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Caffeine Treatment in in the Delivery Room (CAFROOM)

Primary Purpose

Respiratory Distress Syndrome

Status
Completed
Phase
Not Applicable
Locations
Italy
Study Type
Interventional
Intervention
Caffeine Citrate
Sponsored by
University of Florence
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional supportive care trial for Respiratory Distress Syndrome focused on measuring Caffeine, delivery room, preterm infant

Eligibility Criteria

1 Minute - 10 Minutes (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Inborn infants
  • Infants with 25+0-29+6 weeks of gestational age
  • Infants who do not require MV in the delivery room

Exclusion Criteria:

  • Maternal consumption of caffeine before giving birth (> 2 cups of coffee in the 6 hours before birth)
  • Major congenital malformations
  • Chromosomal syndromes
  • Fetal hydrops
  • Inherited metabolic disorders

Sites / Locations

  • Division of Neonatology, Careggi University Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treated infants

Arm Description

Infants who will receive caffeine in the delivery room.

Outcomes

Primary Outcome Measures

Successful rate
Evaluation of the number of infants in which the administration of intravenous or enteral caffeine in the delivery room will occur successfully

Secondary Outcome Measures

Comparison of intravenous versus enteral route
Evaluation of number of infants in whom caffeine will be successfully administered by intravenous versus enteral route
Caffeine administration and its therapeutic range
Number of infants in whom caffeine will be successfully administered that reached the therapeutic plasmatic range after the first dose
Intravenous vs enteral caffeine administration and therapeutic range
Comparison of caffeine blood level obtained with intravenous and enteral administration
Need of mechanical ventilation
Frequency of VM in studied infants

Full Information

First Posted
July 30, 2019
Last Updated
March 8, 2023
Sponsor
University of Florence
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1. Study Identification

Unique Protocol Identification Number
NCT04044976
Brief Title
Caffeine Treatment in in the Delivery Room
Acronym
CAFROOM
Official Title
Treatment With Caffeine of Very Preterm Infant in the Delivery Room: the CAFROOM Feasibility Study
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Completed
Study Start Date
August 1, 2019 (Actual)
Primary Completion Date
June 30, 2021 (Actual)
Study Completion Date
August 31, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Florence

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief 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.
Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Respiratory Distress Syndrome
Keywords
Caffeine, delivery room, preterm infant

7. Study Design

Primary Purpose
Supportive Care
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Model Description
A cohort of preterm infants will be given caffeine in the delivery room
Masking
None (Open Label)
Allocation
N/A
Enrollment
42 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treated infants
Arm Type
Experimental
Arm Description
Infants who will receive caffeine in the delivery room.
Intervention Type
Drug
Intervention Name(s)
Caffeine Citrate
Other Intervention Name(s)
Caffeine
Intervention Description
Infants will receive 20 mg/kg of caffeine citrate intravenously, via the umbilical vein, or enterally, through an orogastric tube, within 10 min of birth.
Primary Outcome Measure Information:
Title
Successful rate
Description
Evaluation of the number of infants in which the administration of intravenous or enteral caffeine in the delivery room will occur successfully
Time Frame
10 minutes after birth
Secondary Outcome Measure Information:
Title
Comparison of intravenous versus enteral route
Description
Evaluation of number of infants in whom caffeine will be successfully administered by intravenous versus enteral route
Time Frame
10 minutes after birth
Title
Caffeine administration and its therapeutic range
Description
Number of infants in whom caffeine will be successfully administered that reached the therapeutic plasmatic range after the first dose
Time Frame
90 minutes after birth
Title
Intravenous vs enteral caffeine administration and therapeutic range
Description
Comparison of caffeine blood level obtained with intravenous and enteral administration
Time Frame
90 minutes after birth
Title
Need of mechanical ventilation
Description
Frequency of VM in studied infants
Time Frame
72 hours of life

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Minute
Maximum Age & Unit of Time
10 Minutes
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Inborn infants Infants with 25+0-29+6 weeks of gestational age Infants who do not require MV in the delivery room Exclusion Criteria: Maternal consumption of caffeine before giving birth (> 2 cups of coffee in the 6 hours before birth) Major congenital malformations Chromosomal syndromes Fetal hydrops Inherited metabolic disorders
Facility Information:
Facility Name
Division of Neonatology, Careggi University Hospital
City
Florence
ZIP/Postal Code
50134
Country
Italy

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Data will be collected in electronic sheet. These data will be available on request.
IPD Sharing Time Frame
Data will become available at the end of the study.
IPD Sharing Access Criteria
Access will be allowed on request.
Citations:
PubMed Identifier
36301511
Citation
Dani C, Cecchi A, Ciarcia M, Miselli F, Luzzati M, Remaschi G, Bona MD, la Marca G, Boni L. Enteral and Parenteral Treatment with Caffeine for Preterm Infants in the Delivery Room: A Randomised Trial. Paediatr Drugs. 2023 Jan;25(1):79-86. doi: 10.1007/s40272-022-00541-y. Epub 2022 Oct 27.
Results Reference
derived
PubMed Identifier
33277284
Citation
Dani C, Cecchi A, Remaschi G, Mercadante D, la Marca G, Boni L, Mosca F. Study protocol: treatment with caffeine of the very preterm infant in the delivery room: a feasibility study. BMJ Open. 2020 Dec 4;10(12):e040105. doi: 10.1136/bmjopen-2020-040105.
Results Reference
derived

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Caffeine Treatment in in the Delivery Room

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