Overview

This trial is active, not recruiting.

Conditions apnea of prematurity, intraventricular hemorrhage, white matter injury
Treatment caffeine citrate
Phase phase 4
Sponsor Washington University School of Medicine
Start date November 2008
End date December 2010
Trial size 80 participants
Trial identifier NCT00809055, 08-0849, HRPO 08-0849, NIH RO1HD057098-01

Summary

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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation randomized
Intervention model parallel assignment
Masking double blind (subject, caregiver, investigator, outcomes assessor)
Primary purpose prevention
Arm
(Experimental)
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.
caffeine citrate
Caffeine to be administered as outlined to compare efficacy of different dosages.
(Active Comparator)
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.
caffeine citrate
Caffeine to be administered as outlined to compare efficacy of different dosages.

Primary Outcomes

Measure
Length of time requiring mechanical ventilation
time frame: Time hospitalized
Brain injury
time frame: 5 years

Secondary Outcomes

Measure
Mortality rates
time frame: 5 years
Length of time requiring any respiratory support
time frame: Time hospitalized
Length of time after birth until resolution of apnea of prematurity
time frame: Time hospitalized
Rates of chronic lung disease
time frame: Time hospitalized
Length of time requiring inotropic support
time frame: Time hospitalized
Length of time after birth until reaching full enteral feeds
time frame: Time hospitalized
Rates of necrotizing enterocolitis
time frame: Time hospitalized
Infant neurobehavioral scoring by Dubowitz scale prior to discharge
time frame: Time hospitalized
Evaluation of EEG seizure burden
time frame: 5 years
Rates of retinopathy of prematurity
time frame: 5 years
Advanced magnetic resonance imaging by diffusion analysis and cortical folding measures
time frame: 5 years
Bayley Scales of Infant Development scores at 2 and 4 years of age
time frame: 5 years
Rates of tachycardia and/or arrhythmias
time frame: Time hospitalized

Eligibility Criteria

Male or female participants from 24 weeks up to 30 weeks old.

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.

Additional Information

Official title Magnetic Resonance Imaging and Neurodevelopmental Outcomes in Preterm Infants Following Administration of High-Dose Caffeine - A Pilot Study
Principal investigator Terrie Inder, MBChB, MD
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.
Trial information was received from ClinicalTrials.gov and was last updated in March 2015.
Information provided to ClinicalTrials.gov by Washington University School of Medicine.