Early Caffeine in Preterm Neonates

July 31, 2021 updated by: Jennifer Shepherd

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

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.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

24

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Los Angeles, California, United States, 90027
        • Hollywood Presbyterian Medical Center
      • Los Angeles, California, United States, 90033
        • LAC+USC Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 1 year (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Caffeine
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.
Drug: Caffeine Citrate
The intervention in this study is timing of the initial caffeine dose. In the Caffeine arm, participants will receive Caffeine Citrate 20mg/kg IV (volume dose 1ml/kg) within 2 hours of life, and Normal Saline (0.9% NaCl) 1ml/kg IV at 12 hours of life.
Other Names:
  • Cafcit
Other: Placebo
Participant will receive placebo (normal saline IV) within 2 hours of life and caffeine citrate 20mg/kg IV at 12 hours of life. Both infusions will be of identical volumes and appearance, and will be administered over 30 minutes.
Drug: Placebo (Normal Saline)
The intervention in this study is timing of the initial caffeine dose. In the Placebo arm, participants will receive Normal Saline (0.9%NaCl) 1ml/kg IV within 2 hours of life, and Caffeine Citrate 20mg/kg IV (volume dose 1ml/kg) at 12 hours of life.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Intubation
Time Frame: Within 12 hours of life
Need for endotracheal intubation within the first 12 hours of life.
Within 12 hours of life

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cardiac output
Time Frame: Prior to and 1 hour after receipt of caffeine/placebo at 2 hours of life and 12 hours of life
Changes in cardiac output after administration of caffeine.
Prior to and 1 hour after receipt of caffeine/placebo at 2 hours of life and 12 hours of life

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Jennifer Shepherd

Collaborators

The Gerber Foundation

Investigators

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

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 1, 2017

Primary Completion (Anticipated)

January 1, 2022

Study Completion (Anticipated)

July 1, 2022

Study Registration Dates

First Submitted

March 16, 2017

First Submitted That Met QC Criteria

March 16, 2017

First Posted (Actual)

March 22, 2017

Study Record Updates

Last Update Posted (Actual)

August 3, 2021

Last Update Submitted That Met QC Criteria

July 31, 2021

Last Verified

July 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HS-15-00899

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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