 304970 0
Days to introduction of oral feeds and achievement of full oral feeds. Once nCPAP is discontinued, the CGA is 33-34 weeks and infants are showing feeding cues, oral feeding (bottle or breast) is commenced. For infants on HHHFNC, oral feeding can be initiated without interrupting respiratory support. Days to reach full feed volumes, commence suck feeds and achieve full suck feeds (8 consecutive suck feeds with no top-up's) will be recorded.
Timepoint [1] 304970 0
At discharge from hospital.
Secondary outcome [2] 304971 0
Growth (weight gain, length, and head circumference).
Timepoint [2] 304971 0
From birth to discharge from hospital.
Secondary outcome [3] 304972 0
Nursing acuity [using modified Winnipeg Assessment of Neonatal Nursing Needs Tool (WANNNT)]
Timepoint [3] 304972 0
36 weeks gestational age.
Secondary outcome [4] 304973 0
Nasal Trauma. Defined as erythema or erosion of nasal mucosa, nares or septum.
Timepoint [4] 304973 0
36 weeks gestational age.
Secondary outcome [5] 304974 0
Parental satisfaction. As assessed by parental satisfaction survey.

Parents will be given a validated survey for measuring neonatal intensive care unit-related parental stress to be completed after one week on the weaning protocol and again at 36 weeks corrected gestational age.
Timepoint [5] 304974 0
After one week on weaning protocol and again at 36 weeks corrected gestational age.
Secondary outcome [6] 304975 0
Incidence of significant neonatal morbidities after trial entry until discharge from hospital.
- necrotising enterocolitis (Bells stage IIA or above)
- chronic lung disease
- late onset sepsis
- retinopathy of prematurity
- intraventricular haemorrhage
Timepoint [6] 304975 0
At discharge from hospital.
Secondary outcome [7] 304976 0
Length of hospitalisation.
Timepoint [7] 304976 0
From birth to discharge from hospital.
Secondary outcome [8] 304977 0
Overall cost of stay

All healthcare resource usage (including NICU, nursing acuity, lab tests, and other ward stays) from randomisation to discharge will be microcosted. Bootstrap simulations and cost-effectiveness acceptability curves will assess the probability that HHHFNC is cost-effective (compared with nCPAP) for a range of willingness-to-pay values for each endpoint.
Timepoint [8] 304977 0
From randomisation to discharge from hospital.

Eligibility
Key inclusion criteria
Preterm infants born at <30 weeks gestational age are eligible. At study entry infants should have at least 48 hours with nCPAP pressure 6cm water, without an oxygen requirement, with a respiratory rate of <60bpm and without significant desaturation or bradycardia events (defined as spontaneous events with oxygen saturation levels <80%, heart rate <100bpm and requiring nursing staff intervention). Infants will be commenced onto the weaning protocol at the discretion of the Neonatologist.
Minimum age
49 Hours
Maximum age
3 Months
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Preterm infants off respiratory support for greater than 7 days.
2. Infants with significant congenital heart disease, surgical conditions, chromosomal abnormalities, genetic syndromes or other major congenital malformations.

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)
A set of consecutively numbered, sealed, opaque envelopes containing the assigned treatment will be placed in the research office in the neonatal intensive care unit. The envelope will be opened once consent has been obtained for registration onto the trial.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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
A per-protocol (PP) analysis will be used for the primary outcome and intention-to-treat (ITT) for the secondary outcomes. These are the standard conservative approaches for non-inferiority and superiority hypothesis, respectively. The primary outcome will be modelled with a generalised linear model (GLM) and GA at birth as a covariate. The specific model and any transformation is expected to be normal but will be established during the blind review. A model for heteroscedasticity will be used if required; pilot data (available from MMH NICU 2006–2012) suggest this is likely. Non-inferiority of the intervention will be tested with a one-sided hypothesis at the 5% significance level. Continuous secondary outcomes will be modelled using linear or generalised linear models accommodating for heteroscedasticity, if required after the blind review. Dichotomous secondary outcomes will be modelled using logistic regression. Two-sided superiority hypotheses will be tested at the 5% significance level.

Extensive simulations using the pilot data indicate that a total study size of 100 (50 per arm) will provide a 92% power to conclude in non-inferiority of primary outcome with a threshold of 15%, which is considered to be the maximum tolerable extra time to wean, based on the clinical judgment of the research team. Major protocol violations (PV) will be removed from the PP analysis set (but not the ITT set), used for the primary analysis. We estimate that no more than 20 PV will occur. No other attrition is expected due to the short follow-up. The target recruitment of 120 will be achieved within 3 years with probability 90%, based on the pilot data. The study will be sufficiently powered to test for superiority of secondary outcomes, which provide meaningful improvements in clinical practice. A study size of 120 is estimated to provide 90% power to detect a change of 7 days for the key secondary outcome, time to full suck feeds. Previous experience with other respiratory interventions at MMH NICU has been well accepted by parents with consent rates of around 90%.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 5460 0
New Zealand
State/province [1] 5460 0
Auckland

Funding & Sponsors
Funding source category [1] 288078 0
Hospital
Name [1] 288078 0
Middlemore Hospital
Address [1] 288078 0
Hospital Rd
Otahuhu
Auckland 1640
Country [1] 288078 0
New Zealand
Primary sponsor type
Hospital
Name
Middlemore Hospital
Address
Hospital Rd
Otahuhu
Auckland 1640
Country
New Zealand
Secondary sponsor category [1] 288889 0
None
Name [1] 288889 0
Address [1] 288889 0
Country [1] 288889 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291886 0
Health and Disability Ethics Committee
Ethics committee address [1] 291886 0
Ministry of Health
PO Box 5013
Wellington 6011
Ethics committee country [1] 291886 0
New Zealand
Date submitted for ethics approval [1] 291886 0
21/01/2015
Approval date [1] 291886 0
20/04/2015
Ethics approval number [1] 291886 0
15/NTA/42

Summary
Brief summary
Reduced duration of respiratory support for preterm infants is associated with fewer health issues and improved outcomes. Although nasal continuous positive airway pressure (nCPAP) is currently the most widely used non-invasive ventilation, heated humidified high-flow nasal cannula (HHHFNC) is now used as an alternative. However, there is limited evidence-based data to support its use as standard practice for weaning infants from nCPAP. In this study we will compare the duration of respiratory support needed by preterm infants when weaning from both nCPAP and HHHFNC, and determine the safety and efficacy of both therapies. We will also compare adverse events, nasal trauma (a common complication of nCPAP), feeding practices, nursing acuity, costs and parental satisfaction. The results of this study will be used to define a weaning strategy for preterm infants needing respiratory support and have the potential to change standard practice in neonatal units.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 43426 0
Miss Joanne Clements
Address 43426 0
Middlemore Hospital
Hospital Road
Otahuhu
Auckland 1640
Country 43426 0
New Zealand
Phone 43426 0
+64 212593279
Fax 43426 0
Email 43426 0
joanne.clements@middlemore.co.nz
Contact person for public queries
Name 43427 0
Miss Joanne Clements
Address 43427 0
Middlemore Hospital
Hospital Road
Otahuhu
Auckland 1640
Country 43427 0
New Zealand
Phone 43427 0
+64 212593279
Fax 43427 0
Email 43427 0
joanne.clements@middlemore.co.nz
Contact person for scientific queries
Name 43428 0
Dr Michael Meyer
Address 43428 0
Middlemore Hospital
Hospital Road
Otahuhu
Auckland 1640
Country 43428 0
New Zealand
Phone 43428 0
+64 9 2760000 extn 8872
Fax 43428 0
Email 43428 0
michael.meyer@middlemore.co.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Ethics consent process has only allowed for restricted viewing of individual participant data.
What supporting documents are/will be available?
Study protocol
Informed consent form
Ethical approval
Summary results
No Results