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BPD - Bronchopulmonary DysplasiaPhase 4NCT03086473

Early Caffeine in Preterm Neonates

A Phase 4 study testing Caffeine Citrate in people with BPD - Bronchopulmonary Dysplasia and Apnea of Prematurity, run by Jennifer Shepherd at 2 sites in United States.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages Up to 1 day
What is being tested?
Caffeine Citrate
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
24 participants
Where
2 sitesUnited States
Study dates
1 Feb 2017to Jul 2022
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 1 day
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • 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.

Who cannot join

  • 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.

Trial locations and contacts

2 sites in 1 country.

United States2 sites
  • Hollywood Presbyterian Medical Center

    Los Angeles, California, 90027

  • LAC+USC Medical Center

    Los Angeles, California, 90033

Other trials in United States

About this study

Official title: 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.

Read the 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.

Being tested
Caffeine Citrate, Placebo (Normal Saline)
Keywords
caffeine, intubation, hemodynamics, mechanical ventilation, cardiac output, near infrared spectroscopy, functional echocardiography
Medical subject headings
Bronchopulmonary Dysplasia, Apnea

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Caffeine CitrateDrug

    Also called Cafcit

    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.

  • Placebo (Normal Saline)Drug

    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.

Study groups in NCT03086473
Study groupRoleWhat they receive
CaffeineOtherParticipant 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.
Receives: Drug: Caffeine Citrate
PlaceboOtherParticipant 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.
Receives: Drug: Placebo (Normal Saline)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Intubation

    Need for endotracheal intubation within the first 12 hours of life.

    Measured: Within 12 hours of life

Secondary outcomes (1)
  1. Cardiac output

    Changes in cardiac output after administration of caffeine.

    Measured: Prior to and 1 hour after receipt of caffeine/placebo at 2 hours of life and 12 hours of life

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted22 Mar 2017
  2. Study start1 Feb 2017
  3. Primary completionJan 2022 (estimated)
  4. Study completionJul 2022 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Model description
Each participant is assigned to one of two arms of the study.
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
24 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03086473
Sponsor's protocol ID
HS-15-00899
Status last verified
Jul 2021
First submitted
16 Mar 2017
Last updated
3 Aug 2021
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Northway WH Jr, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl J Med. 1967 Feb 16;276(7):357-68. doi: 10.1056/NEJM196702162760701. No abstract available.

    PubMed 5334613
  • Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W; Caffeine for Apnea of Prematurity Trial Group. Caffeine therapy for apnea of prematurity. N Engl J Med. 2006 May 18;354(20):2112-21. doi: 10.1056/NEJMoa054065.

    PubMed 16707748
  • Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W; Caffeine for Apnea of Prematurity Trial Group. Long-term effects of caffeine therapy for apnea of prematurity. N Engl J Med. 2007 Nov 8;357(19):1893-902. doi: 10.1056/NEJMoa073679.

    PubMed 17989382
  • Lodha A, Seshia M, McMillan DD, Barrington K, Yang J, Lee SK, Shah PS; Canadian Neonatal Network. Association of early caffeine administration and neonatal outcomes in very preterm neonates. JAMA Pediatr. 2015 Jan;169(1):33-8. doi: 10.1001/jamapediatrics.2014.2223.

    PubMed 25402629
  • Logan JW, O'Shea TM, Allred EN, Laughon MM, Bose CL, Dammann O, Batton DG, Engelke SC, Leviton A; ELGAN Study Investigators. Early postnatal hypotension and developmental delay at 24 months of age among extremely low gestational age newborns. Arch Dis Child Fetal Neonatal Ed. 2011 Sep;96(5):F321-8. doi: 10.1136/adc.2010.183335. Epub 2010 Dec 7.

    PubMed 21138828
  • Laptook AR, O'Shea TM, Shankaran S, Bhaskar B; NICHD Neonatal Network. Adverse neurodevelopmental outcomes among extremely low birth weight infants with a normal head ultrasound: prevalence and antecedents. Pediatrics. 2005 Mar;115(3):673-80. doi: 10.1542/peds.2004-0667.

    PubMed 15741371
  • Aranda JV, Beharry K, Valencia GB, Natarajan G, Davis J. Caffeine impact on neonatal morbidities. J Matern Fetal Neonatal Med. 2010 Oct;23 Suppl 3:20-3. doi: 10.3109/14767058.2010.517704.

    PubMed 20873976
  • Patel RM, Leong T, Carlton DP, Vyas-Read S. Early caffeine therapy and clinical outcomes in extremely preterm infants. J Perinatol. 2013 Feb;33(2):134-40. doi: 10.1038/jp.2012.52. Epub 2012 Apr 26.

    PubMed 22538326
  • Dobson NR, Patel RM, Smith PB, Kuehn DR, Clark J, Vyas-Read S, Herring A, Laughon MM, Carlton D, Hunt CE. Trends in caffeine use and association between clinical outcomes and timing of therapy in very low birth weight infants. J Pediatr. 2014 May;164(5):992-998.e3. doi: 10.1016/j.jpeds.2013.12.025. Epub 2014 Jan 23.

    PubMed 24461786
  • Aranda JV, Cook CE, Gorman W, Collinge JM, Loughnan PM, Outerbridge EW, Aldridge A, Neims AH. Pharmacokinetic profile of caffeine in the premature newborn infant with apnea. J Pediatr. 1979 Apr;94(4):663-8. doi: 10.1016/s0022-3476(79)80047-5.

    PubMed 430317
  • More K, Sakhuja P, Shah PS. Minimally invasive surfactant administration in preterm infants: a meta-narrative review. JAMA Pediatr. 2014 Oct;168(10):901-8. doi: 10.1001/jamapediatrics.2014.1148.

    PubMed 25089718
  • SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network; Finer NN, Carlo WA, Walsh MC, Rich W, Gantz MG, Laptook AR, Yoder BA, Faix RG, Das A, Poole WK, Donovan EF, Newman NS, Ambalavanan N, Frantz ID 3rd, Buchter S, Sanchez PJ, Kennedy KA, Laroia N, Poindexter BB, Cotten CM, Van Meurs KP, Duara S, Narendran V, Sood BG, O'Shea TM, Bell EF, Bhandari V, Watterberg KL, Higgins RD. Early CPAP versus surfactant in extremely preterm infants. N Engl J Med. 2010 May 27;362(21):1970-9. doi: 10.1056/NEJMoa0911783. Epub 2010 May 16.

    PubMed 20472939
  • Cunningham S, Symon AG, Elton RA, Zhu C, McIntosh N. Intra-arterial blood pressure reference ranges, death and morbidity in very low birthweight infants during the first seven days of life. Early Hum Dev. 1999 Dec;56(2-3):151-65. doi: 10.1016/s0378-3782(99)00038-9.

    PubMed 10636594
  • Cordero L, Timan CJ, Waters HH, Sachs LA. Mean arterial pressures during the first 24 hours of life in < or = 600-gram birth weight infants. J Perinatol. 2002 Jul-Aug;22(5):348-53. doi: 10.1038/sj.jp.7210736.

    PubMed 12082467
  • Kluckow M, Evans N. Low superior vena cava flow and intraventricular haemorrhage in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2000 May;82(3):F188-94. doi: 10.1136/fn.82.3.f188.

    PubMed 10794784

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Caffeine Citrate in people with BPD - Bronchopulmonary Dysplasia and Apnea of Prematurity, run by Jennifer Shepherd at 2 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 1 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 3 Aug 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Intubation (time frame: Within 12 hours of life). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03086473, which also lists 28 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Aug 2021.

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