Apnea of PrematurityPhase 4NCT00809055
MRI and Neurodevelopment in Preterm Infants Following Administration of High-Dose Caffeine
A Phase 4 study testing Caffeine citrate in people with Apnea of Prematurity and Intraventricular Hemorrhage, run by Washington University School of Medicine at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 24 to 30 weeks
- Conditions the study is for
- Apnea of Prematurity, Intraventricular Hemorrhage, Brain Injury
- What is being tested?
- Caffeine citrate
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 74 participants
- Where
- 1 siteUnited States
- Study dates
- Nov 2008to Dec 2015
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 24 to 30 weeks
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
St. Louis Children's Hospital
St Louis, Missouri, 63110
About this study
Official title: Magnetic Resonance Imaging and Neurodevelopmental Outcomes in Preterm Infants Following Administration of High-Dose Caffeine - A Pilot Study
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.
Read the 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.
- Being tested
- Caffeine citrate
- Medical subject headings
- Apnea, Brain Injuries
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Caffeine citrateDrug
Also called Cafcit
Caffeine to be administered as outlined to compare efficacy of different dosages.
| Study group | Role | What they receive |
|---|---|---|
| High dose caffeine | 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. Receives: Drug: Caffeine citrate |
| Standard dose caffeine | 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. Receives: Drug: Caffeine citrate |
What is being measured
The primary outcome is the main question the study is designed to answer.
White Matter Microstructural Maturation
Apparent diffusion coefficient is a measure of microstructural maturation obtained from brain MRI.
Measured: Participants were followed for the duration of hospital stay, an average of 12 weeks
Secondary outcomes (9)
Mortality Rates
Measured: Participants were followed for the duration of hospital stay, an average of 12 weeks
Cerebellar Hemorrhage
Measured: Participants were followed for the duration of hospital stay, an average of 12 weeks
Length of Time Requiring Invasive Respiratory Support
Measured: Participants were followed for the duration of hospital stay, an average of 12 weeks
Rates of Chronic Lung Disease
Defined as oxygen requirement at 36 weeks PMA
Measured: Participants were followed for the duration of hospital stay, an average of 12 weeks
Rates of Necrotizing Enterocolitis
Measured: Participants were followed for the duration of hospital stay, an average of 12 weeks
Rates of Retinopathy of Prematurity
Measured: Participants were followed for the duration of hospital stay, an average of 12 weeks
Evaluation of EEG Seizure Burden
For the first 72 hours of life, infants were monitored for seizures using continuous limited channel aEEG. Seizures were defined as a series of sharp waves, at least ten seconds in duration, which evolve in frequency, amplitude, and morphology over time and are clearly distinguishable from the background or artifact.
Measured: First 72 hours of life
Infant Neurobehavioral Scoring by Dubowitz Scale Prior to Discharge
The Dubowitz Neurologic Examination is a standardized neurologic examination for infants at term age. It includes 6 compound optimality scores summed to obtain the total optimality score. Compound optimality scores include tone (range 0-10), tone pattern (range 0-5), reflexes (range 0-6), movements (range 0-3), abnormal signs (range 0-3), and behavior (range 0-7). The range for the compound optimality score is 0 - 34, with scores between 30.5 and 34 considered optimal and scores below 30.5 considered suboptimal.
Measured: Participants were followed for the duration of hospital stay, an average of 12 weeks
Bayley Scales of Infant Development Cognitive Score at 2 Years of Age
The cognitive portion of the Bayley Scales of Infant Development assesses development in infants and toddlers between the ages of 0 and 3 years. Raw scores are converted to scale scores. A scale score of 100 is designed to represent the population mean. Scores below 100 represent developmental delay relative to the mean and scores above 100 represent advanced development relative to the mean.
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Dec 2008 (estimated)
- Study startNov 2008
- Primary completionDec 2010
- Study completionDec 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Apnea of PrematurityStudies of the same condition, open and under way.
- More trials run by Washington University School of MedicineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 74 participants (actual)
Sponsor and investigators
- Lead sponsor
- Washington University School of Medicine
- Sponsor type
- University, hospital or other
- Collaborators
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Responsible party
- Sponsor
- Investigators
- Terrie Inder, MBChB, MD, Principal investigator, Brigham and Women's Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00809055
- Sponsor's protocol ID
- 08-0849
- Other IDs
- R01HD057098-01, HRPO 08-0849
- Status last verified
- Jan 2016
- First submitted
- 15 Dec 2008
- Last updated
- 24 Feb 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 24 Feb 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Magnetic Resonance Imaging and Neurodevelopmental Outcomes in Preterm Infants Following Administration of High-Dose Caffeine - A Pilot Study
- ClinicalTrials.gov ID
- NCT00809055
- Acronym / sponsor ID
- 08-0849
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 74 participants (actual)
- Lead sponsor
- Washington University School of MedicineUniversity, hospital or other
- Collaborators
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Study start
- Nov 2008
- Primary completion
- Dec 2010 (actual)
- Study completion
- Dec 2015 (actual)
- First posted
- 16 Dec 2008 (estimated)
- Results
- Posted 24 Feb 2016
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
Study design
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| High dose caffeine | Experimental | Drug: Caffeine citrateLoading 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. |
| Standard dose caffeine | Active comparator | Drug: Caffeine citrateLoading 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. |
Who may qualify
- Ages
- 24 to 30 weeks
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (2 listed)
- 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.
Key exclusion criteria (3 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Caffeine citrateAlso: CafcitCaffeine to be administered as outlined to compare efficacy of different dosages. | Drug | High dose caffeine, Standard dose caffeine |
Primary outcome
White Matter Microstructural Maturation
Time frame: Participants were followed for the duration of hospital stay, an average of 12 weeks
Apparent diffusion coefficient is a measure of microstructural maturation obtained from brain MRI.
9 secondary outcomes
Mortality Rates
Time frame: Participants were followed for the duration of hospital stay, an average of 12 weeks
Cerebellar Hemorrhage
Time frame: Participants were followed for the duration of hospital stay, an average of 12 weeks
Length of Time Requiring Invasive Respiratory Support
Time frame: Participants were followed for the duration of hospital stay, an average of 12 weeks
Rates of Chronic Lung Disease
Time frame: Participants were followed for the duration of hospital stay, an average of 12 weeks
Rates of Necrotizing Enterocolitis
Time frame: Participants were followed for the duration of hospital stay, an average of 12 weeks
Rates of Retinopathy of Prematurity
Time frame: Participants were followed for the duration of hospital stay, an average of 12 weeks
Evaluation of EEG Seizure Burden
Time frame: First 72 hours of life
Infant Neurobehavioral Scoring by Dubowitz Scale Prior to Discharge
Time frame: Participants were followed for the duration of hospital stay, an average of 12 weeks
Bayley Scales of Infant Development Cognitive Score at 2 Years of Age
Time frame: 2 years
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Feb 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Terrie Inder, MBChB, MD principal investigator
Brigham and Women's Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Caffeine citrate in people with Apnea of Prematurity and Intraventricular Hemorrhage, run by Washington University School of Medicine at 1 site 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 2 inclusion and 3 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: finished, as of the sponsor's last update on 24 Feb 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site 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?
Yes. Results are posted in the registry (first posted 24 Feb 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
White Matter Microstructural Maturation (time frame: Participants were followed for the duration of hospital stay, an average of 12 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 24 Feb 2016.