Caffeine to Reduce Mechanical Ventilation in Preterm Infants

Use of Caffeine to Reduce Length of Mechanical Ventilation in Preterm Infants

Status

Terminated

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01751724

Enrollment

Registered

2012-12-18

Start date

2012-12-31

Completion date

2016-01-31

Last updated

2017-06-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Apnea, Prematurity, Respiratory Failure

Keywords

Premature infants, Caffeine, Methylxanthines, Mechanical ventilation, Oxygen, Weaning, Bronchopulmonary dysplasia

Brief summary

Most premature infants require mechanical ventilation for prolonged periods of time and a significant proportion of them develop Bronchopulmonary Dysplasia (BPD). Caffeine is a stimulant of the respiratory center and has been used for the treatment of Apnea of Prematurity in infants not requiring mechanical ventilation or to facilitate weaning from mechanical ventilation by starting therapy shortly before extubation. Recently the use of Caffeine in ventilated infants has been initiated earlier because of the reported reduction in BPD. However there is paucity of data supporting this practice. Because protracted mechanical ventilation and supplemental oxygen increase the risk of developing BPD, a therapy that would facilitate the reduction of the respiratory support and shorten its duration is desirable. Therefore, it is of importance to evaluate the effects of early Caffeine initiation and administration during the course of mechanical ventilation in preterm infants by means of a randomized placebo-controlled trial. Hypothesis: The primary hypothesis of this study is that early use of caffeine in mechanically ventilated preterm infants will reduce the time to first elective extubation and secondarily, that this will reduce the total duration of mechanical ventilation and oxygen supplementation, and reduce the incidence and severity of BPD. Objective: The objective of this trial is to evaluate the effects of early caffeine use during mechanical ventilation on the time to first elective extubation, total duration of mechanical ventilation and oxygen supplementation, and the incidence of BPD. Study Design: This will be a single-center prospective, randomized, double-blind, placebo controlled clinical trial. Population: Premature neonates born between 23 and 30 completed weeks of gestation, who require mechanical ventilation within the first 5 days of life will be enrolled. Infants with major congenital anomalies or small for gestational age will be excluded. Methods: Infants will be randomized within the first 5 days to receive a study drug consisting of either blinded Caffeine citrate or blinded Placebo (equivalent volume of normal saline). Infants will continue to receive the study drug until the first elective extubation.

Interventions

DRUGCaffeine citrate

Enrolled subjects will be randomized to receive a study drug consisting of either blinded Caffeine citrate. Randomization and study drug preparation will be done by the NICU pharmacy. Investigators and clinicians will be blinded to the assigned drug. After randomization, an initial loading dose of 20 mg/Kg of study drug will be followed by a 5 mg/Kg/day maintenance dose. The assigned study drug will be administered intravenous or orally as determined by the clinical team. Infants will continue to receive the study drug until 12 hours prior to the first elective extubation.

OTHERNormal saline

Enrolled subjects will be randomized to receive a study drug consisting of blinded Placebo (equivalent volume of normal saline). Randomization and study drug preparation will be done by the NICU pharmacy. Investigators and clinicians will be blinded to the assigned drug. After randomization, an initial loading dose of 20 mg/Kg of study drug will be followed by a 5 mg/Kg/day maintenance dose. The assigned study drug will be administered intravenous or orally as determined by the clinical team. Infants will continue to receive the study drug until 12 hours prior to the first elective extubation.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

1 Days to 5 Days

Healthy volunteers

Inclusion criteria

* Premature neonates born between 23 and 30 completed weeks of gestation. * Requiring mechanical ventilation within the first 5 postnatal days * Written-informed parental consent for the study

Exclusion criteria

* Major congenital anomalies * Small for gestational age

Design outcomes

Primary

Measure	Time frame	Description
Age at First Successful Extubation	From birth to until 36 weeks postmenstrual age	Defined as age of extubation with infant remaining extubated for more than 24 hours.

Secondary

Measure	Time frame	Description
Survival	From the time of randomization up to 36 weeks corrected age, or until the time of discharge or death	—
Total Duration of Mechanical Ventilation	From the time of first intubation until the last extubation, up to 36 weeks corrected age	—
Total Duration of Oxygen Supplementation	From the time of first initiation until the last day of oxygen supplementation, up to 36 weeks corrected age	—
Number of Infants With Bronchopulmonary Dysplasia (BPD)	Evaluated at 36 weeks corrected postmenstrual age	BPD defined as need for oxygen for at least 28 days and at 36 weeks post-menstrual age.
Survival Without BPD	From the time of randomization until 36 weeks corrected age, discharge or death	Discharge alive without BPD. BPD defined as need for oxygen for at least 28 days and at 36 weeks post-menstrual age.

Other

Measure	Time frame	Description
Number of Infants With Necrotizing Enterocolitis	From enrollment until 36 weeks postmenstrual age, discharge or death	—
Number of Infants With Septicemia	From enrollment until 36 weeks postmenstrual age, discharge or death	Septicemia defined as positive blood culture
Number of Infants With Severe Intraventricular Hemorrhage	From enrollment until 36 weeks postmenstrual age, discharge or death	Severe intraventricular hemorrhage defined as grade III or higher
Number of Infants With Severe Retinopathy of Prematurity	From enrollment until 36 weeks postmenstrual age, discharge or death	Severe retinopathy of prematurity defined as stage 3 or higher
Number of Infants With Pulmonary Hemorrhage	From enrollment until 36 weeks postmenstrual age, discharge or death	—

Countries

United States

Participant flow

Recruitment details

Recruitment was conducted at the Holtz Children's Hospital newborn intensive care unit of Jackson Health System/University of Miami Medical Center from January 2013 to October 2015.

Pre-assignment details

87 infants were enrolled. Of these, 1 died before randomization. 86 infants were randomized and assigned an intervention arm.

Participants by arm

Arm	Count
Caffeine Arm Subjects randomized to this arm will receive blinded Caffeine citrate. Caffeine citrate: Enrolled subjects will be randomized to receive a study drug consisting of either blinded Caffeine citrate. Randomization and study drug preparation will be done by the NICU pharmacy. Investigators and clinicians will be blinded to the assigned drug. After randomization, an initial loading dose of 20 mg/Kg of study drug will be followed by a 5 mg/Kg/day maintenance dose. The assigned study drug will be administered intravenous or orally as determined by the clinical team. Infants will continue to receive the study drug until 12 hours prior to the first elective extubation.	41
Placebo Arm Subjects randomized to this arm will receive blinded Placebo (equivalent volume of normal saline). Normal saline: Enrolled subjects will be randomized to receive a study drug consisting of blinded Placebo (equivalent volume of normal saline). Randomization and study drug preparation will be done by the NICU pharmacy. Investigators and clinicians will be blinded to the assigned drug. After randomization, an initial loading dose of 20 mg/Kg of study drug will be followed by a 5 mg/Kg/day maintenance dose. The assigned study drug will be administered intravenous or orally as determined by the clinical team. Infants will continue to receive the study drug until 12 hours prior to the first elective extubation.	42
Total	83

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	extubated bef.start assigned treatment	1	0
Overall Study	withdrawn by parent	0	2

Baseline characteristics

Characteristic	Caffeine Arm	Placebo Arm	Total
Age, Continuous	48 hours STANDARD_DEVIATION 25	49 hours STANDARD_DEVIATION 31	48 hours STANDARD_DEVIATION 28
Birth weight	670 grams	720 grams	700 grams
Fraction of inspired oxygen at enrollment	0.25 oxygen fraction	0.23 oxygen fraction	.24 oxygen fraction
Gestational age	25.7 weeks	26.1 weeks	25.9 weeks
Mean airway pressure at enrollment	9 centimeters of water	8 centimeters of water	9 centimeters of water
Race/Ethnicity, Customized Black race	19 Participants	21 Participants	40 Participants
Sex: Female, Male Female	11 Participants	25 Participants	36 Participants
Sex: Female, Male Male	30 Participants	17 Participants	47 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	9 / 41	5 / 42
other Total, other adverse events	0 / 41	0 / 41
serious Total, serious adverse events	0 / 41	0 / 42

Outcome results

Primary

Age at First Successful Extubation

Defined as age of extubation with infant remaining extubated for more than 24 hours.

Time frame: From birth to until 36 weeks postmenstrual age

Arm	Measure	Value (MEDIAN)
Caffeine Arm	Age at First Successful Extubation	24 days
Placebo Arm	Age at First Successful Extubation	20 days

Secondary

Number of Infants With Bronchopulmonary Dysplasia (BPD)

BPD defined as need for oxygen for at least 28 days and at 36 weeks post-menstrual age.

Time frame: Evaluated at 36 weeks corrected postmenstrual age

Population: Infants alive at 36 weeks postmenstrual age

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Caffeine Arm	Number of Infants With Bronchopulmonary Dysplasia (BPD)	15 Participants
Placebo Arm	Number of Infants With Bronchopulmonary Dysplasia (BPD)	20 Participants

Secondary

Survival

Time frame: From the time of randomization up to 36 weeks corrected age, or until the time of discharge or death

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Caffeine Arm	Survival	32 Participants
Placebo Arm	Survival	37 Participants

Secondary

Survival Without BPD

Discharge alive without BPD. BPD defined as need for oxygen for at least 28 days and at 36 weeks post-menstrual age.

Time frame: From the time of randomization until 36 weeks corrected age, discharge or death

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Caffeine Arm	Survival Without BPD	18 Participants
Placebo Arm	Survival Without BPD	18 Participants

Secondary

Total Duration of Mechanical Ventilation

Time frame: From the time of first intubation until the last extubation, up to 36 weeks corrected age

Population: Infants alive at 36 weeks postmenstrual age

Arm	Measure	Value (MEDIAN)
Caffeine Arm	Total Duration of Mechanical Ventilation	32 days
Placebo Arm	Total Duration of Mechanical Ventilation	26 days

Secondary

Total Duration of Oxygen Supplementation

Time frame: From the time of first initiation until the last day of oxygen supplementation, up to 36 weeks corrected age

Population: Infants alive at 36 weeks postmenstrual age

Arm	Measure	Value (MEDIAN)
Caffeine Arm	Total Duration of Oxygen Supplementation	55 days
Placebo Arm	Total Duration of Oxygen Supplementation	59 days

Other Pre-specified