Comparison of Efficacy of Less Invasive Surfactant Treatment Under Nasal CPAP and Nasal IPPV in Premature Babies: CURLISPAP Study
Phase: NA
Conditions: Respiratory Distress Syndrome
Sponsor: Uludag University

Protocol: Version 1 
 
January 7, 2020 
 
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                                       NCT NUMBER:  NCT04698473 
 
 
 
Primary Investigator 
Hilal Ozkan, MD 
Bursa Uludag University Faculty of Medicine, Division of Neonatology 
Bursa Uludag University Campus of Görükle 16059 Nilüfer/BURSA 
Phone:  (224) 2950427 
    Fax:  (224) 294-06291000   
 
 
Sponsor  
                      Bursa Uludag University 
Phone:  (224) 294-0600 
    Fax:  (224) 294-06291000   
 
 
   
 
 
  
 
Comparison of efficacy of less invasive 
surfactant treatment under nasal CPAP and 
nasal IPPV in premature babies:  CURLISPAP 
STUDY 

Protocol: Version 1 
 
January 7, 2020 
 
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STUDY SUMMARY 
  
Title    
 
Comparison of efficacy of less invasive surfactant treatment 
under nasal CPAP and nasal IPPV in premature babies:  
CURLISPAP STUDY 
Methodology  
Randomized, controlled trial  
Study Duration 
Estimated duration for the main protocol (e.g. from start of 
screening to last subject processed and finishing the study) is 
approximately 2.0 years 
Study Center(s) 
Multi-center (Uludag University Hospital Marmara University 
Hospital, Gazi University Hospital, Ankara University Hospital 
Başakşehir Çam ve Sakura City Hospital and Dokuz Eylul 
University Hospital) 
Objectives 
Primary Objective:  
To compare the effectiveness of nasal intermittent positive 
pressure ventilation (NIPPV) versus nasal continuous positive 
airway pressure (CPAP)  in preterm infants with  respiratory 
distress syndrome (RDS). 
Secondary Objectives:  
To evaluate short and long term neonatal outcomes such as 
bronchopulmonary 
dysplasia, 
duration 
of 
mechanical 
ventilation,  retinopathy of premature  and intraventricular 
hemorrhage.     
Number of 
Subjects 
170 randomized patients in two arms;  NCPAP and NIPPV 
group 
Diagnosis and 
Main Inclusion 
Criteria 
Inclusion Criteria 
• 
Gestational age 24 -29 week 
• 
Clinical and radiological diagnosis of RDS  
• 
Born in a hospital with a study center  
• 
Spontaneous breathing  
• 
Within the first 6 hours  
• 
Non-invasive ventilation and FiO2 requirement >0.30    
• 
Parental concent   
 
Exclusion Criteria  
• 
Major congenital malformations 
• 
Need of mechanical ventilation 
• 
Need of entubation in delivery room  
• 
Air weak syndrome  
• 
No parental concent 
 
Study Product, 
Dose, Route, 
Regimen 
 
NCPAP Group:  Will receive standard NCPAP protocol  
 
NIPPV Group:  Will receive standard NIPPV protocol  
 
SURFACTANT: As a surfactant preparation, Curosurf® will 

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be applied in all patients with a standard dose of 200 mg / 
kg and a special catheter Lisacath® as a standard in all of 
patients.  
 
 
PURPOSE 
 
To evaluate the effectiveness of nasal intermittent positive pressure ventilation 
(NIPPV) versus nasal continuous positive airway pressure (CPAP)  in preterm infants 
with respiratory distress syndrome (RDS). 
 
BACKGROUND 
 
Respiratory distress syndrome (RDS) is the leading cause of respiratory failure in 
preterm infants. The incidence and severity of RDS are inversely related to the 
gestational age of the newborn. Despite recent improvements in neonatal care,  RDS 
still remains as major cause of morbidity and mortality in preterm infants. Exogenous 
surfactant treatment is known to reduce mortality and morbidity in premature infants 
with RDS.  
Surfactant therapy should be performed by health care-givers who are experienced 
in intubation and MV of the newborn. Most premature infants can tolerate extubation 
after application of surfactant and continue with CPAP or nasal intermittent positive 
pressure ventilation (NIPPV) so INSURE (INtubate, SURfactant, Extubate) can be 
preferred as the surfactant application method. Researchers have thus been looking 
for less invasive ways to administer surfactant without the need for intubation.  A 
method, called LISA (less invasive surfactant administration) in which a soft flexible 
catheter instead of an endotracheal tube is placed in the trachea under direct 
laryngoscopy using Magill forceps and the surfactant is applied. The method, non 
invasive ventilation (NIV) continues during the surfactant application. All meta-
analyses reviewing LISA methods showed that LISA reduced the need for MV in the 
first 72 hours of life.  LISA method  can be used with NCPAP or NIPPV.    
 
GOALS OF THE STUDY 
 
1. To compare the effectiveness of NIPPV versus  NCPAP in preterm infants 
with   RDS. 
2. To evaluate the development of apnea, bradycardia, desaturation and 
surfactant reflux  
3. To evaluate need of repeat surfactant dose 
4. To evaluate need of mechanical ventilation within 72 hours following 
surfactant treatment 
5. To evaluate duration of non invasive and invasive ventilation  
6. To evaluate long term outcomes such as bronchopulmonary dysplasia, 
retinopathy 
of 
premature, 
intraventricular 
hemorrhage, 
necrotizing 
enterocolitis.  
  
DURATION OF THE STUDY 

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Estimated duration for the main protocol (e.g. from start of screening to last subject 
processed and finishing the study) is approximately 2.0 years 
 
PRODUCT DESCRIPTION 
 
As a surfactant preparation, Curosurf® will be applied in all patients with a standard 
dose of 200 mg / kg and a special catheter Lisacath® as a standard.  
 
STUDY ARMS 
 
1. NCPAP Group:  Will receive standard NCPAP protocol  
a. Ventilator-derived NCPAP will be administered using binasal prongs. 
Standard Devices or infant flow-driver device. Initial NCPAP settings 
are: PEEP:6 cmH2O and FiO2: adjusted to keep preductal sPO2 
between %90-94. Failure is defined as FiO2 requirement of >%50, 
capillary blood gas obtained at the 4th hour of therapy showing 
pH<7.20 or pCO2>60 cmH2O. 
 
2. NIPPV Group:  Will receive standard NIPPV protocol 
a. Ventilator-derived NIPPV will be administered using binasal prongs. 
Standard Devices or infant flow-driver device. Initial NIPPV settings 
are: PEEP:6 cmH2O, PIP: 15 cmH2O, Rate: 30-40/ bpm and FiO2: 
adjusted to keep preductal sPO2 between %90-94. Failure is defined 
as FiO2 requirement of >%50, capillary blood gas obtained at the 4th 
hour of therapy showing pH<7.20 or pCO2>60 cmH2O. 
  
POTENTIAL BENEFITS AND RISKS TO PATIENTS 
 
The study includes routine treatment protocols. LISA is one of the standard 
surfactant treatment applications. Possible complications during surfactant treatment 
such as  apnea, bradycardia, desaturation and surfactant reflux will be followed. 
 
 
METHODS 
 
Study Design. 
 
The prospective, multi-center, randomized, controlled study involving one hundred 
and seventy (170) premature with RDS.  
 
Study population and selection criteria 
 
Premature babies who have spontaneous breathing between 241/7- 296/7 weeks and 
who have FiO2>0.3 required to reach target saturation (90-94%), who are indicated 
for surfactant treatment and who are within the first 6 hours of life. 
 

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Inclusion Criteria 
 
Gestational age 241/7- 296/7 week 
 
Clinical and radiological diagnosis of RDS  
 
Born in a hospital with a study center  
 
Spontaneous breathing  
 
Within the first 6 hours 
 
Non-invasive ventilation and  FiO2 requirement >0.30  
 
Parental concent   
 
Exclusion Criteria  
 
Major congenital malformations 
 
Need of mechanical ventilation 
 
Need of entubation in delivery room  
 
Air weak syndrome  
 
No parental concent 
 
Study centers and collaborators 
 
1. Uludag University Faculty of Medicine, Division of Neonatology 
 
Hilal Ozkan (Coordinator, Principal investigator, Neonatolog) 
 
Nilgun Koksal (Co-investigator, Neonataolog) 
 
Fatma Kocael (Co-investigator, Fellow of Neonatology) 
2. Marmara University Faculty of Medicine, Division of Neonatology 
 
Eren Özek   (Principal investigator, Neonataolog) 
 
Hülya Özdemir  (Co-investigator, Neonataolog) 
 
Sinem Gülcan Kesrin  (Co-investigator, Fellow of Neonatology) 
3. Gazi University  Faculty of Medicine, Division of Neonatology 
 
Esin Koç  (Principal investigator, Neonataolog) 
 
Canan Türkyılmaz  (Co-investigator, Neonataolog) 
 
İbrahim Hirfanoğlu  (Co-investigator, Neonataolog) 
4. Ankara University Faculty of Medicine, Division of Neonatology 
 
Saadet Arsan   (Principal investigator, Neonataolog) 
 
Ömer Erdeve  (Co-investigator, Neonataolog) 
 
Emel Okullu  (Co-investigator, Neonataolog) 
5. Başakşehir Çam-Sakura City Hospital, Neonatology 
 
Merih Çetinkaya  (Principal investigator, Neonataolog) 
 
Beril Yaşa  (Co-investigator, Neonataolog) 
 
İlker Gönen  (Co-investigator, Fellow of Neonatology) 
6. Dokuz Eylul University Faculty of Medicine, Division of Neonatology   
 
Hasan Ozkan  (Principal investigator, Neonataolog) 
 
Nuray Duman  (Co-investigator, Neonataolog) 
 
Funda Tuzun (Co-investigator, Neonataolog) 
  
Recruitment methods 
 

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Subjects will be identified through of investigators in study centers. The Primary 
Investigators and their partners (co-investigators) will be performing the    study 
groups treatment.   
 
Data collection and reporting 
 
Patient data will be collected electronically through the “Turkish Neonatal Society 
Trials Network” operating system. Data from the study will be maintained for two (2) 
years after the date the investigation is completed, terminated or until the records are 
no longer required to support the protocol, whichever date is later. 
 
Expected outcomes 
 
The study objective is to compare the effectiveness of nasal NIPPV versus CPAP in 
preterm infants with  RDS. It is thought that the surfactant treatment by LISA with 
both methods will be effective. 
 
Adverse reactions 
 
There is no expectation of any adverse outcomes. It has been shown that surfactant 
administration can be performed safety with the LISA method. No risk is expected in 
the study, and benefits are expected in both groups. 
 
REASONS FOR WITHDRAWAL OR TERMINATION 
 
Parents may be discontinued from the study at any time, for any reason, specified or 
unspecified, and without prejudice    
The following is a list of possible reasons for study treatment discontinuation: 
 
• Screening Failure 
• Parents withdrawal of consent 
• Lost to follow-up 
• Subject death before 36 week gesatational age 
 
METHODS AND STUDY SCHEDULE 
 
Subjects eligible for the study will review and undergo informed consent. Once 
consented, subjects will be randomly assigned on a 1:1 basis to undergo: 
 
•   NCPAP Group:  Will receive standard NCPAP protocol  
•   NIPPV Group:  Will receive standard NIPPV protocol 
 
  Randomization 
o Patients who are hospitalized in the neonatal intensive care unit (NICU) due to 
RDS within the first 6 hours of life, and who are indicated for non-invasive 

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surfactant administration (LISA) due to their spontaneous breathing, will 
randomized  as NCPAP or  NIPPV.   
o Randomization will be done automatically over the Turkish Neonatal Society 
Trials Network system, without being user dependent. 
o When entered into the system, each patient will be given a number, and each 
center will be able to enter their own patient's data.  
  
 
Standard procedures after randomization  
o Patients in the NCPAP group will start CPAP with an initial pressure of 6 cm H2O, 
while patients in the NIPPV group will be applied 6 cm H2O pressure, 15-20 cm 
H2O peak inspiratory pressure, and NIPPV at a rate of 20-30 per minute. 
o  In both groups, the surfactant will be administered at a dose of 200 mg / kg / 
dose through a special catheter named Lisacath, by visualizing the vocal cords 
by the responsible and experienced physician in each center. 
o In cases with fractional inspired oxygen FiO2
  >0.3, the second dose of surfactant 
will be administered within the first 12 hours at least 6 hours after the first dose. 
o "Study Algorithm" is presented. 
o Data such as possible adverse effects, complications related to the procedure, 
prenatal, natal and postnatal demographic characteristics, need for repeat dose 
surfactant, intubation requirement and time, follow-up NCPAP / NIPPV settings 
will be recorded. 
  
Baseline/Screening  Visit  1 (-14 to -1 days from day 0) 
  
The following procedures will be performed at the Baseline/Screening visit:  
 
 
Review the study with the subject and obtain written informed consent  
 
Review and record antenatal and postnatal medical history to determine 
eligibility based on inclusion/exclusion criteria  
 
Record demographics  
o 
Maternal 
 
Maternal age 
 
Preeclampsia  
 
Diabetes 
 
Antenatal steroid 
 
Drugs 
 
Chorioamnionitis 
 
Premature rupture of membranes 
 
Caesarian or normal vaginal delivery 
 
Multipl pregnancy 
o Neonatal 

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 
Gestational age (week) 
 
Birth weight (gram) 
 
Apgar scores 
 
Gender 
 
Perform physical examination  
 
Record settings of ventilation 
 
NCPAP group: Positive end expiratory pressure (PEEP), FiO2   
 
NIPPV group:  Peak inspiratory pressure (PIP), PEEP, FiO2  , 
rate, flow. 
 
Record blood gas analysis  
 
    Surfactant treatment 
 
Surfactant preparation, standard Curosurf® will be applied at a dose of 200 
mg / kg and a special catheter Lisacath® as standard 
 
Surfactant application with the LISA method, which is routinely used in the 
world and in our country, was well tolerated in most cases. Although sudden 
decreases in heart rate for less than 10 seconds can be seen in 
approximately half of the cases during surfactant administration by LISA 
method, such short-term changes in heart rate are not considered harmful for 
the baby. In current studies, problems such as airway damage or damage to 
the vocal cords have not been encountered. The treatment team will apply 
treatments that will reduce pain and eliminate possible discomfort when 
necessary.  
 
Surfactant reflux may occur during less invasive surfactant application. 
 
Surfactant reflux will be scored according to the status of reflux in the 
catheter, in the mouth and in the nose.  
      Visit 2:  (1st hours after surfactant treatment)   
 
Record settings of ventilation 
 NCPAP group: PEEP, FiO2   
 NIPPV group:  PIP, PEEP, FiO2 , rate, flow. 
 
Record blood gas analysis  
      
      Visit 3:  (4st hours after surfactant treatment)   
 
Record settings of ventilation 
 NCPAP group: PEEP, FiO2   
 NIPPV group:  PIP, PEEP, FiO2 , rate, flow. 
 
Record blood gas analysis  
 

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       Visit 4:  (7nd days)   
 
Neonatal outcomes 1 
o Need of mechanical ventilation and entubation, time of entubation 
o Need of repeat surfactant treatment 
 
       Visit 5:  ( Postnatal 36 gestational week))   
 
 Type of respiratory support 
o NCPAP 
o NIPPV  
o Mechanical ventilation 
o Head box oxygen 
o No resiratory support 
      Visit 6: (discharge date) 
 
Neonatal outcomes 2 
o Duration of total NCPAP, NIPPV, entubation and oxygen 
o Intraventricular hemorrhage 
o Bronchopulmonary dysplasia 
o Necrotizing enterocolitis 
o Retinopathy of prematurity 
o Sepsis 
o Advers events 
Unscheduled Visit 
The following procedures will be performed if the subject presents to the clinic at any 
other time point not specified above 
 
Assess for adverse events 
 
Assess for complications following treatments 
  RANDOMIZATION 
o Patients who are hospitalized in the neonatal intensive care unit (NICU) due to 
RDS within the first 6 hours of life, and who are indicated for non-invasive 
surfactant administration (LISA) due to their spontaneous breathing, will 
randomized  as NCPAP or  NIPPV.   
o Randomization will be done automatically over the Turkish Neonatal Society 
Trials Network system, without being user dependent. 

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o When entered into the system, each patient will be given a number, and each 
center will be able to enter their own patient's data.  
   SAMPLE SİZE JUSTIFICATION 
With the power analysis performed for the study, the number of samples required 
to determine a 15% difference in terms of going to mechanical ventilation 
between both groups was calculated as 170, with a power of 80% for each group.  
In the study, 15% of the difference in babies 26 weeks and younger; Under the 
assumption that the difference will be 10% for babies older than 26 weeks, it is 
planned to have babies aged 26 weeks and younger than 26 weeks equally in 
each group. 
STATISTICAL ANALYSIS PLAN  
 
Primary Endpoint  
 
Need of mechanical ventilation first 72 hours in life  
 
Secondary Endpoints  
 
Development of bronchopulmonary dysplasia and other prematurity-related morbidity  
 
All analyses will be performed using per-protocol population as well as intention-to-
treat population.   
ASSESSMENT OF SAFETY  
Adverse events (AE) will be monitored and collected by the study team  For each AE, 
a detailed explanation will be obtained from the subject and subject’s medical record. 
All AEs will be recorded on the CRFs.  
Definition of Severe Adverse Event (SAE) 
An AE is defined as any unanticipated medical occurrence regardless to relationship 
of the investigative arm of the trial.   
 
Death 
 
Prolong hospitalisation  
Relationship to Study Products 
For all collected AEs, the clinician who examines and evaluates the participant will 
determine the AE’s causality based on temporal relationship and his/her clinical 

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judgment. The degree of certainty about causality will be graded using the categories 
below. 
Definitely: The relationship of the AE and the study device or the study procedure 
can definitely be established. 
Probably: While a clear relationship to the study device or to the study procedure 
cannot be established, the AE is associated with an expected AE or there is no other 
medical condition or intervention, which could explain the occurrence of such an 
event. 
Possibly: There is no clear relationship between the AE and the study device or 
study procedure; however, one cannot definitely conclude that there is no 
relationship. 
Unrelated: There is no relationship between the AE and the study device or study 
procedure.   
SAE Reporting 
In the case of a SAE, the Investigator must notify the Sponsor within 1 working day 
after the Investigator first learns of the event.   
DATA MONITORING 
Study data will be collected electronically via “Turkish Neonatal Society Trials 
Network System”. The Principal Investigator will be responsible to ensure the study is 
conducted in accordance with the protocol, applicable regulatory requirements, and 
that the data recorded is valid. To achieve this objective, the study will be 
continuously monitored and reviewed on a monthly basis by the study team. 
 
 
 
DATA HANDLING AND RECORD KEEPING  
  
Study data will be collected electronically via “Turkish Neonatal Society Trials 
Network System”. Only study personnel will collect data. Data will be exported into 
Excel file format (password protected), which will then be used for data analysis. 
Only de-identified data will be used for data analysis. All  documents will be shredded 
within five years after completion of the study upon Sponsor approval 
CONSENT PROCESS  
 

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Each potential issue must provide written consent with complete information on the 
procedures involved. the informed consent must be fully disclosed by the Researcher 
or study staff, including the purposes, methods, benefits, and risks of the trial, and 
signed by the subject prior to participation in the study. Potential issues will be 
informed that participation in the study is optional and can be withdrawn at any time. 
The parents will be told that choosing to participate will not affect the care received 
for treatment. Parents will be informed that they will allow research staff to access 
confidential medical records. The subject will be given sufficient time to read the 
confirmation and ask any questions. Once the informed consent has been signed, 
the parentswill be given a copy of the document. 
 LAWS AND REGULATIONS 
This study was approved by the “Uludag University Faculty of Medicine Clinical 
Research Ethics Committee” and Turkish Ministry of Health, Turkish Medicines and 
Medical Devices Agency.   This clinical study will be conducted in compliance with all 
national laws and regulations as well as any applicable guidelines. The trial will be 
registered on www.clintrials.gov and on other sites, as appropriate.  
PUBLICATION AND DATA SHARING POLICY  
 
The preparation and submittal for publication of manuscripts containing the study 
results shall be in accordance with a process determined by mutual written 
agreement among the study Sponsor and participating institutions.   
 
STUDY PERSONNEL AND ROLES 
Hilal Ozkan, MD 
 
Uludag University   
Study Coordinator, 
Principal investigator 
Responsible for all study 
related issues 
Data collection; screen, 
consent, randomize, and 
follow up with subjects 
Nilgun Koksal, MD 
Uludag University   
Co-investigator 
Data collection; screen, 
consent, and follow up with 
subjects 
Fatma Kocael 
Uludag University   
Co-investigator 
Data collection; screen, 
consent, and follow up with 
subjects 
Eren Ozek, MD     
 
Marmara University 
Principal investigator 
Data collection; screen, 
consent, randomize, and 
follow up with subjects 
Hülya Ozdemir, MD   
Marmara University 
Co-investigator 
Data collection; screen, 
consent, and follow up with 
subjects 
Sinem Gulcan Kesrin 
Marmara University 
Co-investigator 
Data collection; screen, 
consent, and follow up with 
subjects 
Esin Koç, MD 
Gazi University 
Principal investigator 
Data collection; screen, 
consent, randomize, and 
follow up with subjects 

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Canan Turkyılmaz, MD   
Gazi University 
Co-investigator 
Data collection; screen, 
consent, and follow up with 
subjects 
İbrahim Hirfanoğlu, MD   
Gazi University 
Co-investigator 
Data collection; screen, 
consent, and follow up with 
subjects 
Saadet Arsan, MD    
 
Ankara University 
Principal investigator 
Data collection; screen, 
consent, randomize, and 
follow up with subjects 
Omer Erdeve, MD  
Ankara University 
Co-investigator, 
Data collection; screen, 
consent, and follow up with 
subjects 
Emel Okullu, MD   
Ankara University 
Co-investigator, 
Data collection; screen, 
consent, and follow up with 
subjects 
Merih Cetinkaya, MD, 
PHD 
Başakşehir Çam-   
Sakura City Hospital 
Principal investigator 
Data collection; screen, 
consent, randomize, and 
follow up with subjects 
Beril Yaşa, MD   
Başakşehir Çam-   
Sakura City Hospital 
Co-investigator 
Data collection; screen, 
consent, and follow up with 
subjects 
İlker Gönen   
Başakşehir Çam-   
Sakura City Hospital 
Co-investigator 
Data collection; screen, 
consent, and follow up with 
subjects 
 
CONFLICTS OF INTEREST 
No conflicts of interest have been reported. 
 
APPENDIX   
 
Visit 
Screening/Baseline 
-14 to -1 day from 0 
day 
Treatment  
hour 0 
Treatment 
hour 1 
Treatment 
hour 4  
Postnatal 
7 day 
Postnatal 
36  GW 
Discharged 
Unscheduled 
Visit 
Informed Consent 
  
 
 
 
 
 
 
 
Assign subject ID 
 
 
 
 
 
 
 
 
Medical History   
 
 
 
 
 
 
 
 
Concomitant 
Meds 
Physical Exam 
 
 
 
 
 
 
 
 
Inclusion/ 
exclusion criteria 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
Bloog gas 
analysis  
 
 
 
 
 
 
 
 
AE /complication