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A Trial Comparing Noninvasive Ventilation Strategies in Preterm Infants Following Extubation

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 evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03181958
Recruitment Status : Recruiting
First Posted : June 9, 2017
Last Update Posted : July 22, 2019
Sponsor:
Collaborators:
Children's Hospital of Chongqing Medical University
Jiulongpo No.1 People's Hospital
Chongqing Maternal and Child Health Hospital
The First Affiliated Hospital of Anhui Medical University
Children's Hospital of The Capital Institute of Pediatrics
Peking University Third Hospital
First Hospital of Tsinghua University
Women and Children's Hospital, Branch of Chongqing Sanxia Central Hospital
First Affiliated Hospital of Chongqing Medical University
Quanzhou Children's Hospital
Xiamen Maternity & Child Care Hospital
Zhujiang Hospital
Nanfang Hospital of Southern Medical University
Guangdong Academy of Medical Science and General Hospital
Guangdong Women and Children Hospital
Women and Children's Health Hospital of Yulin
Women and Children Health Care Hospitalof GuangXi Zhuang Autonomous
Second Affiliated Hospital of Guangzhou Medical University
Guiyang Maternal and Child Health Care Hospital
Zunyi First People's Hospital
Second Hospital of Lanzhou University
Gansu Provincial Maternity and Child-Care Hospital
LanZhou University
First Affiliated Hospital of Harbin Medical University
First Affiliated Hospital of Xinjiang Medical University
Zhengzhou Children's Hospital, China
Third Affiliated Hospital of Zhengzhou University
the Maternal and Child Health Hospital of Hainan Province
Bethune International Peace Hospital
Wuhan Union Hospital, China
Children's Hospital of Nanjing Medical University
First Hospital of Jilin University
Children's Hospital of Fudan University
Maternal and Children's Healthcare Hospital of Taian
The Second Hospital of Shandong University
Shanxi Provincial Maternity and Children's Hospital
Chengdu Women and Children's Center Hospital
The Affiliated Hospital Of Southwest Medical University
Affiliated Hospital of Southwest Medical University
Shenzhen People's Hospital, The Second Medical College of Jinan University
Tianjin Central Hospital of Gynecology Obstetrics
People's Hospital of Xinjiang Uygur Autonomous Region
Kunming Children's Hospital
The First People's Hospital of Yunnan
The First Affiliated Hospital of Kunming Medical College
Yan'an Hospital Affiliated to Kunming Medical University
Women and Children's Health Hospital of Qujing
The People's Hospital of Dehong Autonomous Prefecture
Yinchuan No 1 people's Hospital Affiliated of Ningxia Medical University
The Children's Hospital of Zhejiang University School of Medicine
Women's Hospital School Of Medicine Zhejiang University
Beijing 302 Hospital
Hunan Children's Hospital
Women and Children Hospital of Qinghai Province
Jiangxi Province Children's Hospital
Inner Mongolia People's Hospital
Mianyang Central Hospital
People's Liberation Army No.202 Hospital
Ningbo Women & Children's Hospital
Shanghai Children's Medical Center
First Affiliated Hospital of Guangxi Medical University
Nanjing Medical University
Qinhuangdao Maternal and Child Health Care Hospital
Xuzhou Children Hospital
South Paris University Hospitals, Catholic University of the Sacred Heart
The First Affiliated Hospital of Zhengzhou University
Xianyang children's Hospital
Information provided by (Responsible Party):
Ma Juan, Daping Hospital and the Research Institute of Surgery of the Third Military Medical University

Brief Summary:

Respiratory distress syndrome (RDS) is the main cause of respiratory failure in preterm neonates, its incidence varying from 80% to 25% depending on gestational age.When optimal prenatal care is provided, the best approach to treat RDS, according to several recent trials,consists in providing continuous positive airway pressure (CPAP) from the first minutes of life using short binasal prongs or masks, followed by early selective surfactant administration for babies with worsening oxygenation and/or increasing work of breathing. Any effort should be done to minimize the time under invasive mechanical ventilation (IMV).Nonetheless, clinical trials have shown that a relevant proportion of preterm neonates fails this approach and eventually need IMV.The duration of IMV is a well known risk factor for the development of broncho-pulmonary dysplasia (BPD) - a condition associated with significant morbidity and mortality.

To minimize the duration of IMV, various non invasive respiratory support modalities are available in neonatal intensive care units (NICU). CPAP is presently the most common technique used in this regard. However, a systematic review has shown that non-invasive positive pressure ventilation (NIPPV) reduces the need for IMV (within one week from extubation) more effectively than NCPAP, although it is not clear if NIPPV may reduce need for intubation longterm and it seems to have no effect on BPD and mortality. NIPPV main drawback is the lack of synchronization, which is difficult to be accurately achieved and is usually unavailable. A more recent alternative technique is non-invasive high frequency oscillatory ventilation (NHFOV) which consists on the application of a bias flow generating a continuous distending positive pressure with oscillations superimposed on spontaneous tidal breathing with no need for synchronization. The physiological, biological and clinical details about NHFOV have been described elsewhere.

To date, there is only one small observational uncontrolled study about the use of NHFOV after extubation in preterm infants. Other relatively small case series or retrospective cohort studies suggested safety, feasibility and possible usefulness of NHFOV and have been reviewed elsewhere.The only randomized trial published so far compared NHFOV to biphasic CPAP,in babies failing CPAP and it has been criticized for methodological flaws and for not taking into account respiratory physiology.An European survey showed that, despite the absence of large randomized clinical trials, NHFOV is quite widely used, at least in some Countries and no major side effects are reported, although large data about NHFOV safety are lacking. This may be due to the relative NHFOV easiness of use but evidence-based and physiology-driven data are warranted about this technique.


Condition or disease Intervention/treatment Phase
Intubated Infants Were Intend to Extubation Using Noninvasive Ventilation Strategies Device: NHFOV Device: NCPAP Device: NIPPV Not Applicable

Detailed Description:

NHFOV should theoretically provide the advantages of invasive high frequency oscillatory ventilation (no need for synchronization, high efficiency in CO2 removal, less volume/barotrauma) and nasal CPAP (non-invasive interface, oxygenation improvement by the increase in functional residual capacity through alveolar recruitment). NHFOV should allow to increase mean airway pressure (Paw) avoiding gas trapping and hypercarbia, thanks to the superimposed high frequency oscillations. Therefore, NHFOV is more likely to be beneficial for those neonates requiring high distending pressure to open up their lungs, such as babies at high risk of extubation failure due to severity of their lung disease. This may also be the case of extremely preterm, BPD-developing neonates who have increased airway resistances, while they are subjected to a deranged alveolarization and lung growth. Neonates presenting with respiratory acidosis may also benefit from NHFOV. Several animal and bench studies investigated the physiology and peculiarities of NHFOV and these data should be used to conduct a physiology-guided trial in order to avoid errors done in the early trials about invasive high frequency ventilation.

This study will be the first large trial aiming to compare CPAP vs NIPPV vs NHFOV in preterm neonates after surfactant replacement and during their entire NICU stay, to reduce the total need of invasive ventilation. Since there is a lack of formal data regarding NHFOV safety, some safety outcomes will also be considered.Specific subgroup analysis will be conducted for pre-specified groups of patients who may most likely benefit from NHFOV, according to the above-described physiological characteristics.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1440 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

When the neonate had fulfilled the extubation criteria, extubation will took place with a gentle intratracheal suction. Upper airways will then be suctioned and intervention will be started immediately as follows:

Ventilators

  • CPAP: CPAP will be provided by either variable flow or continuous flow devices, as there is no evidence that one type of CPAP generator would be better than any other.
  • NIPPV: NIPPV will be provided by any type of neonatal ventilator. Synchronization will not be applied, as many currently marketed neonatal ventilators usually do not provide it for NIPPV.
  • NHFOV: NHFOV will only be provided with piston/membrane oscillators able to provide a real oscillatory pressure with active expiratory phase (that is, Acutronic FABIAN-III, SLE 5000, Loweinstein Med LEONI+, Sensormedics 3100A). Other machines providing high frequency ventilations will not be used.

Importantly, the randomization should be done within one hour from the extubation to avoid bias.

Masking: Double (Investigator, Outcomes Assessor)
Masking Description: Blinding towards the caregivers is impossible and blinding towards the patients makes no sense. However, outcomes' assessors will be blinded, as endpoints will be recorded by investigators not involved in patients' care. An assessor per each participating NICU will be nominated. Moreover, investigators performing the final statistical analyses will be blinded to the treatment allocation, as data collected by assessors will be inserted in the dedicated website and the arms' allocation will be re-coded.
Primary Purpose: Treatment
Official Title: Nasal High Frequency Oscillation Ventilation(NHFOV) vs. Nasal Continuous Positive Airway Pressure(NCPAP) vs Nasal Intermittent Positive Pressure Ventilation(NIPPV) as Post-extubation Respiratory Support in Preterm Infants With Respiratory Distress Syndrome:a Multicenter Randomized Controlled Trial
Actual Study Start Date : January 1, 2018
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2020


Arm Intervention/treatment
Experimental: NHFOV

neonates assigned to NHFOV will be started with the following boundaries:

a) Paw of 10 cmH2O (can be changed in steps of 1 cmH2O within the range range 5- 16cmH2O); Paw 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≤25-30%. Maximal allowed FiO2 will be 0.40 and SpO2 targets will be 90%-95%. b) frequency of 10Hz(can be changed in steps of 1Hz within the range 8-12Hz). c)Inspiratory time 50% (1:1).d)amplitude 25 cmH2O(can be changed in steps of 5 cmH2O within the range 25-50 cmH2o; amplitude will be titrated according to PaCO2.

Device: NHFOV
Nasal high frequency oscillation ventilation (NHFOV) is used as the noninvasive supporting mode after extubation.

Active Comparator: NCPAP
Neonates assigned to the CPAP group were initiated on a pressure of 5 cmH2O. CPAP can be raised in steps of 1 cmH2O up to 8 cmH2O. If this is not enough to maintain SpO2 between 90% and 95%, FiO2 will be added up to 0.40.
Device: NCPAP
Nasal continuous positive airway pressure(NCPAP) is used as the noninvasive supporting mode after extubation.

Experimental: NIPPV
neonates assigned to the NIPPV group will be started with the following parameters: a) positive end-expiratory pressure (PEEP) of 4 cmH2O (can be raised in steps of 1 cmH2O to max 8 cmH2O, according to the oxygenation).b)Peak Inspiratory Pressure (PIP) of 15 cmH2O (can be raised in steps of 1 cmH2O to max 25 cmH2O, according to oxygenation,PaCO2 levels and the chest expansion); maximal allowed FiO2 will be 0.40 and SpO2 targets will be 90-95%. c) inspiratory time (IT) will be 0.45 - 0.5 sec(according to clinicians' evaluation of leaks and the appearance of the pressure curve: a small pressure plateau is required and flow may be set accordingly) and rate will be started at 30 bpm (can be raised in steps of 5 bpm to max 50 bpm, according to PaCO2 levels).
Device: NIPPV
Nasal intermittent positive pressure ventilation(NIPPV) is used as the noninvasive supporting mode after extubation.




Primary Outcome Measures :
  1. duration of invasive mechanical ventilation [ Time Frame: during hospitalization ]
    the total days of the baby supported with the ventilator

  2. ventilator-free days [ Time Frame: during non-invasive ventilation ]
    non-invasive ventilation was need after extubation

  3. the number of reintubation [ Time Frame: during hospitalization ]
    the total numbers of the baby supported with ventilator


Secondary Outcome Measures :
  1. airleaks [ Time Frame: during hospitalization ]
    airleaks was diagnosed after extubation

  2. bronchopulmonary dysplasia(BPD) [ Time Frame: at 36 weeks'gestational age of 36 weeks or at discharge ]
    bronchopulmonary dysplasia was diagnosed after extubation BPD was defined according to the National Institutes of Health consensus definition

  3. Retinopathy of prematurity> 2nd stage [ Time Frame: during hospitalization ]
    Retinopathy of prematurity> 2nd stage was diagnosed after extubation

  4. Neonatal necrotizing enterocolitis≥ 2nd stage [ Time Frame: during hospitalization ]
    Neonatal necrotizing enterocolitis≥ 2nd stage was diagnosed after extubation

  5. Intraventricular hemorrhage>2nd grade [ Time Frame: during hospitalization ]
    Intraventricular hemorrhage>2nd grade was diagnosed after extubation

  6. need for postnatal steroids [ Time Frame: during hospitalization ]
    steroids was used after birth

  7. in-hospital mortality [ Time Frame: during hospitalization ]
    the baby died in hospital

  8. composite mortality/BPD [ Time Frame: during hospitalization ]
    the baby was dead or diagnosed with BPD.

  9. Weekly weight gain [ Time Frame: during hospitalization ]
    Weekly weight gain (in grams/day) for the first 4 weeks of life or until NICU discharge, whichever comes first

  10. haemodynamically significant patent ductus arteriosus (PDA) [ Time Frame: during hospitalization ]
    haemodynamically significant patent ductus arteriosus (PDA) was diagnosed



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   up to 1 Month   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • gestational age between 25+0 and 32+6 weeks;
  • birth weight more than 600 g;
  • supported with any type of endotracheal ventilation;
  • Has not had first attempt at extubation(extubation readiness requires fulfilling of all the following criteria: a. Having received at least one loading dose of 20 mg/kg and 5 mg/kg daily maintenance dose of caffeine citrate; b. pH>7.20 PaCO2<=60 mmHg (these may be evaluated by arterialized capillary blood gas analysis or appropriately calibrated transcutaneous monitors. Venous blood gas values cannot be used); c. Paw <=7-8 cmH2O; d. FiO2<=0.30; e. sufficient spontaneous breathing effort, as per clinical evaluation).;
  • Obtained parental consent. Informed consent will be obtained antenatally or upon neonatal intensive care unit admission.;

Exclusion Criteria:

  • major congenital anomalies or chromosomal abnormalities;
  • Presence of neuromuscular disease;
  • Upper respiratory tract abnormalities; ;
  • need for surgery known before the first extubation;
  • Grade IV-intraventricular haemorrhage (IVH) occurring before the first extubation
  • congenital lung diseases or malformations or pulmonary hypoplasia

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03181958


Contacts
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Contact: Chen Long, PhD,MD 13508300283 petshi530@vip.163.com

Locations
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China, Chongqing
Daping Hospital and the Research Institute of Surgery of the Third Military Medical University Recruiting
Chongqing, Chongqing, China, 400042
Contact: Chen Long, PhD,MD    13883559467    476679422@qq.com   
Contact: Shi Yuan, PhD,MD    13508300283    petshi530@vip.163.com   
Sponsors and Collaborators
Daping Hospital and the Research Institute of Surgery of the Third Military Medical University
Children's Hospital of Chongqing Medical University
Jiulongpo No.1 People's Hospital
Chongqing Maternal and Child Health Hospital
The First Affiliated Hospital of Anhui Medical University
Children's Hospital of The Capital Institute of Pediatrics
Peking University Third Hospital
First Hospital of Tsinghua University
Women and Children's Hospital, Branch of Chongqing Sanxia Central Hospital
First Affiliated Hospital of Chongqing Medical University
Quanzhou Children's Hospital
Xiamen Maternity & Child Care Hospital
Zhujiang Hospital
Nanfang Hospital of Southern Medical University
Guangdong Academy of Medical Science and General Hospital
Guangdong Women and Children Hospital
Women and Children's Health Hospital of Yulin
Women and Children Health Care Hospitalof GuangXi Zhuang Autonomous
Second Affiliated Hospital of Guangzhou Medical University
Guiyang Maternal and Child Health Care Hospital
Zunyi First People's Hospital
Second Hospital of Lanzhou University
Gansu Provincial Maternity and Child-Care Hospital
LanZhou University
First Affiliated Hospital of Harbin Medical University
First Affiliated Hospital of Xinjiang Medical University
Zhengzhou Children's Hospital, China
Third Affiliated Hospital of Zhengzhou University
the Maternal and Child Health Hospital of Hainan Province
Bethune International Peace Hospital
Wuhan Union Hospital, China
Children's Hospital of Nanjing Medical University
First Hospital of Jilin University
Children's Hospital of Fudan University
Maternal and Children's Healthcare Hospital of Taian
The Second Hospital of Shandong University
Shanxi Provincial Maternity and Children's Hospital
Chengdu Women and Children's Center Hospital
The Affiliated Hospital Of Southwest Medical University
Affiliated Hospital of Southwest Medical University
Shenzhen People's Hospital, The Second Medical College of Jinan University
Tianjin Central Hospital of Gynecology Obstetrics
People's Hospital of Xinjiang Uygur Autonomous Region
Kunming Children's Hospital
The First People's Hospital of Yunnan
The First Affiliated Hospital of Kunming Medical College
Yan'an Hospital Affiliated to Kunming Medical University
Women and Children's Health Hospital of Qujing
The People's Hospital of Dehong Autonomous Prefecture
Yinchuan No 1 people's Hospital Affiliated of Ningxia Medical University
The Children's Hospital of Zhejiang University School of Medicine
Women's Hospital School Of Medicine Zhejiang University
Beijing 302 Hospital
Hunan Children's Hospital
Women and Children Hospital of Qinghai Province
Jiangxi Province Children's Hospital
Inner Mongolia People's Hospital
Mianyang Central Hospital
People's Liberation Army No.202 Hospital
Ningbo Women & Children's Hospital
Shanghai Children's Medical Center
First Affiliated Hospital of Guangxi Medical University
Nanjing Medical University
Qinhuangdao Maternal and Child Health Care Hospital
Xuzhou Children Hospital
South Paris University Hospitals, Catholic University of the Sacred Heart
The First Affiliated Hospital of Zhengzhou University
Xianyang children's Hospital
Investigators
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Principal Investigator: Shi Yuan, PhD,MD Daping Hospital and the Research Institute of Surgery of the Third Military Medical University
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Ma Juan, director, Daping Hospital and the Research Institute of Surgery of the Third Military Medical University
ClinicalTrials.gov Identifier: NCT03181958    
Other Study ID Numbers: 201721
First Posted: June 9, 2017    Key Record Dates
Last Update Posted: July 22, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Every researchers can obtain the IPD after the study completely.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: At Oct-22,2017,Suzhou,PR.China.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Ma Juan, Daping Hospital and the Research Institute of Surgery of the Third Military Medical University:
nasal high frequency oscillation ventilation(NHFOV)
nasal continuous positive airway pressure(NCPAP)
nasal intermittent positive pressure ventilation(NIPPV)
neonatal respiratory distress syndrome(NRDS)
preterm infants
Additional relevant MeSH terms:
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Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Premature Birth
Obstetric Labor, Premature
Obstetric Labor Complications
Pregnancy Complications
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases