NHFOV vs. NCPAP as a Primary Treatment to Neonatal Respiratory Distress Syndrome(NRDS)

• Sponsor: Xingwang Zhu (Other)
• Overall Status: Completed
• CT.gov ID: NCT03099694
• Collaborator: Guiyang Maternity and Child Health Care Hospital (Other), Daping Hospital and the Research Institute of Surgery of the Third Military Medical University (Other), Children's Hospital of Chongqing Medical University (Other), Chongqing Maternal and Child Health Hospital (Other), The Second Hospital of Shandong University (Other), Yan'an Affiliated Hospital of Kunming Medical University (Other), The Children's Hospital of Zhejiang University School of Medicine (Other), Hunan Children's Hospital (Other), Zhengzhou Children's Hospital, China (Other), Chengdu Women's and Children's Central Hospital (Other), The People's Hospital of Dehong Autonomous Prefecture (Other), Kunming Children's Hospital (Other), Chongqing Three Gorges Central Hospital (Other), Shanxi Provincial Maternity and Children's Hospital (Other), University of Southern California (Other), Vilnius University (Other), Children's Hospital of Fudan University (Other), Guangdong Women and Children Hospital (Other), Nanjing Children's Hospital (Other)
• Enrollment: 340
• Location: 1
• Arms: 2
• Actual Duration (Months): 15
• Patients Per Site Per Month: 22.6

Study Details

Study Description

Brief Summary

The investigators compared advantages and disadvantages of two forms of noninvasive respiratory support -noninvasive high-frequency oscillatory ventilation (nHFOV) or nasal continuous positive airway pressure (nCPAP) -as a primary mode of ventilation in premature infants with RDS．

Condition or Disease	Intervention/Treatment	Phase
Preterm Infants	Procedure: noninvasive high-frequency ventilation (nHFOV); Procedure: nasal continuous positive airway pressure (nCPAP)	N/A

Detailed Description

Background: Invasive mechanical ventilation is associated with development of adverse pulmonary and non-pulmonary outcomes in very low birth weight infants. Various modes of non-invasive respiratory support are being increasingly used to minimize the incidence of bronchopulmonary dysplasia (BPD). The aim of this trials to compare the effect of noninvasive high-frequency oscillatory ventilation (NHFOV) and nasal continuous positive airway pressure (NCPAP) in preterm infants with respiratory distress syndrome (RDS) as a primary noninvasive ventilation support mode.

Methods/Design:In this multicenter, randomized, controlled trial, 300 preterm infants at gestational age (GA) less than 34 weeks with a diagnosis of RDS will be randomized to NHFOV or NCPAP as a primary mode of non-invasive respiratory support. Study will be conducted in 18 tertiary neonatal intensive care units in China.

The primary outcome is the need for invasive mechanical ventilation (IMV)during the first 7 days after enrollment in preterm infants randomized to the two groups. The secondary outcomes include days of hospitalization, days on noninvasive respiratory support, days on IMV, days on supplemental oxygen, mortality, need for surfactant, incidence of retinopathy of prematurity(ROP) and bronchopulmonary dysplasia(BPD), occurrence of abdominal distention, air leaks, intraventricular hemorrhage (IVH ≥ grade 3) and necrotizing enterocolitis (NEC> II stage). Other secondary outcomes include scores of Bayley Scales of Infant Development at 2 months and 2 years of corrected age.

Study Design

• Study Type: Interventional
• Actual Enrollment: 340 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Noninvasive Ventilation for Preterm Neonates With Respiratory Distress Syndrome: a Multi-center Randomized Controlled Trial
• Actual Study Start Date: Apr 27, 2017
• Actual Primary Completion Date: Jul 28, 2018
• Actual Study Completion Date: Jul 28, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: nCPAP nasal continuous positive airway pressure (nCPAP) - as a primary mode of ventilation in premature infants with RDS	Procedure: nasal continuous positive airway pressure (nCPAP); Infants assigned to the NCPAP group will be started on a pressure of 6 cmH2O (range: 6-8 cmH2O) by CPAP system (CNO Medin, Germany, Carefusion, USA)
Experimental: nHFOV noninvasive high-frequency ventilation (nHFOV) as a primary mode of ventilation in premature infants with RDS	Procedure: noninvasive high-frequency ventilation (nHFOV); NHFOV will be provided by a high frequency ventilator (CNO, Medin, Germany or SLE 5000, UK). NHFOV will be provided via binasal prongs.

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Required Intubation [during the first 7 days after birth]

   The criteria for endotracheal mechanical ventilation were as follows: severe respiratory acidosis (PaCO2 > 60 mmHg with pH<7.20), severe apnea and bradycardia (defined as recurrent apnea with > 3 episodes per hour associated with heart rate < 100/min, a single episode of apnea that required bag and mask ventilation), hypoxia (FiO2>0.5 with PaO2<50mmHg), severe respiratory distress, neonatal pulmonary hemorrhage, and cardiopulmonary arrest without effective resuscitation needing continued ventilation and rescue

Secondary Outcome Measures

1. the Incidence of Intraventricular Hemorrhage (IVH, ≥ Grade Ⅲ) [first two months after birth]

   The criteria for intraventricular hemorrhage (IVH, ≥ grade Ⅲ): intraventricular hemorrhage with ventricular dilatation and intraventricular hemorrhage with paren- ehymal hemorrhage. Intraventricular hemorrhage (≥ grade Ⅲ) is worse outcome.

2. the Incidence of Pneumothorax [during non-invasive ventilation, up to 7 days]

   the incidence of pneumothorax

3. the Incidence of Neonatal Necrotizing Enterocolitis(>Stage II) [during non-invasive ventilation, up to 7 days]

   The criteria for neonatal necrotizing enterocolitis(>stage II): Unequivocal malfunction of the gastrointestinal tract is demonstrated clinically and by radiographic evaluation. Other disorders such as malrotation and volvulus and Hirschsprung's disease must be excluded. Neonatal necrotizing enterocolitis(>stage II) is worse outcome

4. the Incidence of Retinopathy of Prematurity (>Stage II) [at a post-menstrual age of 36 weeks or at discharge]

   The criteria for Retinopathy of prematurity (>Stage II); extraretinal fibrovascular proliferation neovascularization extends from ridge into the vitreous. Retinopathy of prematurity (>Stage II) is worse outcome.

5. The Score of Bayley Scales of Infant Development [30 months]

   scores of Bayley Scales of Infant Development at 2 months old and 2 years old

6. the Incidence of Bronchopulmonary Dysplasia(BPD) [at a post-menstrual age of 36 weeks or at discharge]

   BPD was defined according to the National Institutes of Health consensus definition: Need for O2 supplementation(FiO2>0.21) for at least 28 days after birth. BPD is worse outcome.

7. the Incidence of Abdominal Distention [during non-invasive ventilation, up to 7 days]

   Abdominal circumference increase 2 centimeter during non-invasive ventilation

8. The Time of Non-invasive Ventilation [during non-invasive ventilation, up to 30 days]

   Hours

9. Length of Hospitalization [during hospitalization, up to 60 days]

   Days

10. Predischarge Mortality [during hospitalization, up to 60 days]

11. Length of O2 Therapy [during hospitalization, up to 60 days]

    Days

12. Number of Participants With Thick Secretions Causing an Airway Obstruction [during non-invasive ventilation, up to 15 days]

    determined by the clinician

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 12 Hours
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion criteria:

(1)Gestational age (GA) is from 26 to 34 weeks; (2) diagnosis of RDS. The diagnosis of RDS will be based on clinical manifestations (tachypnea, nasal flaring and or grunting) and chest X-ray findings; (3) RDS Silverman score>5; (4) informed parental consent has been obtained.

Exclusion criteria

(1) severe RDS requiring early intubation according to the American Academy of Pediatrics guidelines for neonatal resuscitation7; (2)major congenital malformations or complex congenital heart disease; (3) group B hemolytic streptococcus pneumonia, septicemia, pneumothorax, pulmonary hemorrhage; (4) cardiopulmonary arrest needing prolonged resuscitation; (5) transferred out of the NICUs without treatment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Xingwang Zhu	Chongqing	Chongqing	China	400000

Sponsors and Collaborators

• Xingwang Zhu
• Guiyang Maternity and Child Health Care Hospital
• Daping Hospital and the Research Institute of Surgery of the Third Military Medical University
• Children's Hospital of Chongqing Medical University
• Chongqing Maternal and Child Health Hospital
• The Second Hospital of Shandong University
• Yan'an Affiliated Hospital of Kunming Medical University
• The Children's Hospital of Zhejiang University School of Medicine
• Hunan Children's Hospital
• Zhengzhou Children's Hospital, China
• Chengdu Women's and Children's Central Hospital
• The People's Hospital of Dehong Autonomous Prefecture
• Kunming Children's Hospital
• Chongqing Three Gorges Central Hospital
• Shanxi Provincial Maternity and Children's Hospital
• University of Southern California
• Vilnius University
• Children's Hospital of Fudan University
• Guangdong Women and Children Hospital
• Nanjing Children's Hospital

Investigators

• Study Director: Shi Yuan, PhD, Third Military Medical University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 13, 2017
• Informed Consent Form - Jul 13, 2017

More Information

Publications

None provided.

• Responsible Party: Xingwang Zhu, Director of neonatology, Jiulongpo No.1 People's Hospital
• ClinicalTrials.gov Identifier: NCT03099694
• Other Study ID Numbers: Jiulongpo People's Hospital
• First Posted: Apr 4, 2017
• Last Update Posted: Mar 2, 2021
• Last Verified: Feb 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Xingwang Zhu, Director of neonatology, Jiulongpo No.1 People's Hospital: NRDS; nHFOV; nCPAP; preterm infants
• Additional relevant MeSH terms: Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Premature Birth

Study Results

Participant Flow

Recruitment Details	From May, 2017, through July, 2018, a total of 18 centers screened 2509 infants, of which 1385 were eligible. We recruited 340 infants (170 in each group), to account for dropouts. Finally, 302 infants completed the trial (152 in NHFOV; 150 in NCPAP group.)
Pre-assignment Detail	1045 Did not undergo randomization 663 Refused to participate 382 NHFOV devices not available

Arm/Group Title	nCPAP	nHFOV
Arm/Group Description	infants receive primary non-invasive respiratory support by mean of nCPAP	infants receive primary non-invasive respiratory support by mean of NHFOV
Period Title: Overall Study
STARTED	170	170
COMPLETED	150	152
NOT COMPLETED	20	18

Baseline Characteristics

Arm/Group Title	nCPAP	nHFOV	Total
Arm/Group Description	infants receive primary non-invasive respiratory support by mean of nCPAP	infants receive primary non-invasive respiratory support by mean of NIPPV	Total of all reporting groups
Overall Participants	150	152	302
Age (Weeks) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Weeks]	30.9 (1.8)	30.6 (1.7)	30.7 (1.7)
Sex: Female, Male (Count of Participants)
Female	71 47.3%	61 40.1%	132 43.7%
Male	79 52.7%	91 59.9%	170 56.3%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Multiple birth (Count of Participants)
Count of Participants [Participants]	57 38%	36 23.7%	93 30.8%
Antenatal steroids (Count of Participants)
Count of Participants [Participants]	101 67.3%	105 69.1%	206 68.2%
Cesarean delivery (Count of Participants)
Count of Participants [Participants]	81 54%	89 58.6%	170 56.3%
Premature rupture of membranes>18h (Count of Participants)
Count of Participants [Participants]	61 40.7%	59 38.8%	120 39.7%
Gestational diabetes mellitus (Count of Participants)
Count of Participants [Participants]	10 6.7%	10 6.6%	20 6.6%
Birth Weight (g) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [g]	1582 (343)	1564 (367)	1572 (351)

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Required Intubation
Description	The criteria for endotracheal mechanical ventilation were as follows: severe respiratory acidosis (PaCO2 > 60 mmHg with pH<7.20), severe apnea and bradycardia (defined as recurrent apnea with > 3 episodes per hour associated with heart rate < 100/min, a single episode of apnea that required bag and mask ventilation), hypoxia (FiO2>0.5 with PaO2<50mmHg), severe respiratory distress, neonatal pulmonary hemorrhage, and cardiopulmonary arrest without effective resuscitation needing continued ventilation and rescue
Time Frame	during the first 7 days after birth

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	nCPAP	nHFOV
Arm/Group Description	infants receive primary non-invasive respiratory support by mean of nCPAP	infants receive primary non-invasive respiratory support by mean of NHFOV
Measure Participants	150	152
Count of Participants [Participants]	26 17.3%	15 9.9%

2. Secondary Outcome

Title	the Incidence of Intraventricular Hemorrhage (IVH, ≥ Grade Ⅲ)
Description	The criteria for intraventricular hemorrhage (IVH, ≥ grade Ⅲ): intraventricular hemorrhage with ventricular dilatation and intraventricular hemorrhage with paren- ehymal hemorrhage. Intraventricular hemorrhage (≥ grade Ⅲ) is worse outcome.
Time Frame	first two months after birth

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	nCPAP	nHFOV
Arm/Group Description	infants receive primary non-invasive respiratory support by mean of nCPAP	infants receive primary non-invasive respiratory support by mean of NHFOV
Measure Participants	150	152
Count of Participants [Participants]	2 1.3%	4 2.6%

3. Secondary Outcome

Title	the Incidence of Pneumothorax
Description	the incidence of pneumothorax
Time Frame	during non-invasive ventilation, up to 7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	nCPAP	nHFOV
Arm/Group Description	infants receive primary non-invasive respiratory support by mean of nCPAP	infants receive primary non-invasive respiratory support by mean of NHFOV
Measure Participants	150	152
Count of Participants [Participants]	1 0.7%	3 2%

4. Secondary Outcome

Title	the Incidence of Neonatal Necrotizing Enterocolitis(>Stage II)
Description	The criteria for neonatal necrotizing enterocolitis(>stage II): Unequivocal malfunction of the gastrointestinal tract is demonstrated clinically and by radiographic evaluation. Other disorders such as malrotation and volvulus and Hirschsprung's disease must be excluded. Neonatal necrotizing enterocolitis(>stage II) is worse outcome
Time Frame	during non-invasive ventilation, up to 7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	nCPAP	nHFOV
Arm/Group Description	infants receive primary non-invasive respiratory support by mean of nCPAP	infants receive primary non-invasive respiratory support by mean of NHFOV
Measure Participants	150	152
Count of Participants [Participants]	7 4.7%	11 7.2%

5. Secondary Outcome

Title	the Incidence of Retinopathy of Prematurity (>Stage II)
Description	The criteria for Retinopathy of prematurity (>Stage II); extraretinal fibrovascular proliferation neovascularization extends from ridge into the vitreous. Retinopathy of prematurity (>Stage II) is worse outcome.
Time Frame	at a post-menstrual age of 36 weeks or at discharge

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	nCPAP	nHFOV
Arm/Group Description	infants receive primary non-invasive respiratory support by mean of nCPAP	infants receive primary non-invasive respiratory support by mean of NHFOV
Measure Participants	150	152
Count of Participants [Participants]	9 6%	7 4.6%

6. Secondary Outcome

Title	The Score of Bayley Scales of Infant Development
Description	scores of Bayley Scales of Infant Development at 2 months old and 2 years old
Time Frame	30 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	the Incidence of Bronchopulmonary Dysplasia(BPD)
Description	BPD was defined according to the National Institutes of Health consensus definition: Need for O2 supplementation(FiO2>0.21) for at least 28 days after birth. BPD is worse outcome.
Time Frame	at a post-menstrual age of 36 weeks or at discharge

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	nCPAP	nHFOV
Arm/Group Description	infants receive primary non-invasive respiratory support by mean of nCPAP	infants receive primary non-invasive respiratory support by mean of NHFOV
Measure Participants	150	152
Count of Participants [Participants]	15 10%	17 11.2%

8. Secondary Outcome

Title	the Incidence of Abdominal Distention
Description	Abdominal circumference increase 2 centimeter during non-invasive ventilation
Time Frame	during non-invasive ventilation, up to 7 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	nCPAP	nHFOV
Arm/Group Description	infants receive primary non-invasive respiratory support by mean of nCPAP	infants receive primary non-invasive respiratory support by mean of NHFOV
Measure Participants	150	152
Count of Participants [Participants]	19 12.7%	26 17.1%

9. Secondary Outcome

Title	The Time of Non-invasive Ventilation
Description	Hours
Time Frame	during non-invasive ventilation, up to 30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	nCPAP	nHFOV
Arm/Group Description	infants receive primary non-invasive respiratory support by mean of nCPAP	infants receive primary non-invasive respiratory support by mean of NHFOV
Measure Participants	150	152
Median (Inter-Quartile Range) [hours]	81.0	78.5

10. Secondary Outcome

Title	Length of Hospitalization
Description	Days
Time Frame	during hospitalization, up to 60 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	nCPAP	nHFOV
Arm/Group Description	infants receive primary non-invasive respiratory support by mean of nCPAP	infants receive primary non-invasive respiratory support by mean of NHFOV
Measure Participants	150	152
Median (Inter-Quartile Range) [days]	29.0	31.0

11. Secondary Outcome

Title	Predischarge Mortality
Time Frame	during hospitalization, up to 60 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	nCPAP	nHFOV
Arm/Group Description	infants receive primary non-invasive respiratory support by mean of nCPAP	infants receive primary non-invasive respiratory support by mean of NHFOV
Measure Participants	150	152
Count of Participants [Participants]	4 2.7%	6 3.9%

12. Secondary Outcome

Title	Length of O2 Therapy
Description	Days
Time Frame	during hospitalization, up to 60 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	nCPAP	nHFOV
Arm/Group Description	infants receive primary non-invasive respiratory support by mean of nCPAP	infants receive primary non-invasive respiratory support by mean of NHFOV
Measure Participants	150	152
Median (Inter-Quartile Range) [days]	7.0	8.0

13. Secondary Outcome

Title	Number of Participants With Thick Secretions Causing an Airway Obstruction
Description	determined by the clinician
Time Frame	during non-invasive ventilation, up to 15 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	nCPAP	nHFOV
Arm/Group Description	infants receive primary non-invasive respiratory support by mean of nCPAP	infants receive primary non-invasive respiratory support by mean of NIPPV
Measure Participants	150	152
Count of Participants [Participants]	8 5.3%	21 13.8%

Adverse Events

Time Frame	6 months
Arm/Group Title	nHFOV		nCPAP
Arm/Group Description	infants receive primary non-invasive respiratory support by mean of nHFOV		infants receive primary non-invasive respiratory support by mean of nCPAP
All Cause Mortality
	nHFOV		nCPAP
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/152 (3.9%)		4/150 (2.7%)
Serious Adverse Events
	nHFOV		nCPAP
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/152 (0%)		0/150 (0%)
Other (Not Including Serious) Adverse Events
	nHFOV		nCPAP
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/152 (0%)		0/150 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.