The Hydrocortisone and Extubation study will test the safety and efficacy of a 10 day course of hydrocortisone for infants who are less than 30 weeks estimated gestational age and who are intubated at 14-28 days of life. Infants will be randomized to receive hydrocortisone or placebo. This study will determine if hydrocortisone improves infants'survival without moderate or severe BPD and will be associated with improvement in survival without moderate or severe neurodevelopmental impairment at 22 - 26 months corrected age.
Bronchopulmonary dysplasia (BPD) remains a leading morbidity of the extremely preterm infant, and prolonged mechanical ventilation is associated with increased risk for BPD. Dexamethasone has been used previously to facilitate extubation and decrease the incidence of BPD; however, due to adverse effects on neurodevelopmental outcomes, the use of this drug has decreased. One cohort study suggests that hydrocortisone (HC) may facilitate extubation. HC has thus far not been associated with adverse neurodevelopmental outcomes in either cohort studies or randomized controlled trials. A recent meta-analysis of postnatal corticosteroid therapy begun after the first week of life suggested that "late therapy may reduce neonatal mortality without significantly increasing the risk of adverse long-term neurodevelopmental outcomes," although the methodological quality of some of the follow-up was acknowledged to be limited. This is a randomized controlled trial to study the efficacy and safety of a 10-day tapering course of hydrocortisone treatment for infants \<30 weeks estimated gestational age at birth who remain intubated at 14 - 28 days postnatal age. Based on previous Network data these criteria define a population with a risk of death or BPD at 36 weeks postmenstrual age of approximately 65 - 75%. The primary outcome for this study will incorporate both (1) survival without moderate to severe BPD by Network physiologic definition and (2) survival without moderate or severe NDI at 18 - 22 months corrected age. Therefore, the results of this study will be reported only when follow-up data are available unless (1) the trial is stopped early by the DSMC because of strong evidence of benefit or harm, or (2) at the time all subjects have completed treatment the DCC finds a substantial survival benefit favoring hydrocortisone (p\<0.001). Individual study assignment will remain masked until the follow-up is completed. Secondary outcomes will include short term measures such as respiratory morbidities and growth at 36 weeks postmenstrual age and long term measures including growth and other outcomes at 22 - 26 months corrected age. Secondary studies include: 1. Effect of Hydrocortisone on the Cardiac mass of Premature Intubated Infants - will determine left ventricular mass index at 36 weeks postmenstrual age (or prior to discharge/transfer if after 34 weeks) in infants enrolled in the hydrocortisone for BPD RCT, and compare HC-treated infants to placebo-treated infants. It will similarly assess and compare the incidence of pulmonary hypertension in these patients. 2. Extended follow-up: Subjects will be seen for a follow-up visit at 5-6 years corrected age to assess functional developmental and respiratory outcomes at early school age. In a subset of five Neonatal Research Network Clinical Centers, impulse oscillometry (IOS), which is the optimal direct measure of lung capacity and function, will be performed to validate the 6-minute walk test and International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire as functional measures of pulmonary status. Also at these five Centers, the six minute walk test, ISAAAC questionnaire, and IOS will be administered as part of (1) the Healthy Lungs sub-study, which will recruit 120 TOP 5 study participants who had minimal lung disease when they were infants to define normative ranges in healthy, preterm-born children, and (2) the Healthy Lungs Two sub-study, which will recruit 120 healthy, term-born children without history of lung disease to characterize functional and mechanical respiratory outcomes at 5-7 years of age.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
TRIPLE
Enrollment
800
Hydrocortisone sodium succinate for intravenous administration (unpreserved, Solu-Cortef plain, Pfizer®, reconstituted with unpreserved normal saline to avoid exposure to the benzyl alcohol contained in preserved diluents), to be administered either intravenously or orally if no intravenous line is available at the same dose, and tapered as follows: 4mg/kg/day ¸ q 6 hours x 2 days, then 2mg/kg/day ¸ q 6 hours x 3 days; then 1mg/kg/day ¸ q 12 hours x 3 days; then 0.5mg/kg/d as a single dose x 2 days
Saline placebo to be administered either intravenously or orally if no intravenous line is available, at the same dose, and tapered as follows: 4mg/kg/day ¸ q 6 hours x 2 days, then 2mg/kg/day ¸ q 6 hours x 3 days; then 1mg/kg/day ¸ q 12 hours x 3 days; then 0.5mg/kg/d as a single dose x 2 days
University of Alabama at Birmingham
Birmingham, Alabama, United States
University of California - Los Angeles
Los Angeles, California, United States
Stanford University
Palo Alto, California, United States
Emory University
Atlanta, Georgia, United States
Indiana University
Indianapolis, Indiana, United States
University of Iowa
Iowa City, Iowa, United States
Wayne State University
Detroit, Michigan, United States
Children's Mercy Hospital
Kansas City, Missouri, United States
University of New Mexico
Albuquerque, New Mexico, United States
University of Rochester
Rochester, New York, United States
...and 10 more locations
Survival Without Moderate/Severe Physiologic Bronchopulmonary Dysplasia (BPD)
Survival without moderate or severe physiologic BPD at 36 weeks postmenstrual age. Moderate or severe physiologic BPD is defined as a requirement for supplemental oxygen and/or positive airway pressure to maintain oxygen saturation greater than 90 percent. A room air challenge was performed for infants estimated to be receiving less than 0.30 FiO2 by nasal cannula.
Time frame: From day of randomization to 36 weeks post menstrual age
Survival Without Moderate/Severe Neurodevelopmental Impairment (NDI)
Survival without moderate or severe neurodevelopmental impairment (NDI) at 22-26 months corrected age. NDI is defined as defined as any of: Bayley Scales of Infant and Toddler Development-III (Bayley-III) cognitive composite score less than 85 (standardized mean 100, SD 15, range 55-145) or motor composite score less than 85 (standardized mean 100, range 45-155) (lower scores indicating greater impairment), Gross Motor Function Classification System (GMFCS) level greater than or equal to II (on a scale from level I to V; I=normal and progressively higher levels indicate greater impairment), severe vision impairment in both eyes (consistent with refraction from less than 20 to 200), or bilateral hearing impairment with or without amplification (by report).
Time frame: From day of randomization to 22-26 months corrected age
Number of Participants With Successful Extubation
Successful extubation during the intervention period, defined as remaining extubated for greater than or equal to 1 week, including greater than or equal to 3 days after the last dose of study medication. An extubation attempt was required after 72 hours of study drug and 24 hours after meeting the following: FiO2 less than 0.40 to maintain a saturation of greater than or equal to 88 percent, mean airway pressure less than 8 cm H2O, and hemodynamically stable in the opinion of the clinical team.
Time frame: From day of randomization to day 14 post randomization
Total Deaths Before Discharge
Infant died before discharge home.
Time frame: From day of randomization to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Number of Participants With Bronchopulmonary Dysplasia (BPD) Grade at 36 Weeks Postmenstrual Age
BPD grade at 36 weeks postmenstrual age. BPD grades are defined as: 1. No support/room air; 2. Nasal cannula (NC) O2 less than or equal to 2L; 3. NC O2 greater than 2L or CPAP/NIPPV; 4. Invasive PPV
Time frame: At 36 weeks postmenstrual age
Days of Mechanical Ventilation to 36 Weeks Postmenstrual Age (PMA)
Number of days on mechanical ventilation (using high frequency ventilator or conventional ventilator)
Time frame: From birth to 36 weeks postmenstrual age
Duration of Oxygen Supplementation up to Status
Number of days of oxygen supplementation from birth to discharge home
Time frame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Length of Hospital Stay in Days Among Survivors to Discharge
Number of days infant stayed in hospitals, among those who survived to discharge
Time frame: From birth up to one year
Number of Participants With Dexamethasone Given Before 36 Weeks Postmenstrual Age (PMA)
Infant received dexamethasone anytime before 36 weeks postmenstrual age.
Time frame: From birth to 36 weeks postmenstrual age
Number of Participants With Normal/Mild, Moderate or Severe/Profound NDI
Severity of neurodevelopmental impairment, defined as one or more of: Bayley Scales of Infant Development-III (Bayley-III) cognitive score \<85 (standardized mean 100, SD 15, range 55-145), Bayley-III motor score \<85 (standardized mean 100, range 45-155), Gross Motor Function Classification System (GMFCS) level ≥2, severe vision impairment in both eyes (consistent with refraction \<20-200), or bilateral hearing impairment with or without amplification (by report). Bayley-III = Bayley Scales of Infant Development III (Cognitive score standardized mean 100, SD 15, range 55-145 motor score standardized mean 100, range 45-155; higher score indicates better performance (20))
Time frame: At 22-26 months corrected age
Number of Participants With Gross Motor Function Greater Than or Equal to Level 2
Number of infants with Gross Motor Function Classification System (GMFCS) level greater than or equal to II (on a scale from level I to V; I=normal and progressively higher levels indicate greater impairment)
Time frame: At 22-26 months corrected age
Number of Participants With Moderate-severe Cerebral Palsy
Number of infants with moderate or severe grade of cerebral palsy. Cerebral Palsy was diagnosed when there were definite abnormalities observed in the neuromotor exam, and functional challenges as classified by GMFCS level, and classified as moderate if GMFCS level was II or III and severe if level IV or V (40).
Time frame: At 22-26 months corrected age
Number of Participants With Severe Hearing Impairment (by Report)
Number of infants with bilateral hearing impairment with or without amplification (by report)
Time frame: At 22-26 months corrected age
Number of Participants With no/Some Functional Vision
Number of infants with severe vision impairment in both eyes (consistent with refraction less than 20-200)
Time frame: At 22-26 months corrected age
Weight Growth Measure Following Extremely Preterm Birth
This is measured as the weight Z-score at 36 weeks postmenstrual age. The Z-score is derived using Fenton growth curves, and follows a standardized normal distribution with a mean 0. A z-score of 0 designates average weight, and negative scores denote less than average weight.
Time frame: At 36 weeks post-menstrual age
Follow-up Weight Growth Measure Following Extremely Preterm Birth
This is measured as the weight Z-score at 22-26 months corrected age. The Z-score is determined using the WHO weight-for-age chart, and is derived from a standardized normal distribution, where 0 designates average weight-for-age, and negative scores denote less than average weight-for-age.
Time frame: At 22-26 months corrected age
Length Growth Measure Following Extremely Preterm Birth
This is measured as the length Z-score at 36 weeks postmenstrual age. The Z-score is derived using Fenton growth curves, and follows a standardized normal distribution with a mean 0. A z-score of 0 designates average length, and negative scores denote less than average length.
Time frame: At 36 weeks post-menstrual age
Follow-up Length Growth Measure Following Extremely Preterm Birth
This is measured as the length Z-score at 22-26 months corrected age. The Z-score is determined using the WHO length-for-age chart, and is derived from a standardized normal distribution, where 0 designates average length-for-age, and negative scores denote less than average length-for-age.
Time frame: At 22-26 months corrected age
Head Circumference Growth Measure Following Extremely Preterm Birth
This is measured as the head circumference Z-score at 36 weeks postmenstrual age. The Z-score is derived using Fenton growth curves, and follows a standardized normal distribution with a mean 0. A z-score of 0 designates average head circumference, and negative scores denote less than average head circumference.
Time frame: At 36 weeks post-menstrual age
Follow-up Head Circumference Growth Measure Following Extremely Preterm Birth
This is measured as the head circumference Z-score at 22-26 months corrected age. The Z-score is determined using the WHO head circumference-for-age chart, and is derived from a standardized normal distribution, where 0 designates average head circumference-for-age, and negative scores denote less than average head circumference-for-age.
Time frame: At 22-26 months corrected age
Number of Participants With Bronchopulmonary Dysplasia (BPD) Grade 40 Weeks Postmenstrual Age
BPD grade at 40 weeks postmenstrual age. BPD grades are defined as: 1. No support/room air; 2. Nasal cannula (NC) O2 less than or equal to 2L; 3. NC O2 greater than 2L or CPAP/NIPPV; 4. Invasive PPV
Time frame: At 40 weeks post menstrual age
Days of Mechanical Ventilation up to Status
Number of days on mechanical ventilation (using high frequency ventilator or conventional ventilator) up to status
Time frame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Duration of Oxygen Supplementation Among Survivors to 36 Weeks
Number of days of oxygen supplementation from birth to 36 weeks post menstrual age
Time frame: From birth to 36 weeks postmenstrual age
Duration of Invasive Positive Pressure Ventilation (PPV) After Postnatal Day 14
Number of days on invasive PPV after postnatal day 14
Time frame: From postnatal day 15 to 36 weeks post menstrual age or Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Duration of Non-invasive Positive Pressure Ventilation (PPV) (Nasal IPPV/CPAP) After Postnatal Day 14
Number of days of non-invasive PPV after postnatal day 14
Time frame: From postnatal day 15 to 36 weeks post menstrual age or Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Number of Participants Who Received Inhaled Glucocorticoids During Study Period
Number of infants who received Inhaled glucocorticoids during the study intervention period
Time frame: From randomization to day 14 post randomization
Number of Participants Who Received Other Systemic Glucocorticoids During Study Period
Number of infants who received other systemic glucocorticoids during the study intervention period
Time frame: From randomization to day 14 post randomization
Number of Days Dexamethasone Given Before 36 Weeks PMA
Number of days infant received dexamethasone anytime before 36 weeks postmenstrual age.
Time frame: From birth to 36 weeks postmenstrual age
Number of Participants With Patent Ductus Arteriosus (PDA) Treated With Medication or Surgery
Number of infants with a Patent Ductus Arteriosus (PDA) that was treated with medicine or surgery
Time frame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Number of Participants Diagnosed With Necrotizing Enterocolitis (NEC)
Number of infants diagnosed with Necrotizing Enterocolitis (NEC)
Time frame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Number of Participants With Retinopathy of Prematurity (ROP) Stage 3 or Worse
Number of infants diagnosed with ROP stage 3 or worse in either eye. ROP stage 3 or worse is determined based on the extent of extraretinal fibrovascular proliferation. Higher stages of ROP indicate a worse outcome; the stages range from 1 for "mild" disease, to 5 for "severe" disease.
Time frame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Number of Participants Receiving Therapy for Retinopathy of Prematurity (ROP)
Number of infants receiving therapy for Retinopathy of prematurity (ROP)
Time frame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Number of Participants With Severe Intraventricular Hemorrhage (IVH)
Number of infants with severe IVH, grade 3 or 4. Severity of IVH is hierarchical. Grade 3 occurs when the ventricular size is enlarged and blood/echodensity is in the ventricle. Grade 4 occurs when blood/echodensity is in the parenchyma.
Time frame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Number of Participants With Periventricular Leukomalacia
Number of infants with Periventricular leukomalacia
Time frame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Number of Participants With Neurodevelopmental Impairment (NDI)
Number of infants with NDI. NDI is defined as defined as any of: Bayley Scales of Infant and Toddler Development-III (Bayley-III) cognitive composite score less than 85 (standardized mean 100, SD 15, range 55-145) or motor composite score less than 85 (standardized mean 100, range 45-155) (lower scores indicating greater impairment), Gross Motor Function Classification System (GMFCS) level greater than or equal to II (on a scale from level I to V; I=normal and progressively higher levels indicate greater impairment), severe vision impairment in both eyes (consistent with refraction less than 20-200), or bilateral hearing impairment with or without amplification (by report).
Time frame: At 22-26 months corrected age
Number of Participants With a Bayley Scales of Infant Development (BSID) Cognitive Composite Score Less Than 85
Number of infants with a BSID-III cognitive composite score less than 85. (standardized mean 100, SD 15, range 55-145). Higher scores indicate better performance. Composite BSID-III scores of less than 85 are less than 1 standard deviation below the mean of 100.
Time frame: At 22-26 months corrected age
Number of Participants With a Bayley Scales of Infant Development (BSID) Cognitive Composite Score Less Than 70
Number of infants with a BSID-III cognitive composite score less than 70. (standardized mean 100, SD 15, range 55-145). Composite BSID-III scores of less than 70 are less than 2 standard deviations below the mean of 100.
Time frame: At 22-26 months corrected age
Number of Participants With a Bayley Scales of Infant Development (BSID) Motor Composite Score Less Than 85
Number of infants with a BSID-III motor composite score less than 85. (standardized mean 100, SD 15, range 55-145). Composite BSID-III scores of less than 85 are less than 1 standard deviation below the mean of 100.
Time frame: At 22-26 months corrected age
Number of Participants With a Bayley Scales of Infant Development (BSID) Motor Composite Score Less Than 70
Number of infants with a BSID-III motor composite score less than 70. (standardized mean 100, SD 15, range 55-145). Composite BSID-III scores of less than 70 are less than 2 standard deviations below the mean of 100.
Time frame: At 22-26 months corrected age
Number of Participants With Any Cerebral Palsy
Number of infants with cerebral palsy. Cerebral Palsy was diagnosed when there were definite abnormalities observed in the neuromotor exam, and functional challenges as classified by GMFCS level, and classified as moderate if GMFCS level was II or III and severe if level IV or V (40).
Time frame: At 22-26 months corrected age
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