NHFOV vs nCPAP in Very Preterm Infants With Respiratory Distress Syndrome: A Multi-center, Prospective, Randomized, Controlled Clinical Superior Trial
Phase: NA
Conditions: to Test the Hypothesis That NHFOV is More Effective Than nCPAP in the Treatment of Respiratory Distress Syndrome (RDS) in Verypreterm Neonates
Sponsor: Jiulongpo No.1 People's Hospital

NHFOV vs nCPAP in Very Preterm Infants With Respiratory 
Distress Syndrome: A Multi-center, Prospective, Randomized, 
Controlled Clinical Superior Trial 
 
NCT05141435 
 
DATE: August 1, 2022 
 
 
            
 
              
 
 
 
 
 
 
 
 
 
 
 
 
 

NHFOV vs nCPAP in Very Preterm Infants With Respiratory 
Distress Syndrome: A Multi-center, Prospective, Randomized, 
Controlled Clinical Superior Trial 
 
Trial Design 
This will be a multicentre, randomised controlled, superiority trial conducted in 20 
tertiary NICUs in China from August 2022 to August 2024.We preform this trial to 
compare the need for invasive mechanical ventilation (IMV) in very preterm infants 
with respiratory distress syndrome (RDS) randomized to Noninvasive high-Frequency 
oscillatory ventilation (NHFOV) versus nasal continuous positive airway pressure 
(NCPAP). 
Inclusion criteria:  
i.  GA between 240/7 and 286/7 weeks 
ii. Diagnosis of RDS. The diagnosis of RDS will be based on clinical mani festations 
(tachypnea, nasal flaring and or grunting) and a fraction of inspired oxygen (FiO2 ) 
greater than 0.25 for target saturation of peripheral oxygen (SpO2) 89%–94% 
iii. Age <2hours 
iv. Informed parental consent has been obtained 
Exclusion criteria 
i. Intubated for any reasons at birth 
ii. major congen ital malformations or known complex congenital heart disease 
iii. transferred out of the NICU before randomisation 
Randomization 
Neonates will be randomised and assigned either to NCPAP or NHFOV arms with a 
1:1 ratio, when patients fulfil all inclusion criteria. Simple randomisation will be done 
according to a computer-generated random number table and will be posted in a 

specific secured website available on 24/7. Twins will all be allocated in the same 
treatment group. Infants randomised to one arm cannot crossover to the other or 
vice-versa during the study. 
Blinding  
Operators and care providers will not be blinded, and the outcome assessors and data 
analysts will be blinded to the intervention 
Trial intervention 
Delivery room 
In the delivery room, all eligible infants with spon taneously breathing shoud be 
supported by NCPAP(pressure: 6–8cm H2O) and transferred to NICUs on NCPAP 
immediately 
Nasal continuous positive airway pressure  
The infants assigned to NCPAP will be provided by either variable flow or continuous 
flow devices. The starting pressure will be set at 6 cmH2 O and can be raised in steps 
of 1 cmH2 O up to 10 cmH2 O. If this is not enough to maintain SpO2 between 90% 
and 95%, FiO2 will be added up to 0.40. 
Non-invasive high-frequency oscillatory ventilation  
NHFOV will only be provided with piston/membrane oscillators able to provide a real 
oscillatory pressure with active expiratory phase (Acutronic FABIAN-III, SLE 5000, 
Loweinstein Med LEONI+). Infants assigned to NHFOV will be started with the 
following boundaries: (1) mean airway pressure (MAP) of 6 cmH2O (can be changed 
in steps of 1 cmH2O within the range range 6–10 cmH2O); MAP will be titrated 

(within the range) according to open lung strategy, performing alveolar recruitment, 
similar to what is done in endotracheal high frequency oscillatory ventilation targeting 
a FiO2 ≤25% to 30%.12 (2) frequency of 10Hz (can be changed in steps of 1Hz within 
the range 8–12Hz). (3) Inspiratory time 50% (1:1). (4) amplitude 15 cmH2O (can be 
changed in steps of 5 cmH2O within the range 15–30 cmH2O). In case of hypoxaemia, 
MAP and FiO2 will be increased (within the above-described ranges). In case of 
hypercarbia, amplitude will be increased first and then frequency will be lowered 
(within the above-described ranges). 
Interface  
NCPAP and NHFOV will be all administered through short, binasal prongs. Nasal 
prongs size will be chosen according to the nares’ diameter as the best fitting ones 
(the largest ones that fit the nares without blanching the surrounding tissues) and 
following manufacturer’s recommendations. 
Surfactant treatment  
Surfactant (Curosurf; 200mg/kg) will be administered if infants have FiO2 >30%to 
maintain the target SpO2 89%–94% by less invasive surfactant administration. 
Caffeine treatment  
Caffeine (Caffeine Citrate Injection. Chiesi Pharmaceu ticals, Parma, Italy) will be 
prophylactic administered. The initial loading dose is 20mg/kg, and the mainte nance 
dose is 5mg/kg per day. Caffeine treatment will be stopped when no apneas occur or 
corrected GA 36 weeks was reached. 
Other treatments or tests  

(1) Heart ultrasound to evaluate cardiac morphology, pulmonary pressures and patent 
ductus arteriosus (PDA), within the first 3days of life and subsequently repeated, if 
needed; (2) Cerebral ultrasound within 48 hours of life and weekly thereafter, until 
discharge, if needed; (3) Routine measures to prevent BPD; routine fluid/nutri tional 
policy; (4) Placement of umbilical central venous catheter and/or peripherally inserted 
central venous lines. Placement of arterial lines if needed, according to local policies 
and (5) Routine therapies according to local policies (ie, antibiotics, PDA closure 
drugs…). 
Primary outcomes  
The primary outcomes will be the respiratory support failure determined by the need 
for IMV within 72 hours from birth. The respiratory support failure will be 
consid ered if one of the following occurs: (1) severe respiratory acidosis (defined as 
PaCO2 >60mm Hg with pH<7.2) for at least 1hour; (2) hypoxia refractory to study 
interven tion (defined as SpO2 <90%, with FiO2 =0.4 and maximal pressures allowed 
in the study arm) for at least 1 hour after the administration of surfactant; (3) severe 
apnoea (defined as recurrent apnoea with >3 episodes/hour associated with heart rate 
＜100/min or a single episode of apnoea requiring bag and mask ventilation) and (4) 
attending physician determined that urgent intubation is necessary. 
Secondary outcomes  
(1)Airleaks (pneumothorax and/or pneumomediasti num) occurred during treatment 
of RDS.  
(2)BPD, defined according to the NICHD definition.  

(3) Haemodynamically significant PDA, defined accord ing to local NICU protocols. 
(4) Retinopathy of prematurity (ROP) >2nd stage. 
(5) Necrotising enterocolitis (NEC) ≥2nd stage.  
(6) Intracranial haemorrhage (IVH) ≥3rd grade. 
(7) In-hospital mortality.  
(8) Composite mortality/BPD 
(9) Weekly weight gain (in grams/day) for the first 4 weeks of life or until NICU 
discharge, whichever comes first 
(10) Duration of non-invasive respiratory assistance.  
(11) Duration of hospitalisation. 
(12) Rate of surfactant treatment.  
(13) Rate of thick secretions causing an airway obstruction.  
(14) Rate of nasal trauma 
End of the study  
A patient may exit from the study for any of the following reasons: 1. Death. 2. In any 
case, when the 36 weeks’ postconceptional age is reached. 3. If parents or guardians 
withdraw an already given con sent for the participation (in that case the patient will 
keep receiving the whole routine clinical assistance data acquired up to that point will 
be immediately destroyed) 
Data collection  
All data for trial analysis are routine clinical items that can be obtained from the 
clinical notes. Data will be recorded in real time (every day) on web-based case report 

forms provided by OpenCDMS. The website will be tested with fictitious data before 
the actual enrollment 
Before the intervention begins: information on eligibility; baseline clinical 
informations, Silverman score, Critical risk index for babies-II score. 
Following study intervention: ventilator parameters, SpO2, blood gas values (PaO2, 
PaCO2, SpO2 and pH) before intervention and intubation.  
Follow-up: failed on assigned NIV at 72 hours or 7days, surfactant treatment, duration 
of the study intervention (NCPAP or NHFOV), airleaks, PDA, BPD, ROP >2nd stage, 
NEC ≥2nd stage, IVH >2nd grade, in-hospital mortality, composite mortality/BPD, 
weekly weight gain (in grams/day), duration of hospitalisation, thick secre tions 
causing an airway obstruction, nasal trauma.ictitious data before the actual enrolment. 
Sample size calculation  
According to the results of our last multicentre study, the risk of failure while 
receiving NCPAP for very preterm infants with RDS was 30%, and a reduction of 
20% for babies receiving NHFOV. We decide to aim a difference of 15% in the rate 
of the respiratory support failure. Considering an alpha error of 0.05 and a power of 
90%, 170 neonates would be needed in each group. 
Statistical methods  
Outcomes will be analysed on an intention-to-treat basis. We will calculate a risk 
difference (with 95%CI) for dichotomous outcomes and mean (with 95%CI) or 
median (25–75th percentile, using Hodges-Lehmann) differences for continuous 
outcomes between the study groups. Continuous variables will be compared using 

Student’s t test or the Mann-Whitney rank sum test as appropriate. Categorical 
variables were compared using the χ2 test. P values ＜0.05 were considered 
statistically significant. 
Data monitoring board 
An independent data monitoring committee belonging to the Central Ethics 
Committee of Children’s Hospital of Chongqing Medical University has been 
established for the trial. This committee will perform interim data analysis, investigate 
compliance with the trial and monitor adverse events. Formal interim analyses of 
efficacy will be carried out by the DMB when 25%, 50% and 75% of the outcome 
data were available. The board will advise the principal investigator who will remain 
the only responsible for the trial conduction and for any eventual decision to stop or 
continue it. 
Ethics and dissemination  
The study protocol was approved by the Ethics Committee of Children’s Hospital of 
Chongqing Medical University (n.2019.161) and registered in the ClinicalTrials.gov 
registry (ID: NCT05141435). The trial was performed in accordance with the 
approved guidelines and regula tions of the participating institutions. Informed 
consent will be obtained antenatally or on NICU admission from parents or guardians. 
Hospitals participating in the study will share the findings and results of the study, 
which will be presented at national conferences and peer-reviewed paediatrics 
journals