Hydrocortisone for BPD

Bronchopulmonary Dysplasia Clinical Trial

Official title:

A Randomized Controlled Trial of the Effect of Hydrocortisone on Survival Without Bronchopulmonary Dysplasia and on Neurodevelopmental Outcomes at 22 - 26 Months of Age in Intubated Infants < 30 Weeks Gestation Age

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01353313
• Other study ID #: NICHD-NRN-0045
• Secondary ID: U10HD034216U10HD
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: August 11, 2011
• Est. completion date: January 2025

Study information

• Verified date: December 2023
• Source: NICHD Neonatal Research Network
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 800
• Est. completion date: January 2025
• Est. primary completion date: September 21, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 30 Weeks

Eligibility

Inclusion Criteria:

• infants <30 weeks estimated gestational age

• inborn at an NRN site or were admitted to an NRN site before 72 hours postnatal age

• have received at least 7days of mechanical ventilation;

• are receiving mechanical ventilation through an endotracheal tube .

Exclusion Criteria:

• Major congenital anomalies

• Decision to limit support

• Indomethacin or ibuprofen treatment within 48 hours of study drug

• Previous corticosteroid treatment for BPD

• Received hydrocortisone for 14 or more cumulative days

• Received hydrocortisone within 7 days of study entry

Related Conditions & MeSH terms

• Birth Weight
• Bronchopulmonary Dysplasia
• Infant, Newborn
• Infant, Premature
• Infant, Small for Gestational Age
• Infant, Very Low Birth Weight

Intervention

Drug:
• Hydrocortisone
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
• Placebo
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

Locations

Country	Name	City	State
United States	University of New Mexico	Albuquerque	New Mexico
United States	Emory University	Atlanta	Georgia
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Cincinnati Children's Medical Center	Cincinnati	Ohio
United States	Case Western Reserve University, Rainbow Babies and Children's Hospital	Cleveland	Ohio
United States	Research Institute at Nationwide Children's Hospital	Columbus	Ohio
United States	University of Texas Southwestern Medical Center at Dallas	Dallas	Texas
United States	Wayne State University	Detroit	Michigan
United States	Duke University	Durham	North Carolina
United States	RTI International	Durham	North Carolina
United States	University of Texas Health Science Center at Houston	Houston	Texas
United States	Indiana University	Indianapolis	Indiana
United States	University of Iowa	Iowa City	Iowa
United States	Children's Mercy Hospital	Kansas City	Missouri
United States	University of California - Los Angeles	Los Angeles	California
United States	Stanford University	Palo Alto	California
United States	Univeristy of Pennsylvania	Philadelphia	Pennsylvania
United States	Brown University, Women & Infants Hospital of Rhode Island	Providence	Rhode Island
United States	University of Rochester	Rochester	New York
United States	University of Utah	Salt Lake City	Utah

Sponsors (5)

Lead Sponsor	Collaborator
NICHD Neonatal Research Network	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Center for Advancing Translational Sciences (NCATS), National Center for Research Resources (NCRR), National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	From day of randomization to 36 weeks post menstrual age
Primary	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).	From day of randomization to 22-26 months corrected age
Secondary	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.	From day of randomization to day 14 post randomization
Secondary	Total Deaths Before Discharge	Infant died before discharge home.	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
Secondary	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	At 36 weeks postmenstrual age
Secondary	Days of Mechanical Ventilation to 36 Weeks Postmenstrual Age (PMA)	Number of days on mechanical ventilation (using high frequency ventilator or conventional ventilator)	From birth to 36 weeks postmenstrual age
Secondary	Duration of Oxygen Supplementation up to Status	Number of days of oxygen supplementation from birth to discharge home	From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Secondary	Length of Hospital Stay in Days Among Survivors to Discharge	Number of days infant stayed in hospitals, among those who survived to discharge	From birth up to one year
Secondary	Number of Participants With Dexamethasone Given Before 36 Weeks Postmenstrual Age (PMA)	Infant received dexamethasone anytime before 36 weeks postmenstrual age.	From birth to 36 weeks postmenstrual age
Secondary	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))	At 22-26 months corrected age
Secondary	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)	At 22-26 months corrected age
Secondary	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).	At 22-26 months corrected age
Secondary	Number of Participants With Severe Hearing Impairment (by Report)	Number of infants with bilateral hearing impairment with or without amplification (by report)	At 22-26 months corrected age
Secondary	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)	At 22-26 months corrected age
Secondary	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.	At 36 weeks post-menstrual age
Secondary	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.	At 22-26 months corrected age
Secondary	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.	At 36 weeks post-menstrual age
Secondary	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.	At 22-26 months corrected age
Secondary	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.	At 36 weeks post-menstrual age
Secondary	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.	At 22-26 months corrected age
Secondary	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	At 40 weeks post menstrual age
Secondary	Days of Mechanical Ventilation up to Status	Number of days on mechanical ventilation (using high frequency ventilator or conventional ventilator) up to status	From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Secondary	Duration of Oxygen Supplementation Among Survivors to 36 Weeks	Number of days of oxygen supplementation from birth to 36 weeks post menstrual age	From birth to 36 weeks postmenstrual age
Secondary	Duration of Invasive Positive Pressure Ventilation (PPV) After Postnatal Day 14	Number of days on invasive PPV after postnatal day 14	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
Secondary	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	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
Secondary	Number of Participants Who Received Inhaled Glucocorticoids During Study Period	Number of infants who received Inhaled glucocorticoids during the study intervention period	From randomization to day 14 post randomization
Secondary	Number of Participants Who Received Other Systemic Glucocorticoids During Study Period	Number of infants who received other systemic glucocorticoids during the study intervention period	From randomization to day 14 post randomization
Secondary	Number of Days Dexamethasone Given Before 36 Weeks PMA	Number of days infant received dexamethasone anytime before 36 weeks postmenstrual age.	From birth to 36 weeks postmenstrual age
Secondary	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	From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Secondary	Number of Participants Diagnosed With Necrotizing Enterocolitis (NEC)	Number of infants diagnosed with Necrotizing Enterocolitis (NEC)	From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Secondary	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.	From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Secondary	Number of Participants Receiving Therapy for Retinopathy of Prematurity (ROP)	Number of infants receiving therapy for Retinopathy of prematurity (ROP)	From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Secondary	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.	From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Secondary	Number of Participants With Periventricular Leukomalacia	Number of infants with Periventricular leukomalacia	From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
Secondary	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).	At 22-26 months corrected age
Secondary	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.	At 22-26 months corrected age
Secondary	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.	At 22-26 months corrected age
Secondary	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.	At 22-26 months corrected age
Secondary	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.	At 22-26 months corrected age
Secondary	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).	At 22-26 months corrected age

External Links

•   NICHD Neonatal Research Network site
•   NICHD Pregnancy & Perinatology Branch