Please be advised that due to the high volume of submissions, the ANZCTR is currently experiencing delays in processing submissions from those outside of Australia and New Zealand. As the ANZCTR is funded by Australia and New Zealand, we must prioritise submissions from these countries first. International submissions should allow additional time for registration. Apologies for any inconvenience caused.

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
ACTRN12616001516471
Ethics application status
Approved
Date submitted
31/10/2016
Date registered
3/11/2016
Date last updated
19/12/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Nasal High-Frequency Oscillation to Improve Respiratory Stability of Preterm Infants: A Randomized Crossover Study
Scientific title
Nasal High-Frequency Oscillation to Improve Respiratory Stability of Preterm Infants: A Randomized Crossover Study
Secondary ID [1] 290364 0
None
Universal Trial Number (UTN)
Trial acronym
The Wiggle Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Desaturations and bradycardias related to apnoea of prematurity 300653 0
Condition category
Condition code
Reproductive Health and Childbirth 300502 300502 0 0
Childbirth and postnatal care
Respiratory 300503 300503 0 0
Other respiratory disorders / diseases
Cardiovascular 300630 300630 0 0
Other cardiovascular diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Non-invasive high-frequency oscillatory ventilation (nHFO) will be delivered using Hudson binasal prongs (Hudson Respiratory Care Inc, Temecula, California, USA) and a Draeger VN500 ventilator (Draeger Medical System, Luebeck, Germany). Babies will be in prone and 15 degrees head-up tilt position.

The first 30 minutes of nHFO treatment will be defined as washout period. The subsequent 2-hour period will be used for the primary outcome. After 2.5 hours of nHFO treatment, standard care ventilation (CPAP) will be recommenced. The researcher will stay on the bedside during the whole study time to record handling of the infant and other possible influencing factors.

Ventilator settings at the beginning of nHFO:
- Frequency: 8 Hz. Will not be changed during the 2-hour treatment period.
- Mean airway pressure: Previous set CPAP pressure. Will not be changed during the 2-hour treatment period.
- Amplitude: 20 cm H20. Will be adjusted to the smallest amplitude needed for visible chest wall vibration.
- Fraction of inspired oxygen (FiO2): Will be adjusted to maintan oxygen saturation of 91 - 95 percent

The duration of the washout period between treatments will be 30 minutes.
Intervention code [1] 296176 0
Treatment: Other
Intervention code [2] 296297 0
Treatment: Devices
Comparator / control treatment
Continuous positive airway pressure (CPAP) will be delivered using Hudson binasal prongs (Hudson Respiratory Care Inc, Temecula, California, USA) and a Draeger VN500 ventilator (Draeger Medical System, Luebeck, Germany). CPAP is the most widely used form of ‘non-invasive’ ventilation in very preterm infants and the current standard of care for the treatment of desaturations and bradycardias.

The first 30 minutes of CPAP treatment will be defined as washout period. The subsequent 2-hour period will be used for the primary outcome.

Ventilator settings at the beginning of CPAP:
- Positive end expiratory pressure: Previous set CPAP pressure. Will not be changed during the 2-hour treatment period.
- Fraction of inspired oxygen (FiO2): Will be adjusted to maintan oxygen saturation of 91 - 95 percent.
Control group
Active

Outcomes
Primary outcome [1] 299929 0
Difference in the total number of desaturations and bradycardias between CPAP and nHFO treatment during 120-minute recording periods for each therapy.
Timepoint [1] 299929 0
120 minutes of nHFO (intervention period) compared to 120 minutes of CPAP (baseline period).

An oximetry sensor (LNOP Neo sensor; Masimo, Irvine, California, USA) will be placed around the infant’s wrist or foot and connected to the pulse oximeter (Radical7 V5; Masimo, 2 second averaging mode). Continuous data will be recorded using a neonatal respiratory monitor (NewLifeBox Neo-RSD, Advanced Life Diagnostics UG, Weener, Germany).
Secondary outcome [1] 328643 0
Difference in fraction of inspired oxygen between CPAP and nHFO treatment.
Timepoint [1] 328643 0
120 minutes of nHFO (intervention period) compared to 120 minutes of CPAP (baseline period).

The concentration of inspired oxygen will be measured with an oxygen analyser (Teledyne Analytical Instruments, California, USA). The analyser will be inserted into the inspiratory limb of the Draeger VN500 ventilator circuit (Draeger Medical System, Luebeck, Germany) and connected to a neonatal respiratory monitor (NewLifeBox Neo-RSD, Advanced Life Diagnostics UG, Weener, Germany). Continuous data will be recorded.
Secondary outcome [2] 328644 0
Difference in peripheral oxygen saturation between CPAP and nHFO treatment.
Timepoint [2] 328644 0
120 minutes of nHFO (intervention period) compared to 120 minutes of CPAP (baseline period).

An oximetry sensor (LNOP Neo sensor; Masimo, Irvine, California, USA) will be placed around the infant’s wrist or foot and connected to the pulse oximeter (Radical7 V5; Masimo, 2 second averaging mode). Continuous data will be recorded using a neonatal respiratory monitor (NewLifeBox Neo-RSD, Advanced Life Diagnostics UG, Weener, Germany).
Secondary outcome [3] 328645 0
Difference in respiratory rate between CPAP and nHFO treatment.
Timepoint [3] 328645 0
120 minutes of nHFO (intervention period) compared to 120 minutes of CPAP (baseline period).

Transthoracic impedance with ECG electrodes (Teledyne X2 Philips) placed on the infant’s chest will be used to obtain the respiration signal. The signal will be continuously recorded with a neonatal monitor (NewLifeBox Neo-RSD, Advanced Life Diagnostics UG, Weener, Germany).
Secondary outcome [4] 328646 0
Difference in heart rate between CPAP and nHFO treatment.
Timepoint [4] 328646 0
120 minutes of nHFO (intervention period) compared to 120 minutes of CPAP (baseline period).

ECG electrodes (Teledyne X2 Philips) will be placed on the infant’s chest to obtain the ECG signal. The signal will be continuously recorded with a neonatal monitor (NewLifeBox Neo-RSD, Advanced Life Diagnostics UG, Weener, Germany).
Secondary outcome [5] 328647 0
Difference in the proportion of time spent with oxygen saturations < 80% between CPAP and nHFO treatment.
Timepoint [5] 328647 0
120 minutes of nHFO (intervention period) compared to 120 minutes of CPAP (baseline period).

An oximetry sensor (LNOP Neo sensor; Masimo, Irvine, California, USA) will be placed around the infant’s wrist or foot and connected to the pulse oximeter (Radical7 V5; Masimo, 2 second averaging mode). Continuous data using a neonatal respiratory monitor (NewLifeBox Neo-RSD, Advanced Life Diagnostics UG, Weener, Germany) will be used.
Secondary outcome [6] 328648 0
Difference in the proportion of time spent with heart rates < 80 beats per minute between CPAP and nHFO treatment.
Timepoint [6] 328648 0
120 minutes of nHFO (intervention period) compared to 120 minutes of CPAP (baseline period).

ECG electrodes (Teledyne X2 Philips) will be placed on the infant’s chest to obtain the ECG signal. The signal will be continuously recorded with a neonatal monitor (NewLifeBox Neo-RSD, Advanced Life Diagnostics UG, Weener, Germany).
Secondary outcome [7] 328649 0
Difference in the number of desaturations < 60% and < 80% between CPAP and nHFO treatment.
Timepoint [7] 328649 0
120 minutes of nHFO (intervention period) compared to 120 minutes of CPAP (baseline period).

An oximetry sensor (LNOP Neo sensor; Masimo, Irvine, California, USA) will be placed around the infant’s wrist or foot and connected to the pulse oximeter (Radical7 V5; Masimo, 2 second averaging mode). Continuous data using a neonatal respiratory monitor (NewLifeBox Neo-RSD, Advanced Life Diagnostics UG, Weener, Germany) will be used.
Secondary outcome [8] 328650 0
Difference in the number of bradycardias < 60 beats per minute and < 100 beats per minute between CPAP and nHFO treatment.
Timepoint [8] 328650 0
120 minutes of nHFO (intervention period) compared to 120 minutes of CPAP (baseline period).

ECG electrodes (Teledyne X2 Philips) will be placed on the infant’s chest to obtain ECG signal. The signal will be continuously recorded with a neonatal monitor (NewLifeBox Neo-RSD, Advanced Life Diagnostics UG, Weener, Germany).
Secondary outcome [9] 328651 0
Difference in the number of apnoeas requiring stimulation by nursing staff between CPAP and nHFO treatment.
Timepoint [9] 328651 0
120 minutes of nHFO (intervention period) compared to 120 minutes of CPAP (baseline period).

The researcher who is present during both treatment periods (nHFO and CPAP) will document the number of apnoeas requiring stimulation on a predefined case report form.
Secondary outcome [10] 328652 0
Difference in regional cerebral oxygenation (rcO2) between the two treatment period measured by near-infrared spectroscopy (NIRS).
Timepoint [10] 328652 0
120 minutes of nHFO (intervention period) compared to 120 minutes of CPAP (baseline period).

Before the beginning of the study, a near infrared spectroscopy sensor (Fore-Sight Sensor, CAS Med. Medical Systems Inc., Branford, CT, USA) will be placed on the infant’s forehead underneath the CPAP hat. The sensor will not be removed during the whole study period.
Secondary outcome [11] 328653 0
Difference in the regional ventilation between CPAP and nHFO treatment measured by Electrical Impedance Tomography (EIT).
Timepoint [11] 328653 0
120 minutes of nHFO (intervention period) compared to 120 minutes of CPAP (baseline period).

The EIT system (Swisstom BB2 system, Landquart, Switzerland) includes EIT electrodes that are contained in a belt-like disposable textile patient interface. This EIT belt will be fastened to patient's thorax before beginning of the study and not be removed during the whole study period.
Secondary outcome [12] 328654 0
Effect of delivered amplitude on regional ventilation measured with Electrical Impedance Tomography (EIT).
Timepoint [12] 328654 0
The effect of delivered amplitude on EIT will be recorded during nHFO only.

The EIT system (Swisstom BB2 system, Landquart, Switzerland) includes EIT electrodes that are contained in a belt-like disposable textile patient interface. This EIT belt will be fastened to patient's thorax before beginning of the study and not be removed during the whole study period.
Secondary outcome [13] 328655 0
Difference in Premature Infant Pain Profile (PIPP) between CPAP and nHFO treatment.
Timepoint [13] 328655 0
PIPP will be assessed by nursing staff at the beginning and at the end of each treatment period and documented manually.
Secondary outcome [14] 328656 0
Number of changes in ventilator settings.
Timepoint [14] 328656 0
Will be documented manually during nHFO period only.

The number of changes made on the ventilator (Draeger Medical System, Luebeck, Germany) will be documented manually on a predefined case report form.
Secondary outcome [15] 328657 0
Safety related events 1:
Transcutaneous carbon dioxide (tcCO2) measurements.
Timepoint [15] 328657 0
Will be documented manually during nHFO period only.

Before each nHFO washout period, a tcCO2 transducer (M1018A module, Philips Electronics, Andover, Massachusetts, USA) will be placed on the infant’s skin. Given that the tcCO2 transducer needs to be calibrated every two hours, the maximum tcCO2 recording time is limited to 2 hours. Since the baby will be in prone position during both treatment periods and the abdominal area is not available, the transducer will be placed on the back or the lateral thigh. After 120 minutes of recording time (30 minutes before the end of the nHFO treatment period) the transducer will be removed to avoid prolonged application of heat to baby’s skin.
Secondary outcome [16] 328658 0
Safety related events 2:
Number of events with hypocarbia defined as a tcCO2 < 30 millimetres of mercury (mmHg)
Timepoint [16] 328658 0
Will be documented during nHFO period only.

Number of events with hypocarbia (TcCO2 transducer: M1018A module, Philips Electronics, Andover, Massachusetts, USA) will be documented manually.
Secondary outcome [17] 328659 0
Safety related events 3:
Number of hypercarbia defined as a tcCO2 > 60 millimetres of mercury (mmHg)
Timepoint [17] 328659 0
Will be documented during nHFO period only.

Number of events with hypercarbia (TcCO2 transducer: M1018A module, Philips Electronics, Andover, Massachusetts, USA) will be documented manually.
Secondary outcome [18] 328660 0
Safety related events 4:
Nasal Trauma Score
Timepoint [18] 328660 0
Will be documented at the end of nHFO treatment only.

The Nasal Trauma Score will be assessed by nursing stuff and documented manually.
Secondary outcome [19] 328661 0
Safety related events 5:
Gaseous distension (abdominal girth)
Timepoint [19] 328661 0
Will be documented at the beginning and at the end of nHFO period.

Abdominal girth will be assessed by nursing stuff and documented manually.
Secondary outcome [20] 328662 0
Safety related events 6:
Feeding intolerance expressed as the number of vomits.
Timepoint [20] 328662 0
Will be documented during nHFO period only.

The number of vomits will be documented manually.

Eligibility
Key inclusion criteria
- Gestational age at birth: < 30 weeks
- Postmenstrual age: greater than or equal to 26 and < 34 completed weeks of gestation
- Postnatal age: > 7 days
- Respiratory support: Receiving nasal CPAP and extubated for greater than or equal to 24 hours.
Minimum age
8 Days
Maximum age
10 Weeks
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Participation in another study that prohibits inclusion
- Nasal trauma and Pressure Injury score greater than or equal to 2 (stage 2: partial thickness skin loss involving epidermis, dermis or both) before study entry

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)
Allocation is 1:1. variable block randomisation will be used to ensure balance is achieved over the recruiting period. Sealed consecutively numbered opaque envelopes will be used.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The sequence of randomisation will be generated by an independent statistician using a randomisation table created by computer software. Sealed consecutively numbered opaque envelopes will be used.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
It is not possible to blind the operator to the non-invasive ventilation mode.
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The primary outcome is the paired difference in the total number of desaturations and bradycardias per 120 minutes of recording time between CPAP and nHFO. The required sample size is therefore dependant on the standard deviation (SD) of these paired differences.
Before we began the study, no data were available to estimate the probable size of this SD. Therefore, we decided to use a generic sample size calculation based on the effect size after consultation with our biostatistician.
For reassurance that our sample size calculation is able to demonstrate an effect size that is clinically relevant, a re-calculation of the sample size was performed after enrolment of the first 20 patients. With a total 40 patients, we will be able to show an effect size of 45%.

Recruitment
Recruitment status
Completed
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 in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 6844 0
The Royal Women's Hospital - Parkville
Recruitment postcode(s) [1] 14509 0
3052 - Parkville

Funding & Sponsors
Funding source category [1] 294744 0
Hospital
Name [1] 294744 0
The Royal Women's Hospital
Address [1] 294744 0
20 Flemington Road
Parkville VIC 3052
Country [1] 294744 0
Australia
Primary sponsor type
Hospital
Name
The Royal Women's Hospital
Address
20 Flemington Road
Parkville VIC 3052
Country
Australia
Secondary sponsor category [1] 293593 0
None
Name [1] 293593 0
Address [1] 293593 0
Country [1] 293593 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296161 0
The Royal Women's Hospital Human Research Ethics Committee
Ethics committee address [1] 296161 0
Research & Ethics Secretariat
Arthur Hui
20 Flemington Rd
Parkville VIC 3052
Ethics committee country [1] 296161 0
Australia
Date submitted for ethics approval [1] 296161 0
07/09/2016
Approval date [1] 296161 0
14/11/2016
Ethics approval number [1] 296161 0

Summary
Brief summary
Intermittent hypoxia (pulse oximetry saturation <80%) and bradycardia (pulse rate <80 beats per minute) frequently occur in preterm infants, often associated with apnoea of prematurity. Such episodes of hypoxia and re-oxygenation have the potential to trigger a pro-inflammatory cascade leading to multisystem morbidity including retinopathy of prematurity, impaired growth, longer-term cardiorespiratory instability, and poor neurodevelopmental outcome. Widely used treatments such as methylxanthines and continuous positive airway pressure (CPAP) are sometimes insufficient and endotracheal intubation and mechanical ventilation are required.

Nasal CPAP is the most widely used from of 'non-invasive' ventilation (NIV) in very preterm infants. NIV refers to respiratory support without the need for an endotracheal tube, usually delivered via nasal prongs. Nasal CPAP is an alternative to mechanical ventilation in preterm infants soon after birth. A meta-analysis comparing early CPAP with intubation and mechanical ventilation showed that CPAP reduce the risk of the combined outcome of death or bronchopulmonary dysplasia (BPD). CPAP failure primarily occurs due to AOP, oxygen requirements pre-specified thresholds, and hypercapnia related to hypoventilation. Ventilation failure in infants treated with CPAP may be due to inadequate alveolar ventilation and carbon dioxide elimination.

High-frequency oscillatory ventilation (HFOV) delivered via an endotracheal tube leads to excellent carbon dioxide removal using a tidal volume less than the volume of the dead space. HFOV, which has until recently only been delivered via endotracheal tube, uses oscillations of low amplitude and high frequencies quite different from those of normal respiration. It may cause less lung injury than conventional mechanical ventilation.

The combination of HFOV and NIV could provide lung-protection, improved oxygenation, better gas exchange, and reduced rates of AOP compared to NIV alone. Therefore, we aim to assess the effect of nHFO versus CPAP therapy in very preterm infants born <30 weeks’ gestation on the cumulative event rate of all bradycardias (< 80 bpm) and desaturations (< 80%) during a 120-minute recording period for each therapy. We hypothesize that in very preterm infants, nHFO is associated with a significant decrease in the number of bradycardias and desaturations compared with CPAP.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 69818 0
Dr Christoph Ruegger
Address 69818 0
Newborn Research Department
The Royal Women's Hospital
20 Flemington Road
Parkville Melbourne, 3052 VIC
Country 69818 0
Australia
Phone 69818 0
+61-477793772
Fax 69818 0
Email 69818 0
christoph.ruegger@thewomens.org.au
Contact person for public queries
Name 69819 0
Dr Christoph Ruegger
Address 69819 0
Newborn Research Department
The Royal Women's Hospital
20 Flemington Road
Parkville Melbourne, 3052 VIC
Country 69819 0
Australia
Phone 69819 0
+61-477793772
Fax 69819 0
Email 69819 0
christoph.ruegger@thewomens.org.au
Contact person for scientific queries
Name 69820 0
Dr Christoph Ruegger
Address 69820 0
Newborn Research Department
The Royal Women's Hospital
20 Flemington Road
Parkville Melbourne, 3052 VIC
Country 69820 0
Australia
Phone 69820 0
+61-477793772
Fax 69820 0
Email 69820 0
christoph.ruegger@thewomens.org.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary