Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04044976 |
| Other study ID # |
02/2019 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
August 1, 2019 |
| Est. completion date |
August 31, 2021 |
Study information
| Verified date |
March 2023 |
| Source |
University of Florence |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Background. In recent years, particular attention has been paid to all interventions that
could help reduce the need for mechanical ventilation MV and, therefore, the risk of BPD.
However, early application of non-invasive respiratory supports and early treatment with
surfactant fail in 45-50% of cases. Failure frequently depends on the onset of apnea episodes
and, therefore, it has been proposed to treat very preterm infants with caffeine already in
the delivery room in the first min of life.
Hypothesis and objectives of the study. Our aim is to verify the hypothesis that it is
possible to administer caffeine in the delivery room intravenously and enterally via an
orogastric tube.
Study design. Infants 25-29 weeks of gestational age will be enrolled and will be randomized
to receive 20 mg/kg of caffeine citrate intravenously, via the umbilical vein, or enterally,
through an orogastric tube, within 10 min of birth. The dosage of plasma caffeine
concentration will be performed 60+15 min after administration to measure its peak and 60+15
min before the next dose (5 mg/kg/day i.v.).
Endpoints. The primary endpoint will be the evaluation of the success rate of intravenous or
enteral administration of caffeine in the delivery room. Secondary endpoints will be the
evaluation of: number of infants in whom caffeine will be successfully administered by
intravenous versus enteral route; number of infants where caffeine will be successfully
administered that reached the therapeutic plasmatic range the first dose, confirming the
success of the administration; comparison of caffeine blood level obtained with intravenous
and enteral administration; frequency of successes in obtaining the therapeutic range after
the second dose; frequency of MV within the first 72 hours of life in studied infants.
Statistical analysis. In the absence of previous studies to use as a reference and this study
being a feasibility study, it was decided arbitrarily to study 20 infants treated in the
delivery room with caffeine administered intravenously and 20 infants treated in the delivery
room with caffeine administered enterally. The clinical characteristics of the two groups
will be described by calculating the mean value and the standard deviation or the rate and
percentage. The primary endpoint will be evaluated by calculating the percentage of cases in
which caffeine will be successfully administered. The comparison between the number of
infants in which caffeine will be successfully administered intravenously versus the enteral
route and the comparison between the caffeine plasma level obtained with intravenous and
enteral administration will be performed using the Student "t" test for continuous parametric
variables, the Wilcoxon rank sum test for non-parametric continuous variables and the χ2 test
for categorical variables. A p <0.05 will be considered as statistically significant.
Description:
INTRODUCTION Background Mechanical ventilation (MV) is one of the most important risk factors
for the development of bronchopulmonary dysplasia (BPD) in the preterm infant, due to the
early pulmonary inflammation from volume- and baro-trauma and the secondary 1. Despite this,
around 80% of infants born with gestational age <27 weeks must be treated with MV 2 for a
respiratory distress syndrome (RDS), and in about 65% of cases it starts already in the
delivery room in the first min of life 3.
Therefore, in recent years particular attention has been paid to all interventions that could
help reduce the need of MV, thus reducing the risk of BPD. Among these interventions, the
early application of non-invasive continuous positive airway pressure (CPAP), the use of
sustained lung inflation (SLI), and early treatment with surfactant with INSurE (Intubation-
Surfactant-Extubation) or LISA (less invasive surfactant administration) 1,4. These
interventions have the common objective of promoting lung recruitment by promoting the
development and maintenance of alveolar residual functional capacity (CFR), improving
pulmonary compliance, reducing work of breathing and favoring gas exchange 1,4.
Unfortunately, these treatments are not always effective and recent studies have shown that
CPAP in combination or not with surfactant administration fails to prevent MV in about 45-50%
of treated infants 3; similarly the SLI strategy in association with non-invasive CPAP and
with the possible administration of surfactant fails to prevent MV in approximately 60% of
treated infants 5. In fact, in many cases the failure of MV prevention does not depend on
severity of RDS, which also remains a very important factor, but especially in mild-moderate
forms of RDS is due to the onset of relapsing episodes of apnea. Therefore, it has been
proposed to treat very preterm infants with caffeine in the delivery room already in the
first min of life. This drug is very effective in the preterm infant in whom it has been
shown to decrease the frequency of apnea, the risk of BPD, the duration of non-invasive
respiratory supports, and the risk of re-intubation 6, also in infants without previous
crisis of apnea 7.In fact, caffeine stimulates spontaneous respiratory activity, improves
lung compliance and minute volume, reduces airway resistance, and increases diaphragm
contractility, together with a good safety profile and without significant side effects at
current doses 6. In a recent pilot study, Katheria et al. randomized 21 infants with
gestational age <29 weeks to receive 20 mg/kg of caffeine citrate within 2 h of life or at 12
hours of life obtaining in treated infants a decrease, although not statistically
significant, of the need of VM (27 vs. 70%) in association with an overall hemodynamic
improvement 8. Subsequently, Dekker et al. randomized 23 infants of 24-29 gestational weeks
to receive 10 mg/kg of caffeine in the delivery room or immediately after arrival in neonatal
intensive care unit (4.4 vs. 48 min of life) demonstrating that early treatment is associated
with a significant increase in tidal volume and a lower need for oxygen-therapy 9. Although
the results were promising, neither study measured the plasma concentration of caffeine or
had sufficient statistical power to assess whether caffeine administered in the delivery room
is effective in reducing the risk of mechanical ventilation.
Study hypothesis The present feasibility study aims to evaluate the possibility of
administering caffeine in the delivery room intravenously and enterally through an orogastric
tube during the postnatal stabilization of the preterm infant. It is preliminary to the
planning of a subsequent randomized controlled trial of adequate size, which will aim to
assess whether caffeine administered so early can actually reduce the risk of MV in preterm
infants.
Objectives of the study Primary objectives of the study. The primary objective will be the
evaluation of the feasibility of the administration of intravenous or enteral caffeine in the
very preterm infant in the delivery room during assistance for cardiorespiratory
stabilization of the infant.
Secondary objectives of the study. The secondary objectives will be to compare the
feasibility of administering caffeine intravenously vs. enteral and evaluation of the need
for MV in treated infants.
MATERIALS AND METHODS Patients. The study will be conducted in 2 Third Level Neonatal
Intensive Care Units after approval by local ethics committees.
Inclusion criteria. Once the written informed consent of the parents or legal guardians has
been obtained, inborn infants of 25+0-29+6 weeks of gestational age at high risk of
developing "respiratory distress syndrome" (RDS), who do not require MV in the delivery room,
will be enrolled in the study.
Exclusion criteria. Exclusion criteria will be: maternal consumption of caffeine before
giving birth (> 2 cups of coffee in the 6 hours before birth), major congenital
malformations, chromosomal syndromes, fetal hydrops, and inherited metabolic disorders.
Design of the study. Infants will be electronically randomized to receive 20 mg/kg (1 mL=20
mg) of caffeine citrate (Peyona®, Chiesi Farmaceutici Spa, Parma, Italy) intravenously, via
the umbilical vein, or enterally, through an orogastric tube, within 10 min of birth.
Intravenous administration may take place via an umbilical venous catheter or a "butterfly"
needle inserted into the umbilical vein. The bolus of caffeine will be followed by the
administration of a 2 mL "flush" of saline both in the case of administration by venous and
enteral route. Successes and failures of the administration with the two different methods
will be recorded.
The level of plasma caffeine concentration will be measured 60+15 min after the
administration to evaluate its peak and 60+15 min before the administration of the second
dose (5 mg/kg/day i.v.) which will be given after admission in neonatal intensive care unit
10. The plasma level will be measured using the "dried blood spots" method with spectrometry
and "tandem-mass" liquid chromatography 11 in the Laboratory of Clinical Chemistry and
Pharmacology of the A. Meyer Pediatric Hospital of Florence. Blood samples will be collected
with heel punctures commonly performed for monitoring these patients and stored at -80°C
until to analysis.
If necessary, resuscitation in the delivery room will be performed following the guidelines
of the AAP/ AAH 12. After admission in neonatal intensive care, infants who have not required
VM in the delivery room will be assisted with the following non-invasive respiratory
supports: nasal continuous positive airway pressure (NCPAP), "bi-level" NCPAP (BiPAP), nasal
intermittent mandatory ventilation (N-IMV) using a CDP/ PEEP of 5-8 cmH2O. Surfactant
(Curosurf ®, Chiesi, Parma, Italy) will be given (200 mg/kg) according to the INSURE
(Intubation-SURfactant-Extubation) or LISA (Less-Invasive-Surfactant-Administration)
technique in infants requiring FiO2 >0.30 to maintain a SpO2 90-95% and in all infants who
will need MV.
MV will be started in the case of pCO2 >65 mmHg and pH <7.20, or pO2 <50 mm Hg with FiO2
>0.50 after surfactant administration or in case of apnea (> 4 episodes in 1 hour or> 2
episodes in 1 hour requiring manual ventilation), and will be conducted with the aim of
maintaining a pCO2 of 55-65 mmHg and a SpO2 of 90-95% 9, using synchronized VM (patient
triggered ventilation: PTV), or the volume controlled VM, or high frequency ventilation
(HFV).
Collected data. For each infant will be recorded: gestational age; birth weight; birth weight
<10th percentile; gender; type of delivery; Apgar score at 5 min; main disorders of pregnancy
(pre-eclampsia, premature rupture of membranes, clinical chorioamniositis, placental
abruption); RDS, whose diagnosis will be based on the occurrence of oxygen-dependence,
tachypnea, dyspnea, exclusion of other causes of respiratory failure, and the presence of a
typical radiological pattern; treatment with surfactant and nitric oxide; need, type and
duration of respiratory assistance (oxygen therapy, NCPAP, BiPAP, N-IMV, PTV, HFV); prenatal
and postnatal steroid treatment. In addition, common complications of prematurity will be
recorded: patency of the ductus arteriosus (PDA) requiring drug therapy, bronchopulmonary
dysplasia (BPD), intraventricular hemorrhage (ICH) of 3-4 grade 13, periventricular
leukomalacia (LPV) 14, retinopathy of prematurity (ROP) of grade >3 15, necrotizing
enterocolitis (NEC) <2 grade 16, and sepsis. In addition, mortality and the duration of
hospitalization will be reported.
Permitted concomitant pharmacological treatments. The enrolled patients can be treated with
the following drugs: surfactant, caffeine, doxapram, ibuprofen, paracetamol, indomethacin,
dopamine, dobutamine, milrinone, adrenaline, diuretics, antibiotics, glucocorticoids,
immunoglobulins, antiepileptics, nitric oxide, analgesics, sedatives.
List of participating centers. Patients will be enrolled at the neonatal intensive care units
of Careggi University Hospital of Florence and of IRCCS Foundation - Ospedale Maggiore
Policlinico Mangiagalli and Regina Elena of Milan.
ENDPOINTS Primary endpoint. The primary endpoint will be the evaluation of the number of
infants in whom the administration of caffeine intravenously or enterally will occur
successfully in the delivery room delivery within 10 min of life.
Secondary endpoints. Secondary endpoints will be the evaluation of: number of infants in whom
caffeine will be successfully administered by intravenous versus enteral route; number of
infants where caffeine will be successfully administered that reached the therapeutic
plasmatic range the first dose, confirming the success of the administration; comparison of
caffeine blood level obtained with intravenous and enteral administration; frequency of
successes in reaching the therapeutic range after the second dose; frequency of VM within the
first 72 hours of life in studied infants.
STATISTICAL ANALYSIS Sample size. In the absence of previous studies to use as a reference
and this study being a feasibility study, it was decided arbitrarily to study 20 infants
treated in the delivery room with caffeine administered intravenously and 20 infants treated
in the delivery room with caffeine administered enterally.
Description and analysis of data. The clinical characteristics of the two groups will be
described by calculating the mean value and the standard deviation or the rate and
percentage.
The primary endpoint will be evaluated by calculating the percentage of cases in which
caffeine will be successfully administered. Similarly, the secondary endpoints, represented
by the number of cases in which the therapeutic plasmatic range will be reached after the
first and the second dose of caffeine and the frequency of VM within the first 72 hours of
life, will be evaluated. The comparison between the number of infants in which caffeine will
be successfully administered intravenously versus the enteral route and the comparison
between the caffeine plasma level obtained with intravenous and enteral administration will
be performed using the Student "t" test for continuous parametric variables, the Wilcoxon
rank sum test for non-parametric continuous variables and the χ2 test for categorical
variables. A p <0.05 will be considered as statistically significant.
