Early Caffeine in Preterm Neonates

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Brief Title

Early Caffeine in Preterm Neonates

Official Title

A Randomized, Placebo-controlled Trial of Early Caffeine in Preterm Neonates

Brief Summary

      This is a clinical trial which will investigate whether administration of caffeine, a
      respiratory stimulant, to preterm babies soon after birth can prevent the need for a
      breathing tube, or intubation. Many preterm babies who require intubation are intubated soon
      after birth, often within the first few hours. If caffeine is given early enough and is
      sufficient to stimulate effective breathing, perhaps these babies may not require intubation.
      Additionally, caffeine may improve blood flow in preterm babies when given soon after birth.
      Approximately half of babies in this study will receive caffeine within two hours after
      birth, and half will receive caffeine 12 hours after birth. The hypothesis is that preterm
      babies who receive caffeine within 2 hours after birth will have a lower incidence of
      intubation than preterm babies who receive caffeine 12 hours after birth. The main secondary
      hypothesis is that caffeine given soon after birth will enhance blood flow in preterm babies.
    

Detailed Description

      Caffeine is routinely administered to extremely preterm neonates as a respiratory stimulant
      to prevent or treat apnea of prematurity, or prolonged pauses in breathing in preterm babies.
      Caffeine, a methylxanthine, is an adenosine receptor antagonist that has the effects of
      relaxing smooth muscle in the airways, stimulating the central nervous system and cardiac
      muscle, and acting as a diuretic. The mode of action in apnea of prematurity could be from
      several mechanisms, including stimulation of respiratory drive, enhancement of minute
      ventilation, increased response to hypercapnia, increase in skeletal muscle tone, and
      decrease in diaphragmatic fatigue.

      The timing of caffeine administration is highly variable, ranging from the first hours of
      life to several days after birth. In the Caffeine for Apnea of Prematurity (CAP) trial, in
      which the average day of initial caffeine dose was 3 days of life, the incidence of
      bronchopulmonary dysplasia (BPD) was significantly reduced in the caffeine group compared to
      the placebo group (47% vs 36%, p<0.001). Neonates in the caffeine group also had fewer days
      of mechanical ventilation and oxygen exposure, both of which are known risk factors in the
      development of BPD. Further studies have demonstrated greater benefit of caffeine given in
      the first 2-3 days of life versus later. These studies suggest that caffeine administered
      earlier in life may be beneficial in terms of respiratory outcomes. However, the effects of
      caffeine administered shortly after birth are unknown and need to be studied with a
      randomized, placebo-controlled trial.

      The investigators postulate that by giving caffeine as soon as possible after birth,
      intrinsic respiratory function will be supported sufficiently to avoid intubation altogether,
      thus eliminating a major risk factor for BPD. Intravenous caffeine reaches therapeutic level
      almost immediately, typically within thirty minutes of administration. However, the majority
      of infants who require invasive ventilation are intubated within the first few hours of life,
      usually before the infant has received caffeine. Additionally, many centers utilize minimally
      invasive administration of surfactant, a medication that helps keep lungs open by lowering
      surface tension, to treat respiratory distress syndrome of the newborn in attempt to avoid
      intubation, as preterm neonates who do not require immediate intubation and instead receive
      non-invasive continuous positive airway pressure (CPAP) at birth have decreased risk of BPD.
      These techniques require spontaneous, effective breathing, and early caffeine administration
      may aid in this process. This study aims to deliver caffeine to preterm infants immediately
      after birth to determine whether intubation can be avoided.

      While the primary outcome of this study is aimed at reducing intubation rates and thus
      affecting rates of BPD, beneficial cardiovascular effects may also be noted. The incidence of
      hypotension in preterm infants <28 weeks is as high as 78%.This study will also be using
      non-invasive technologies to continuously monitor hemodynamic parameters including cardiac
      function, output, blood flow, oxygenation to the brain surrounding the administration of
      caffeine. Very early caffeine therapy may improve cardiovascular function in this early
      transitional period, potentially decreasing the risk of devastating complications of
      prematurity such as intraventricular hemorrhage.

      This is a double-blinded, randomized, placebo-controlled clinical trial which will
      investigate whether administration of caffeine to preterm neonates (<32 weeks' gestation)
      within the first 2 hours of life compared to 12 hours of life will decrease the rate of
      intubation during the first 12 hours of life. This study will also investigate whether
      caffeine administration to preterm neonates (<32 weeks' gestation) increases cardiac output.
      A total of 88 infants will be included in this study, randomized to two study arms. One arm
      will receive intravenous caffeine citrate within 2 hours of life and placebo (normal saline)
      at 12 hours of life, and the other arm will receive placebo within 2 hours of life and
      caffeine citrate at 12 hours of life. Therefore, all participants will receive caffeine by 12
      hours of life, and the only variable is the timing of caffeine.
    

Study Phase

Phase 4

Study Type

Interventional


Primary Outcome

Intubation

Secondary Outcome

 Cardiac output

Condition

BPD - Bronchopulmonary Dysplasia

Intervention

Caffeine Citrate

Study Arms / Comparison Groups

 Caffeine
Description:  Participant will receive caffeine citrate 20mg/kg IV within 2 hours of life and placebo (normal saline IV) at 12 hours of life. Both infusions will be of identical volumes and appearance, and will be administered over 30 minutes.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

88

Start Date

February 1, 2017

Completion Date

July 2021

Primary Completion Date

January 2021

Eligibility Criteria

        Inclusion Criteria:

          -  Neonates <32 weeks' gestational age born at LAC+USC Medical Center, Hollywood
             Presbyterian Medical Center, or other sites affiliated with USC or CHLA will be
             considered for enrollment.

        Exclusion Criteria:

          -  Exclusions are major congenital anomalies, major cardiac defects (other than patent
             ductus arteriosus, patent foramen ovale, small atrial septal defect, and small
             ventricular septal defect), and intubation in the delivery room

          -  If intravenous access is not obtained within the first 2 hours of life (either through
             peripheral IV or central venous catheter), then the neonate will no longer be eligible
             for the study.
      

Gender

All

Ages

N/A - 1 Day

Accepts Healthy Volunteers

No

Contacts

Jennifer L Shepherd, MD, (361) 323-5939, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT03086473

Organization ID

HS-15-00899


Responsible Party

Sponsor-Investigator

Study Sponsor

Jennifer Shepherd

Collaborators

 The Gerber Foundation

Study Sponsor

Jennifer L Shepherd, MD, Principal Investigator, University of Southern California


Verification Date

July 2019