Magnetic Resonance Imaging (MRI) and Neurodevelopmental Outcomes in Preterm Infants Following Administration of High-Dose Caffeine

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2012 by Washington University School of Medicine
Sponsor:
Information provided by (Responsible Party):
Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT00809055
First received: December 15, 2008
Last updated: December 20, 2012
Last verified: December 2012
  Purpose

Over the last 30 years the survival rates for babies born prematurely have improved greatly with research. As these babies grow up, we have found that many of the premature babies have learning and movement problems. The purpose of this research is to learn why premature infants are at risk for learning disabilities and movement problems later in childhood and whether this is changed by caffeine therapy. Caffeine is often used in premature babies to help them to breathe on their own. Nearly all babies born before 30 weeks gestation receive caffeine while they are in the neonatal intensive care unit (NICU). Scientists have shown that caffeine therapy given to premature babies reduces their disabilities.

We will use brain monitoring, including electro-encephalogram (EEG) and magnetic resonance imaging (MRI) to understand how the brain of a premature baby develops and whether caffeine in high doses enhances protection of the developing brain. Just as we monitor the heart and lungs to improve our care of premature babies, we wish to monitor the brain so that we can understand how to improve our care for the brain.


Condition Intervention Phase
Apnea of Prematurity
Intraventricular Hemorrhage
White Matter Injury
Drug: Caffeine citrate
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Magnetic Resonance Imaging and Neurodevelopmental Outcomes in Preterm Infants Following Administration of High-Dose Caffeine - A Pilot Study

Resource links provided by NLM:


Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • Length of time requiring mechanical ventilation [ Time Frame: Time hospitalized ] [ Designated as safety issue: No ]
  • Brain injury [ Time Frame: 5 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Mortality rates [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
  • Length of time requiring any respiratory support [ Time Frame: Time hospitalized ] [ Designated as safety issue: No ]
  • Length of time after birth until resolution of apnea of prematurity [ Time Frame: Time hospitalized ] [ Designated as safety issue: No ]
  • Rates of chronic lung disease [ Time Frame: Time hospitalized ] [ Designated as safety issue: No ]
  • Length of time requiring inotropic support [ Time Frame: Time hospitalized ] [ Designated as safety issue: No ]
  • Length of time after birth until reaching full enteral feeds [ Time Frame: Time hospitalized ] [ Designated as safety issue: No ]
  • Rates of necrotizing enterocolitis [ Time Frame: Time hospitalized ] [ Designated as safety issue: Yes ]
  • Infant neurobehavioral scoring by Dubowitz scale prior to discharge [ Time Frame: Time hospitalized ] [ Designated as safety issue: No ]
  • Evaluation of EEG seizure burden [ Time Frame: 5 years ] [ Designated as safety issue: Yes ]
  • Rates of retinopathy of prematurity [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  • Advanced magnetic resonance imaging by diffusion analysis and cortical folding measures [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  • Bayley Scales of Infant Development scores at 2 and 4 years of age [ Time Frame: 5 years ] [ Designated as safety issue: No ]
  • Rates of tachycardia and/or arrhythmias [ Time Frame: Time hospitalized ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 80
Study Start Date: October 2008
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: High dose caffeine
Loading dose 40mg/kg IV caffeine citrate, followed 12 hours later by 20mg/kg IV caffeine citrate, followed 12 hours later by 10mg/kg IV caffeine citrate, followed 12 hours later by 10mg/kg IV caffeine citrate.
Drug: Caffeine citrate
Caffeine to be administered as outlined to compare efficacy of different dosages.
Active Comparator: Standard dose caffeine
Loading dose 20mg/kg IV caffeine citrate, followed 12 hours later with D5W placebo, followed 12 hours later with 10mg/kg IV caffeine citrate, followed 12 hours later with D5W placebo.
Drug: Caffeine citrate
Caffeine to be administered as outlined to compare efficacy of different dosages.

Detailed Description:

Apnea is defined as a cessation of breathing for twenty seconds or greater, or as a brief episode if associated with bradycardia, cyanosis, or pallor. Recurrent apnea of prematurity occurs in up to 85% of infants born under 1000g. Standard treatment of care for apnea of prematurity is the administration of methylxanthines, specifically caffeine citrate, as a respiratory stimulant. This class of pharmacotherapy is a nonselective inhibitor of adenosine receptors. Adenosine inhibits respiratory neural output both directly and through interactions with another inhibitor of respiratory control, GABA. Adenosine A1 receptors are also thought to play a role in hypoxia-induced brain injury, and features of perinatal white matter injury have been observed in rodents treated with A1AR agonists during early postnatal life. By inhibiting adenosine effects, caffeine may play a role in preventing white matter injury. Recently, caffeine therapy for apnea of prematurity has been shown to improve the rate of survival without neurodevelopmental disability at 18 to 21 months, reduce the incidence of cerebral palsy, and reduce the incidence of cognitive delay in infants with very low birth weight.

In the last five years, multiple trials have studied the effects of using higher doses of caffeine citrate in the treatment of apnea of prematurity. Steer compared the efficacy of three dosing regimens of caffeine citrate (3, 15, and 30 mg/kg) and found that higher doses of caffeine correlated with less documented apnea and less time with oxygen saturations <85%. The effectiveness of higher caffeine doses was confirmed when Scanlon showed that a loading dose of 50 mg/kg of caffeine citrate is more effective in reducing apneic episodes within eight hours than a caffeine citrate loading dose of 25 mg/kg. Studies evaluating the long-term neurologic effects of higher doses of methylxanthines, however, have resulted in conflicting conclusions. For patients at 12 months of corrected gestational age, Steer found a higher incidence of major disabilities in the low dose caffeine group compared with the high-dose group (18% to 7.5%). Conversely, Davis reported a higher incidence of cerebral palsy in 14 year old children with birth weight below 1501g who were treated with theophylline in the newborn period than prematurely born infants without methylxanthine treatment (13% to 1.6%).

Recent advances in magnetic resonance imaging (MRI) have allowed for new techniques in visualizing brain injury and development in preterm infants by non-invasive means. Diffusion tensor imaging (DTI) is a modality of MRI that measures the translational motion of water within tissue, or "apparent diffusion." If the direction of diffusion is hindered more in one direction than another, the water motion is considered anisotropic. Water apparent diffusion in mature white matter is highly anisotropic; the directionally averaged water apparent diffusion coefficient (ADC) has been referenced at 1.0-2.0 x 10^-3 mm2/s for the infant brain, 0.8 x 10^-3 mm2/s for the adult brain. Normative values obtained by DTI have been shown to be a sensitive indicator for white and gray matter development and complexity. Both Dyet and Woodward have been able to correlate abnormal white matter signals on brain MRI in preterm infants with subsequent impairment in cognitive, motor, and neurosensory outcomes.

As caffeine use in the CAPT study has been demonstrated in low doses commenced around 3 days of life to have a positive impact on neurodevelopmental outcomes at 18 to 21 months, it would be beneficial to understand the effects of a higher dose of caffeine on both short- and long-term outcomes with an emphasis on the prevention of brain injury (intraventricular hemorrhage and white matter injury) and the improvement of neurodevelopmental development.

Thus, we propose a randomized controlled trial of high-dose versus standard low-dose caffeine therapy postulating that high doses of caffeine citrate will have beneficial effects on both short- and long-term neurologic outcomes.

  Eligibility

Ages Eligible for Study:   24 Weeks to 30 Weeks
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Preterm infants from 24 to 30 weeks completed PMA admitted to the neonatal intensive care unit (NICU) at St. Louis Children's Hospital. The estimated post menstrual age will be provided by the obstetrical records and compared with a Dubowitz exam at admission. The provided PMA will be used unless the Dubowitz exam has a discrepancy of greater or equal to 2 weeks, where then the Dubowitz age will be used.
  • Infants must be recruited within the first 24 hours of life.

Exclusion Criteria:

  • Infants over 30 weeks gestation.
  • Infants who are moribund with severe sepsis, in respiratory failure, or have severe brain injury present in the first 24 hours of life. This would be defined as physiologic instability requiring >80% FiO2 for 6 hours and/or more than 2 inotropic drugs (excluding hydrocortisone), or in the attending or recruiting physicians' opinion the infant is likely to die within 24 hours or would not tolerate any handling for the protocol.
  • Infants must not have received any doses of caffeine citrate prior to enrollment.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00809055

Contacts
Contact: Terrie E Inder, MBChB, MD 314-454-2200 Inder_T@kids.wustl.edu
Contact: Tiong H Tjoeng, MD, MPH 314-286-2150 Tjoeng_T@kids.wustl.edu

Locations
United States, Missouri
St. Louis Children's Hospital Recruiting
St. Louis, Missouri, United States, 63110
Contact: F S Cole, MD    314-454-6037      
Principal Investigator: Terrie Inder, MBChB, MD         
Sub-Investigator: Tiong H Tjoeng, MD, MPH         
Sub-Investigator: Claudine Vavasseur, MD         
Sub-Investigator: Jeffrey Neil, MD, PhD         
Sub-Investigator: Amit Mathur, MD         
Sub-Investigator: Joshua Shimony, MD, PhD         
Sub-Investigator: Robert McKinstry, MD, PhD         
Sub-Investigator: Clare Knutsen         
Sub-Investigator: Steven Liao, MD         
Sub-Investigator: Divyen Shah, MD, PhD         
Sub-Investigator: Jim Alexopoulos         
Sub-Investigator: Jennifer Walker         
Sub-Investigator: Karen Lukas         
Sub-Investigator: Jordan Gutovich         
Sub-Investigator: Chris Smyser         
Sponsors and Collaborators
Washington University School of Medicine
Investigators
Principal Investigator: Terrie Inder, MBChB, MD Washington University Medical Center, St. Louis Children's Hospital
  More Information

No publications provided

Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT00809055     History of Changes
Other Study ID Numbers: 08-0849, NIH RO1HD057098-01, HRPO 08-0849
Study First Received: December 15, 2008
Last Updated: December 20, 2012
Health Authority: United States: Institutional Review Board

Additional relevant MeSH terms:
Hemorrhage
Cerebral Hemorrhage
Wounds and Injuries
Pathologic Processes
Intracranial Hemorrhages
Cerebrovascular Disorders
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Vascular Diseases
Cardiovascular Diseases
Caffeine
Caffeine citrate
Central Nervous System Stimulants
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Purinergic P1 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents

ClinicalTrials.gov processed this record on August 19, 2014