Brain Injury, Intraventricular Hemorrhage, Periventricular Leukomalacia, Renal Injury
Conditions
Keywords
infant, brain injury, renal, indomethacin
Brief summary
Intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL) are brain lesions that commonly occur in preterm infants and are well-recognized major contributors to long-term brain injury and related disabilities later in life. Despite its prevalence, long term consequences, and enormous medical and social costs, mechanisms of IVH and optimal strategies to prevent or treat its occurrence are poorly defined, especially for extremely premature infants. Only one medical therapy, prophylactic indomethacin during the first 3 days of life, has been shown to prevent or decrease the severity of IVH in preterm infants, but its use is limited by toxic side effects and debatable effects on long-term outcomes. Several small studies and case reports suggest that delayed umbilical cord-clamping (DCC) may also decrease the incidence of IVH in premature infants, but thus far these trials have indomethacin treatment mixed within their cord clamping protocols. The investigators are conducting a randomized, blinded investigation of 4 treatment groups: 1) Control (no intervention); 2) DCC alone; 3) Prophylactic indomethacin alone; 4) Combination of DCC/indomethacin, with respect to survival, IVH or PVL incidence and severity, neurodevelopmental outcomes, and relevant mechanistic effects. With the steady rise in extreme prematurity births and clear links of IVH to long-term disabilities there is a need to improve care for these patients. This multi- disciplinary project addresses an important medical problem for an understudied patient population, where the current practice has clear limitations.
Detailed description
The investigators will compare efficacy and safety of prophylactic indomethacin, DCC, and their combination, in affecting the incidence and severity of IVH/PVL in infants \<30wks gestational age (primary outcome measure of 'fraction of survivors with no severe IVH or PVL' among the 4 groups), and longer term neurocognitive function. Other secondary endpoints and investigations include mechanistic effects of prophylactic indomethacin, DCC, and their combination (blood volume/circulatory status, inflammatory stress, progenitor cells) as well as defining relationships between clinical outcomes and mechanistic measurements among treatment groups.
Interventions
DRUGIndomethacin
indomethacin at standard dose for prevention of intraventricular hemorrhage in preterm infants
PROCEDUREdelay in umbilical cord clamp at birth
provision of a \ 45 second delay of umbilical cord clamping at birth in preterm infants (recorded in delivery note)
DRUGplacebo infusion
saline infusion to match input of indomethacin treatment group (and serve as drug-dosing 'blinding' for bedside staff)
PROCEDUREimmediate cord clamp at birth
no delay in umbilical cord clamp; \<10sec (recorded in delivery note)
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Hong Huang
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
24 Weeks to 30 Weeks
Healthy volunteers
No
Inclusion criteria
* pregnant women admitted \>24weeks and \<30weeks gestational age, * in-hospital birth (allowing for cord clamp randomization)
Exclusion criteria
* preterm infant \<24weeks or \>30weeks at birth * maternal risks identified by obstetrician * fetal risks identified by obstetrician * any congenital abnormality of newborn infant * placental abruption/placental previa * delivery less than 2hrs from consenting to study participation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Survivors With no Severe IVH (Grades 3 or 4) or PVL | within first 60 days of life | determined by head ultrasound in Neonatal Intensive Care Unit (NICU) and single head MRI at 38weeks corrected gestational age |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Acute Kidney Injury | first 60 days of life | measures of serum creatinine and urine output during Neonatal Intensive Care Unit (NICU) stay. General measures of renal injury (which is a common risk of indomethacin treatment in this patient population). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Hematological Status | first 60 days of life | hematocrit, ferritin, hemoglobin at various times during NICU stay |
| Inflammatory Stress | first 60 days of life | measurement of inflammatory biomarkers (CRP, Interleukin-6, soluble ICAM) at various times during NICU stay |
| Circulating Progenitor Cell Subpopulations | first 60 days of life | measures of several progenitor cell subtypes in blood during the NICU stay |
| Neurocognitive Assessments at Post-NICU Followup | up to 24 months of corrected gestational age | standardized neurocognitive assessments done at NICU graduate clinic. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Immediate Cord Clamp & Placebo IV Solution This Arm will receive immediate clamp of umbilical cord at birth, and an intravenous delivery of placebo drug solution (diluent for active drug, indomethacin) within the first 12hrs of life.
placebo infusion: saline infusion to match input of indomethacin treatment group (and serve as drug-dosing 'blinding' for bedside staff)
immediate cord clamp at birth: no delay in umbilical cord clamp; \<10sec (recorded in delivery note) | 36 |
| Delay Cord Clamp & Placebo IV Solution A delay in cord clamp for 45 seconds will be instituted in the delivery room. Placebo drug solution will be administered within 12hrs post-birth.
delay in umbilical cord clamp at birth: provision of a \
45 second delay of umbilical cord clamping at birth in preterm infants (recorded in delivery note)
placebo infusion: saline infusion to match input of indomethacin treatment group (and serve as drug-dosing 'blinding' for bedside staff) | 87 |
| Immediate Cord Clamp & Indomethacin IV Umbilical cord will be clamped immediately at birth. Indomethacin will be administered IV, starting within 12hrs of life (0.1mg/kg every 24 hrs for three total doses.This intervention is considered 'standard care' at many Neonatology medical facilities. The dose of indomethacin has been shown to be effective in reducing brain bleeds in preterm infants (although there are also data showing safety concerns).
Indomethacin: indomethacin at standard dose for prevention of intraventricular hemorrhage in preterm infants
immediate cord clamp at birth: no delay in umbilical cord clamp; \<10sec (recorded in delivery note) | 41 |
| Indomethacin iv & Delayed Cord Clamp A delay in cord clamp of 45 seconds will be instituted in the delivery room. In addition, indomethacin will be administered iv (initiated within 12hrs of life), 0.1mg/kg every 24 hrs for three total doses.
Indomethacin: indomethacin at standard dose for prevention of intraventricular hemorrhage in preterm infants
delay in umbilical cord clamp at birth: provision of a \
45 second delay of umbilical cord clamping at birth in preterm infants (recorded in delivery note) | 92 |
| Total | 256 |
Baseline characteristics
| Characteristic | Total | Immediate Cord Clamp & Placebo IV Solution | Delay Cord Clamp & Placebo IV Solution | Immediate Cord Clamp & Indomethacin IV | Indomethacin iv & Delayed Cord Clamp |
|---|---|---|---|---|---|
| Age, Continuous | 26.5 weeks STANDARD_DEVIATION 1.9 | 26.2 weeks STANDARD_DEVIATION 1.8 | 26.6 weeks STANDARD_DEVIATION 2 | 26.6 weeks STANDARD_DEVIATION 1.8 | 26.4 weeks STANDARD_DEVIATION 1.8 |
| Birth Weight | 903.9 grams STANDARD_DEVIATION 291.2 | 797.2 grams STANDARD_DEVIATION 267.4 | 935.1 grams STANDARD_DEVIATION 295 | 902.4 grams STANDARD_DEVIATION 369.8 | 916.8 grams STANDARD_DEVIATION 254.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 7 Participants | 2 Participants | 2 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 245 Participants | 32 Participants | 84 Participants | 39 Participants | 90 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 31 Participants | 6 Participants | 10 Participants | 3 Participants | 12 Participants |
| Race (NIH/OMB) More than one race | 7 Participants | 1 Participants | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 2 Participants | 1 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 213 Participants | 27 Participants | 74 Participants | 36 Participants | 76 Participants |
| Region of Enrollment United States | 256 participants | 36 participants | 87 participants | 41 participants | 92 participants |
| Sex/Gender, Customized Female | 122 Participants | 17 Participants | 39 Participants | 21 Participants | 45 Participants |
| Sex/Gender, Customized Male | 132 Participants | 19 Participants | 47 Participants | 19 Participants | 47 Participants |
| Sex/Gender, Customized Unknown | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 36 | 10 / 87 | 2 / 41 | 6 / 92 |
| other Total, other adverse events | 0 / 36 | 0 / 87 | 0 / 41 | 0 / 92 |
| serious Total, serious adverse events | 5 / 36 | 7 / 87 | 3 / 41 | 10 / 92 |
Outcome results
Primary
Percent of Survivors With no Severe IVH (Grades 3 or 4) or PVL
determined by head ultrasound in Neonatal Intensive Care Unit (NICU) and single head MRI at 38weeks corrected gestational age
Time frame: within first 60 days of life
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Cord Clamp & Placebo IV Solution | Percent of Survivors With no Severe IVH (Grades 3 or 4) or PVL | 22.2 percent of participants |
| Delay Cord Clamp & Placebo IV Solution | Percent of Survivors With no Severe IVH (Grades 3 or 4) or PVL | 14.9 percent of participants |
| Immediate Cord Clamp & Indomethacin IV | Percent of Survivors With no Severe IVH (Grades 3 or 4) or PVL | 17.1 percent of participants |
| Indomethacin iv & Delayed Cord Clamp | Percent of Survivors With no Severe IVH (Grades 3 or 4) or PVL | 10.9 percent of participants |
Secondary
Number of Participants With Acute Kidney Injury
measures of serum creatinine and urine output during Neonatal Intensive Care Unit (NICU) stay. General measures of renal injury (which is a common risk of indomethacin treatment in this patient population).
Time frame: first 60 days of life
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Immediate Cord Clamp & Placebo IV Solution | Number of Participants With Acute Kidney Injury | Grade 3 Acute Kidney Injury | 2 participants |
| Immediate Cord Clamp & Placebo IV Solution | Number of Participants With Acute Kidney Injury | Grade 1 Acute Kidney Injury | 8 participants |
| Immediate Cord Clamp & Placebo IV Solution | Number of Participants With Acute Kidney Injury | Grade 4 Acute Kidney Injury | 0 participants |
| Immediate Cord Clamp & Placebo IV Solution | Number of Participants With Acute Kidney Injury | Grade 2 Acute Kidney Injury | 6 participants |
| Immediate Cord Clamp & Placebo IV Solution | Number of Participants With Acute Kidney Injury | No acute kidney injury | 20 participants |
| Delay Cord Clamp & Placebo IV Solution | Number of Participants With Acute Kidney Injury | Grade 2 Acute Kidney Injury | 8 participants |
| Delay Cord Clamp & Placebo IV Solution | Number of Participants With Acute Kidney Injury | Grade 3 Acute Kidney Injury | 4 participants |
| Delay Cord Clamp & Placebo IV Solution | Number of Participants With Acute Kidney Injury | Grade 4 Acute Kidney Injury | 0 participants |
| Delay Cord Clamp & Placebo IV Solution | Number of Participants With Acute Kidney Injury | Grade 1 Acute Kidney Injury | 27 participants |
| Delay Cord Clamp & Placebo IV Solution | Number of Participants With Acute Kidney Injury | No acute kidney injury | 48 participants |
| Immediate Cord Clamp & Indomethacin IV | Number of Participants With Acute Kidney Injury | Grade 2 Acute Kidney Injury | 3 participants |
| Immediate Cord Clamp & Indomethacin IV | Number of Participants With Acute Kidney Injury | No acute kidney injury | 23 participants |
| Immediate Cord Clamp & Indomethacin IV | Number of Participants With Acute Kidney Injury | Grade 1 Acute Kidney Injury | 15 participants |
| Immediate Cord Clamp & Indomethacin IV | Number of Participants With Acute Kidney Injury | Grade 3 Acute Kidney Injury | 0 participants |
| Immediate Cord Clamp & Indomethacin IV | Number of Participants With Acute Kidney Injury | Grade 4 Acute Kidney Injury | 0 participants |
| Indomethacin iv & Delayed Cord Clamp | Number of Participants With Acute Kidney Injury | Grade 3 Acute Kidney Injury | 1 participants |
| Indomethacin iv & Delayed Cord Clamp | Number of Participants With Acute Kidney Injury | Grade 1 Acute Kidney Injury | 29 participants |
| Indomethacin iv & Delayed Cord Clamp | Number of Participants With Acute Kidney Injury | No acute kidney injury | 48 participants |
| Indomethacin iv & Delayed Cord Clamp | Number of Participants With Acute Kidney Injury | Grade 2 Acute Kidney Injury | 14 participants |
| Indomethacin iv & Delayed Cord Clamp | Number of Participants With Acute Kidney Injury | Grade 4 Acute Kidney Injury | 0 participants |
Other Pre-specified
Circulating Progenitor Cell Subpopulations
measures of several progenitor cell subtypes in blood during the NICU stay
Time frame: first 60 days of life
Other Pre-specified
Hematological Status
hematocrit, ferritin, hemoglobin at various times during NICU stay
Time frame: first 60 days of life
Other Pre-specified
Inflammatory Stress
measurement of inflammatory biomarkers (CRP, Interleukin-6, soluble ICAM) at various times during NICU stay
Time frame: first 60 days of life
Other Pre-specified
Neurocognitive Assessments at Post-NICU Followup
standardized neurocognitive assessments done at NICU graduate clinic.
Time frame: up to 24 months of corrected gestational age