Study Design
This protocol describes a pilot randomised, unblinded, controlled trial. The study flow is outlined in fig.1. The study will be held in a III level NICU in Fondazione Policlinico Agostino Gemelli – IRCCS in Rome – Italy. The study will last 18 months and will involve 20 patients (10 for each group).
Participants
ELGANs still requiring invasive mechanical ventilation at 7-10 days of life with a fraction of inspired oxygen (FiO2) of more than 0.30 and/or an oxygenation index of 8 or more for at least 6 hours will be eligible for the study. Only infants for whom written consent from the parents or legal guardian will be obtained will be randomized. Infants will be randomly assigned to receive mechanical ventilation and poractant alfa (Treatment Group) or continue mechanical ventilation following local protocols (Control Group). Mechanical ventilation will be High Frequency Oscillatory ventilation in either group, since in our centre it is the elective modality for ELGANs. In the control arm, HFOV will be used according to the department protocol which includes the modification of the ventilatory parameters every 8-12 hours on the bases of the blood gases analyses, the SpO2 value and the chest x-rays. In both groups, extubation will be performed when a Mean Airway Pressure <9 cmH2O and a FiO2 <0.3 will be required to maintain the SpO2 stably between 90 and 95% and the deltaP will not exceed 20 cmH2O with a Frequency equal to 13-15 Hz to maintain pCO2 value between 45 and 55 mmHg with. The patients enrolled will be 10 for each group. Enrolled infants will be under supervision in the NICU.
Inclusion criteria
- Extremely low gestational age newborn infants (GA < 28 weeks) – gestational age matching between maternal dates and/or early antenatal ultrasound
- Singleton or multiple birth
- Postnatal age between 7 and 10 days
- Invasive mechanical ventilation still needed
- Fraction of inspired oxygen (FiO2) of more than 0.30 and/or an oxygenation index of 8 or
- more for at least 6 hours
- Stable cardiovascular condition
- Informed consent form signed by parents or legal guardian
Exclusion Criteria
- Major congenital malformation (i.e., infants with genetic, metabolic or endocrine disorder diagnosed before enrolment)
- High index of suspicion of infection before enrolment
- Neurological conditions that might contraindicate extubation
- Inotropic agents needed
- Pneumothorax
- Hemodynamically significant ductus arteriosus
- Surgical intervention within the past 72 hours
- Partecipation in another interventional clinical study that may interfere with the results of this trial
- Known hypersensitivity to the drug or to one of the excipient
Procedures
Once the informed consent form is signed, eligibility will be confirmed. All inclusion and exclusion criteria must be confirmed within 24 hours prior to the first dose of study drug. Complete medical history and physical examination will be performed and blood tests will be documented from the infant’s charts. Information regarding siblings and mother’s medication during and after pregnancy will be collected. Screening procedures will be performed and recorded in the infant’s source document and eCRF. Following screening procedures eligible infants will be randomly assigned to one of the two treatment groups. Randomization will be performed using random allocation generated by computer code. The randomization will be performed in permuted unequal blocks. The random allocation sequence will be generated using the module ralloc.ado in Stata/IC 16.1 (Stata-Corp, College Station, Texas). Concealment will be performed by closed envelopes.
After randomisation, during the treatment period, the following data will be recorded every day: physical examination, ventilation parameters, need of oxygen, OI, pH, pCO2, pO2, BE, vital signs as SpO2, Heart rate, Diastolic and Systolic Blood pressure, respiratory rate, Silverman Score; recording of concomitant medications; lung expansion at lung Xray if performed; weight; any adverse event. The same data will be recorded weekly until 36 weeks PMA and then at 40 weeks PMA or discharge whichever comes first. Follow-up will continue after discharge until the first year of corrected term-age: babies will be visited at 3 months of corrected term-age and at one year of corrected term-age. During the follow-up visits, parents will fulfil a questionnaire regarding the respiratory condition of their baby at home. For all procedures see fig.2.
Intervention
Intervention group will receive up to 4 doses (100 mg/Kg) of Poractant alfa (Curosurf – Chiesi) every 12 hours; each dose will be preceded by a recruitment manoeuvre in HFOV. Optimal recruitment is defined as adequate oxygenation using a fraction of inspired oxygen (FiO2) of 0.30 or less. The continuous distending pressure (CDP) will be increased stepwise (1 cmH2O every 2–3 min) as long as pulse oximetry (SpO2) improves. The FiO2 will be reduced stepwise, keeping SpO2 within the target range (87–94 %). The recruitment procedure will be stopped if oxygenation no longer improves or if the FiO2 is equal to or less than 0.30. The corresponding CDP will be called the opening pressure (CDPO). Next, the CDP will be reduced stepwise (1–2 cmH2O every 2–3 min) until the SpO2 deteriorates (by at least 2–3 points). The corresponding CDP will be called the closing pressure (CDPC). After a second recruitment maneuver at CDPO for 5 min, the optimal CDP (CDPOPT) will be set 2 cmH2O above the CDPC for at least 3 min. All infants will receive caffeine at a dose of 5 mg/kg/die. All infants will receive remifentanil infusion during mechanical ventilation (0.075-0.3 mcg/kg/min). Infants still requiring MV at days 13 of age will be started on the low dose corticosteroid regime used in the DART study by Doyle et al (13).
Outcome measures
Primary outcome: The time to first successful extubation (day of life).
Defining an extubation as “successful” is a very hard task, since in preterm newborns many reintubation occur for extra-respiratory reasons. In a recent study, reintubations due to non-respiratory causes were negligible in the first week after extubation, but became much more frequent after 14 days. For these reasons, we chose to define an extubation “successful” if it is not followed by a reintubation in the subsequent 7 days (14). This will provide a more complete overview of the true reintubation rates, making them easier to compare. Extubation criteria include: FiO2 less than 0.30 for arterial oxygen percent saturation between 88% and 92% and partial pressure of carbon dioxide between 40 and 55 mm Hg for at least 6 hours with a MAP ≤ 9 cmH2O. Criteria for reintubation: 6 episodes of apnea and/or bradycardia that require stimulation over a 6-hour period; 1 episode of apnea and/or bradycardia that require resuscitation with positive pressure; FiO2 greater than 0.40 with a MAP> 8 cmH2O for more than 4 hours; or partial pressure of carbon dioxide greater than 60 mmHg and a pH < 7.20; Silvermann Score > 6; respiratory rate > 100/min; haemodynamic instability; need of surgery; new onset of contraindications to non invasive ventilation. All babies will be on Caffeine therapy at a dosage of 5 mg/kg/die.
Secondary outcomes: incidence of pneumothorax, incidence of interstitial emphysema, incidence of pulmonary haemorrhage, incidence of necrotising enterocolitis, incidence of intraventricular haemorrhage occurring after the randomization, incidence of periventricular leukomalacia, and chronic lung disease of prematurity, length of hospital stay, length of mechanical ventilation, length
of oxygen-therapy, length of respiratory support, use of post-natal steroids. All surviving infants will be reviewed for follow-up at 1 year of age. Parents will be interview to record all events occurring after discharge (rehospitalisation for respiratory problems with the need for reintubation, invasive ventilation, and oxygen supplementation; corticosteroid use after discharge; outpatient visits for respiratory problem). Ventilator, clinical and blood gases data will be recorded during the procedure and every 12 hours in the first 3 days after intervention. A lung ultrasound will be performed before the first intervention and then daily until extubation or for the following 3 days.
Statistical analysis
No formal sample size calculation was performed because this is a pilot study whose results will permit to design a full-scale RCT. Revising our past records, we estimate that there will be a number of 20-25 patients having the eligibility criteria in the study period. Therefore, we chose to recruit 10 patients in each group. Clinical characteristics of infants will be described using mean values and standard deviation, median value and range, or rate and percentage. Univariate statistical analysis will be performed using the Student “t” test for parametric continuous variables, the Wilcoxon rank-sum test for non-parametric continuous variables, and Fisher’s exact test for categorical variables. A p <0.05 will be considered statistically significant.
Data management
The Sponsor’s designees will monitor all aspects of the study carefully with respect to ICH GCPs and SOPs for compliance with applicable government regulations. eCRF will be periodically monitored and source verified against corresponding source documentation (e.g., office and clinical laboratory records) for each subject. Clinical monitors will evaluate periodically the progress of the study, including the verification of appropriate consent form procedures, review of drug accountability and study drug preparation procedures, adherence to dosing procedures, the investigator’s adherence to the protocol, maintenance of records and reports, review of source documents for accuracy, completeness, and legibility, and review of study regulatory documents, including, but not limited to: study agreement, study insurance. In addition, the monitor shall review completed eCRF and study documentation for accuracy and completeness, and protocol compliance. The monitor should assure that data captured in the eCRF is fully supported by the source documents.