NIV-MISA-NRDS Trial: a Multicenter Study in China

Nasal Continuous Positive Airway Pressure Versus Non-invasive Positive Pressure Ventilation as Primary Support Before Minimally Invasive Surfactant Administration for Preterm Infants With NRDS

BACKGROUND Non-invasive ventilation (NIV) treatment have been developed to minimize lung damage and to avoid invasive mechanical ventilation (IMV) in preterm infants, especially in those with gestational age less than 30 weeks. Our hypothesis is that for preterm infants less than 30 weeks with potential to develop neonatal respiratory distress syndrome (NRDS), nasal continuous positive airway pressure (NCPAP) is non-inferior to the nasal intermittent positive pressure ventilation (NIPPV) as primary respiratory support before minimal invasive surfactant administration (MISA).

DESIGN, SETTING, AND PARTICIPANTS The NIV-MISA-NRDS trial is planned as an unblinded, multicenter, randomized, non-inferiority trial at 11 tertiary care neonatal intensive care units in China. Eligible infants are preterm infants of 24 to 29+6 weeks' gestational age who have spontaneous breaths at birth and require primary NIV support for NRDS in the first 2 h of life. Infants are randomized 1:1 to treatment with either NCPAP or NIPPV once admitted into neonatal intensive care unit (NICU). If the patient with progressively aggravates respiratory distress and clinically diagnose as NRDS, pulmonary surfactant will be supplemented by minimal invasive surfactant administration (MISA) in the first 2 hours .

MAIN OUTCOMES AND MEASURES The primary outcome is NIV treatment failure within 72 hours after birth, as determined by objective oxygenation, blood gas, and apnea criteria, or the need for intubation and mechanical ventilation. Secondary outcomes mainly include the incidence of complications during hospitalization . With a specified noninferiority margin of 10%, using a two-sided 95% CI and 80% power, the study requires 480 infants per group (total 960 infants in the study).

Study Overview

• Status: Terminated
• Conditions: Minimal Invasive Surfactant Administration in Two Different Non-invasive Ventilation Modes to NRDS Infants
• Intervention / Treatment: Other: Nasal continuous positive airway pressure; Other: Non-invasive positive pressure ventilation

Detailed Description

The ventilator parameter of NCPAP group are set with positive end expiratory pressure [PEEP] of 6cmH2O (adjustment range 6-8cmH2O) and FiO2 of 0.21-0.40, in order to maintain an oxygen saturation level of 90%-95%.

NIPPV group are set with PEEP of 6cmH2O (adjustment range 6-8cmH2O), peak inspiratory pressure [PIP] of 15cmH2O (regulation range 15-20cmH2O), inspiratory time of 0.3s (regulation range 0.3-0.4s), respiratory rate of 30 times/min (regulation range 20-40 times/min) and FiO2 of 0.21-0.40.

• Study Type: Interventional
• Enrollment (Actual): 312
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Beijing, China
    • Peking University Third Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 hour to 4 months (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

Infants who meet all of the following criteria will be included:

1. Infants of 24 to 29+6 weeks GA.
2. Infants with spontaneous breathing and signs of respiratory distress will receive non-invasive respiratory support (PEEP of 6 cmH2O and fraction of inspired oxygen[FiO2]≤0.40) immediately after birth in the delivery room and during transfer to NICU. Once the infant is settled down in the incubator, and the ventilation support of NCPAP or NIPPV by ventilator in NICU will by started according to the randomization of protocol.
3. Under NCPAP or NIPPV, the surfactant will be administered via MISA approach within 120 minutes after birth if the infant required FiO2>0.3 for transcutaneous oxygen saturation [SpO2]>85%, or Silverman Anderson Score [SAS] >5 points or SAS increasing >2 points per hour.
4. Parental consent will be obtained for all participants.

Exclusion Criteria

Infants who meet any of the following criteria will be excluded:

1. Infants who have been intubated prior to pulmonary surfactant administration due to postnatal resuscitation or other reasons.
2. Infants with obvious malformations affecting respiratory function.
3. Infants who have been transferred out to other hospitals for surgery or died for other complications with uncompleted data.
4. Infants who have participated in other interventional researches.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NCPAP group; The ventilator parameter of NCPAP group are set with positive end expiratory pressure [PEEP] of 6cmH2O (adjustment range 6-8cmH2O) and FiO2 of 0.21-0.40, in order to maintain an oxygen saturation level of 90%-95%.	Other: Nasal continuous positive airway pressure; Preterm infants with spontaneous breathing are stabilized on non-invasive respiratory support (PEEP of 6 cmH2O and FiO2≤0.40) in the delivery room and during admission to NICU, and then randomly selected to start NCPAP within 30 minutes of birth. Under NCPAP, the calf pulmonary surfactant will be administered via MISA method within 120 minutes after birth if infants are clinically diagnosed with RDS.
Active Comparator: NIPPV group; NIPPV group are set with PEEP of 6cmH2O (adjustment range 6-8cmH2O), peak inspiratory pressure [PIP] of 15cmH2O (regulation range 15-20cmH2O), inspiratory time of 0.3s (regulation range 0.3-0.4s), respiratory rate of 30 times/min (regulation range 20-40 times/min) and FiO2 of 0.21-0.40.	Other: Non-invasive positive pressure ventilation; Preterm infants with spontaneous breathing are stabilized on non-invasive respiratory support (PEEP of 6 cmH2O and FiO2≤0.40) in the delivery room and during admission to NICU, and then randomly selected to start NIPPV within 30 minutes of birth. Under NIPPV, the calf pulmonary surfactant will be administered via MISA method within 120 minutes after birth if infants are clinically diagnosed with RDS.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
NIV treatment failure within the first 72 hours of life	The failure of non-invasive nasal respiratory support(NIPPV or NCPAP) within the first 72 hours of life	From enrollment to the first 72 hours of life

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
NIV treatment failure within 7days after birth	The failure of non-invasive nasal respiratory support(NIPPV or NCPAP) within 7days after birth	From enrollment to 7days after birth
Rate of pneumothorax	Rate of pneumothorax	Through study completion and up to corrected three months
Rate of pulmonary hemorrhage	Rate of pulmonary hemorrhage	Through study completion and up to corrected three months
Rate of hemodynamically significant patent ductus arteriosus (hsPDA)	Rate of hemodynamically significant patent ductus arteriosus (hsPDA)	Through study completion and up to corrected three months
Rate of intraventricular hemorrhages (IVH, grade III or Ⅳ)	Rate of intraventricular hemorrhages (IVH, grade III or Ⅳ)	Through study completion and up to corrected three months
Rate of periventricular leukomalacia	Rate of periventricular leukomalacia	Through study completion and up to corrected three months
Rate of late-onset sepsis	Rate of late-onset sepsis	Through study completion and up to corrected three months
Rate of bronchopulmonary dysplasia (BPD)	Rate of bronchopulmonary dysplasia (BPD)	At 36 weeks PMA
Rate of necrotizing enterocolitis (NEC)	Rate of necrotizing enterocolitis (NEC)	Through study completion and up to corrected three months
Rate of retinopathy of prematurity (ROP)	Rate of retinopathy of prematurity (ROP)	Through study completion and up to corrected three months
Duration of non-invasive ventilation, IMV, and supplemental oxygen	Duration of non-invasive ventilation, duration of IMV, and days on supplemental oxygen	Through study completion and up to corrected three months
Length of hospital stay	Length of hospital stay	From enrollment to the end of treatment at an average of 8 weeks
Required>1 doses of surfactant	rate of required>1 doses of surfactant	From enrollment to 5 days after birth
In-hospital mortality	In-hospital mortality	Through study completion and up to corrected three months
Pneumonia	rate of pneumonia	Through study completion and up to corrected three months
Persistent pulmonary hypertension of newborn	rate of persistent pulmonary hypertension of newborn	Through study completion and up to corrected three months

Collaborators and Investigators

• Sponsor: Peking University Third Hospital
• Investigators: Principal Investigator: Xiaomei Tong, Tong,, Peking University Third Hospital

Publications and helpful links

General Publications

• Zhang H, Li J, Zeng L, Gao Y, Zhao W, Han T, Tong X. A multicenter, randomized controlled, non-inferiority trial, comparing nasal continuous positive airway pressure with nasal intermittent positive pressure ventilation as primary support before minimally invasive surfactant administration for preterm infants with respiratory distress syndrome (the NIV-MISA-RDS trial): Study protocol. Front Pediatr. 2022 Jul 29;10:968462. doi: 10.3389/fped.2022.968462. eCollection 2022.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2021
• Primary Completion (Actual): February 1, 2025
• Study Completion (Actual): March 10, 2025

Study Registration Dates

• First Submitted: November 28, 2021
• First Submitted That Met QC Criteria: November 28, 2021
• First Posted (Actual): November 30, 2021

Study Record Updates

• Last Update Posted (Actual): July 9, 2025
• Last Update Submitted That Met QC Criteria: July 4, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Other Study ID Numbers: M2021378

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No