Hydrocortisone for BPD

• Sponsor: NICHD Neonatal Research Network (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01353313
• Collaborator: National Center for Research Resources (NCRR) (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH), National Heart, Lung, and Blood Institute (NHLBI) (NIH), National Center for Advancing Translational Science (NCATS) (NIH)
• Enrollment: 800
• Locations: 20
• Arms: 2
• Anticipated Duration (Months): 160.7
• Patients Per Site: 40
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Infant, Newborn; Infant, Small for Gestational Age; Infant, Very Low Birth Weight; Infant, Premature; Bronchopulmonary Dysplasia	Drug: Hydrocortisone; Drug: Placebo	Phase 3

Detailed 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 800 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Prevention
• 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
• Actual Study Start Date: Aug 11, 2011
• Actual Primary Completion Date: Sep 21, 2020
• Anticipated Study Completion Date: Jan 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Saline placebo	Drug: 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
Experimental: 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)	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

Outcome Measures

Primary Outcome Measures

1. Survival Without Moderate/Severe Physiologic Bronchopulmonary Dysplasia (BPD) [From day of randomization to 36 weeks post menstrual age]

   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.

2. Survival Without Moderate/Severe Neurodevelopmental Impairment (NDI) [From day of randomization to 22-26 months corrected age]

   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).

Secondary Outcome Measures

1. Number of Participants With Successful Extubation [From day of randomization to day 14 post randomization]

   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.

2. Total Deaths Before Discharge [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]

   Infant died before discharge home.

3. Number of Participants With Bronchopulmonary Dysplasia (BPD) Grade at 36 Weeks Postmenstrual Age [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

4. Days of Mechanical Ventilation to 36 Weeks Postmenstrual Age (PMA) [From birth to 36 weeks postmenstrual age]

   Number of days on mechanical ventilation (using high frequency ventilator or conventional ventilator)

5. Duration of Oxygen Supplementation 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]

   Number of days of oxygen supplementation from birth to discharge home

6. Length of Hospital Stay in Days Among Survivors to Discharge [From birth up to one year]

   Number of days infant stayed in hospitals, among those who survived to discharge

7. Number of Participants With Dexamethasone Given Before 36 Weeks Postmenstrual Age (PMA) [From birth to 36 weeks postmenstrual age]

   Infant received dexamethasone anytime before 36 weeks postmenstrual age.

8. Number of Participants With Normal/Mild, Moderate or Severe/Profound NDI [At 22-26 months corrected age]

   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))

9. Number of Participants With Gross Motor Function Greater Than or Equal to Level 2 [At 22-26 months corrected age]

   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)

10. Number of Participants With Moderate-severe Cerebral Palsy [At 22-26 months corrected age]

    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).

11. Number of Participants With Severe Hearing Impairment (by Report) [At 22-26 months corrected age]

    Number of infants with bilateral hearing impairment with or without amplification (by report)

12. Number of Participants With no/Some Functional Vision [At 22-26 months corrected age]

    Number of infants with severe vision impairment in both eyes (consistent with refraction less than 20-200)

13. Weight Growth Measure Following Extremely Preterm Birth [At 36 weeks post-menstrual age]

    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.

14. Follow-up Weight Growth Measure Following Extremely Preterm Birth [At 22-26 months corrected age]

    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.

15. Length Growth Measure Following Extremely Preterm Birth [At 36 weeks post-menstrual age]

    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.

16. Follow-up Length Growth Measure Following Extremely Preterm Birth [At 22-26 months corrected age]

    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.

17. Head Circumference Growth Measure Following Extremely Preterm Birth [At 36 weeks post-menstrual age]

    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.

18. Follow-up Head Circumference Growth Measure Following Extremely Preterm Birth [At 22-26 months corrected age]

    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.

19. Number of Participants With Bronchopulmonary Dysplasia (BPD) Grade 40 Weeks Postmenstrual Age [At 40 weeks post menstrual 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

20. Days of Mechanical Ventilation 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]

    Number of days on mechanical ventilation (using high frequency ventilator or conventional ventilator) up to status

21. Duration of Oxygen Supplementation Among Survivors to 36 Weeks [From birth to 36 weeks postmenstrual age]

    Number of days of oxygen supplementation from birth to 36 weeks post menstrual age

22. Duration of Invasive Positive Pressure Ventilation (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]

    Number of days on invasive PPV after postnatal day 14

23. Duration of Non-invasive Positive Pressure Ventilation (PPV) (Nasal IPPV/CPAP) 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]

    Number of days of non-invasive PPV after postnatal day 14

24. Number of Participants Who Received Inhaled Glucocorticoids During Study Period [From randomization to day 14 post randomization]

    Number of infants who received Inhaled glucocorticoids during the study intervention period

25. Number of Participants Who Received Other Systemic Glucocorticoids During Study Period [From randomization to day 14 post randomization]

    Number of infants who received other systemic glucocorticoids during the study intervention period

26. Number of Days Dexamethasone Given Before 36 Weeks PMA [From birth to 36 weeks postmenstrual age]

    Number of days infant received dexamethasone anytime before 36 weeks postmenstrual age.

27. Number of Participants With Patent Ductus Arteriosus (PDA) Treated With Medication 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]

    Number of infants with a Patent Ductus Arteriosus (PDA) that was treated with medicine or surgery

28. Number of Participants 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]

    Number of infants diagnosed with Necrotizing Enterocolitis (NEC)

29. Number of Participants With Retinopathy of Prematurity (ROP) Stage 3 or Worse [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 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.

30. Number of Participants 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]

    Number of infants receiving therapy for Retinopathy of prematurity (ROP)

31. Number of Participants With Severe Intraventricular Hemorrhage (IVH) [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 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.

32. Number of Participants 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]

    Number of infants with Periventricular leukomalacia

33. Number of Participants With Neurodevelopmental Impairment (NDI) [At 22-26 months corrected age]

    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).

34. Number of Participants With a Bayley Scales of Infant Development (BSID) Cognitive Composite Score Less Than 85 [At 22-26 months corrected age]

    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.

35. Number of Participants With a Bayley Scales of Infant Development (BSID) Cognitive Composite Score Less Than 70 [At 22-26 months corrected age]

    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.

36. Number of Participants With a Bayley Scales of Infant Development (BSID) Motor Composite Score Less Than 85 [At 22-26 months corrected age]

    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.

37. Number of Participants With a Bayley Scales of Infant Development (BSID) Motor Composite Score Less Than 70 [At 22-26 months corrected age]

    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.

38. Number of Participants With Any Cerebral Palsy [At 22-26 months corrected age]

    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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 30 Weeks
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35233
2	University of California - Los Angeles	Los Angeles	California	United States	90025
3	Stanford University	Palo Alto	California	United States	94304
4	Emory University	Atlanta	Georgia	United States	30303
5	Indiana University	Indianapolis	Indiana	United States	46202
6	University of Iowa	Iowa City	Iowa	United States	52242
7	Wayne State University	Detroit	Michigan	United States	48201
8	Children's Mercy Hospital	Kansas City	Missouri	United States	64108
9	University of New Mexico	Albuquerque	New Mexico	United States	87131
10	University of Rochester	Rochester	New York	United States	14642
11	RTI International	Durham	North Carolina	United States	27705
12	Duke University	Durham	North Carolina	United States	27710
13	Cincinnati Children's Medical Center	Cincinnati	Ohio	United States	45267
14	Case Western Reserve University, Rainbow Babies and Children's Hospital	Cleveland	Ohio	United States	44106
15	Research Institute at Nationwide Children's Hospital	Columbus	Ohio	United States	43205
16	Univeristy of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
17	Brown University, Women & Infants Hospital of Rhode Island	Providence	Rhode Island	United States	02905
18	University of Texas Southwestern Medical Center at Dallas	Dallas	Texas	United States	75235
19	University of Texas Health Science Center at Houston	Houston	Texas	United States	77030
20	University of Utah	Salt Lake City	Utah	United States	84108

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Michele C Walsh, MD, Case Western Reserve University, Rainbow Babies and Children's Hospital
• Principal Investigator: Seetha Shankaran, MD, Wayne State University
• Principal Investigator: Abbot R Laptook, MD, Brown University, Women & Infants Hospital of Rhode Island
• Principal Investigator: C. Michael Cotten, MD, Duke University
• Principal Investigator: David Carlton, MD, Emory University
• Principal Investigator: Greg Sokol, MD, Indiana University
• Principal Investigator: Abhik Das, PhD, RTI International
• Principal Investigator: Krisa P Van Meurs, MD, Stanford University
• Principal Investigator: Brenda P Poindexter, MD, Children's Hospital Medical Center, Cincinnati
• Principal Investigator: Waldemar A Carlo, MD, University of Alabama at Birmingham
• Principal Investigator: Edward F Bell, MD, University of Iowa
• Study Chair: Kristi L Watterberg, MD, University of New Mexico
• Principal Investigator: Myra Wyckoff, MD, University of Texas, Southwestern Medical Center at Dallas
• Principal Investigator: Jon E Tyson, MD, MPH, The University of Texas Health Science Center, Houston
• Principal Investigator: Eric Eichenwald, MD, University of Pennsylvania
• Principal Investigator: Carl T D'Angio, MD, University of Rochester
• Principal Investigator: Uday Devaskar, MD, University of California, Los Angeles
• Principal Investigator: Pablo J Sanchez, MD, Research Institute at Nationwide Children's Hospital
• Principal Investigator: William Truog, MD, Children's Mercy Hospital Kansas City
• Principal Investigator: Bradley Yoder, MD, University of Utah

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 27, 2013

More Information

Additional Information:

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

Publications

None provided.

• Responsible Party: NICHD Neonatal Research Network
• ClinicalTrials.gov Identifier: NCT01353313
• Other Study ID Numbers: NICHD-NRN-0045; U10HD034216; U10HD027904; U10HD021364; U10HD027853; U10HD040689; U10HD040492; U10HD027851; U10HD021373; U10HD027856; U10HD053109; U10HD036790; U10HD027880; U10HD053089; U10HD021385; U10HD068244; U10HD068263; U10HD068270; U10HD068278; U10HD068284; U24HL137729; 1UG3HL137872
• First Posted: May 13, 2011
• Last Update Posted: Aug 19, 2022
• Last Verified: Jul 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by NICHD Neonatal Research Network: NICHD Neonatal Research Network; Extremely Low Birth Weight (ELBW); Very Low Birth Weight (VLBW); Prematurity; Mechanical ventilation; Intubation; Neurodevelopmental impairment
• Additional relevant MeSH terms: Bronchopulmonary Dysplasia; Birth Weight; Hydrocortisone

Study Results

Participant Flow

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Period Title: Overall Study
STARTED	398	402
Completed Assessment for Neurodevelopmental Impairment	321	318
Died After Discharge	8	6
Died Before Discharge	35	40
Survived to Discharge	363	362
COMPLETED	364	364
NOT COMPLETED	34	38

Baseline Characteristics

Arm/Group Title	Hydrocortisone	Placebo	Total
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.	Total of all reporting groups
Overall Participants	398	402	800
Age (weeks) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [weeks]	24.9 (2)	24.9 (2)	24.9 (2)
Sex: Female, Male (Count of Participants)
Female	212 53.3%	167 41.5%	379 47.4%
Male	186 46.7%	235 58.5%	421 52.6%
Race/Ethnicity, Customized (Count of Participants)
Black	139 34.9%	168 41.8%	307 38.4%
Missing	10 2.5%	11 2.7%	21 2.6%
Other	18 4.5%	17 4.2%	35 4.4%
White	231 58%	206 51.2%	437 54.6%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	66 16.6%	60 14.9%	126 15.8%
Not Hispanic or Latino	326 81.9%	337 83.8%	663 82.9%
Unknown or Not Reported	6 1.5%	5 1.2%	11 1.4%
Infant Body Weight (grams) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [grams]	710.3 (162.7)	720.4 (171.8)	715.4 (167.3)
Maternal Education (Count of Participants)
College degree/more	66 16.6%	69 17.2%	135 16.9%
High school degree	101 25.4%	108 26.9%	209 26.1%
Less than High school degree	68 17.1%	59 14.7%	127 15.9%
Partial college	78 19.6%	85 21.1%	163 20.4%
Unknown	85 21.4%	81 20.1%	166 20.8%

Outcome Measures

1. Primary Outcome

Title	Survival Without Moderate/Severe Physiologic Bronchopulmonary Dysplasia (BPD)
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data at hospital discharge.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	398	402
Moderate/severe BPD or death	332 83.4%	349 86.8%
Survival without moderate/severe physiologic bronchopulmonary dysplasia (BPD)	66 16.6%	53 13.2%

2. Primary Outcome

Title	Survival Without Moderate/Severe Neurodevelopmental Impairment (NDI)
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data at the two-year followup.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	358	360
Moderate/severe NDI or death	226 56.8%	226 56.2%
Survival without moderate/severe neurodevelopmental impairment (NDI)	132 33.2%	134 33.3%

3. Secondary Outcome

Title	Number of Participants With Successful Extubation
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data at hospital discharge.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	398	402
Successful extubation	178 44.7%	135 33.6%
Unsuccessful or no extubation	220 55.3%	267 66.4%

4. Secondary Outcome

Title	Total Deaths Before Discharge
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data at hospital discharge.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	398	402
Death before discharge	35 8.8%	40 10%
Survival to discharge	363 91.2%	362 90%

5. Secondary Outcome

Title	Number of Participants With Bronchopulmonary Dysplasia (BPD) Grade at 36 Weeks Postmenstrual Age
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data at hospital discharge.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	375	367
Invasive PPV	63 15.8%	51 12.7%
NC O2 greater than 2L or CPAP/NIPPV	152 38.2%	159 39.6%
Nasal cannula O2 less than or equal to 2L	120 30.2%	124 30.8%
No support, room air	40 10.1%	33 8.2%

6. Secondary Outcome

Title	Days of Mechanical Ventilation to 36 Weeks Postmenstrual Age (PMA)
Description	Number of days on mechanical ventilation (using high frequency ventilator or conventional ventilator)
Time Frame	From birth to 36 weeks postmenstrual age

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data at hospital discharge.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	368	368
Median (Inter-Quartile Range) [Days]	37	40

7. Secondary Outcome

Title	Duration of Oxygen Supplementation up to Status
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data who survived up to hospital discharge.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	362	362
Median (Inter-Quartile Range) [Days]	104.5	104

8. Secondary Outcome

Title	Length of Hospital Stay in Days Among Survivors to Discharge
Description	Number of days infant stayed in hospitals, among those who survived to discharge
Time Frame	From birth up to one year

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data at hospital discharge.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	362	362
Median (Inter-Quartile Range) [Days]	127.5	125.5

9. Secondary Outcome

Title	Number of Participants With Dexamethasone Given Before 36 Weeks Postmenstrual Age (PMA)
Description	Infant received dexamethasone anytime before 36 weeks postmenstrual age.
Time Frame	From birth to 36 weeks postmenstrual age

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data at hospital discharge.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	379	377
Dexamethasone given before 36 weeks PMA	150 37.7%	157 39.1%
Dexamethasone not given before 36 weeks PMA	229 57.5%	220 54.7%

10. Secondary Outcome

Title	Number of Participants With Normal/Mild, Moderate or Severe/Profound NDI
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data who survived up to the two-year followup.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	315	314
Moderate	98 24.6%	98 24.4%
Normal/mild	132 33.2%	134 33.3%
Severe/profound	85 21.4%	82 20.4%

11. Secondary Outcome

Title	Number of Participants With Gross Motor Function Greater Than or Equal to Level 2
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data who survived up to the two-year followup.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	331	329
Gross motor function less than II	283 71.1%	288 71.6%
Gross motor function level II or greater	48 12.1%	41 10.2%

12. Secondary Outcome

Title	Number of Participants With Moderate-severe Cerebral Palsy
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data who survived up to the two-year followup.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	330	330
Moderate or severe cerebral palsy	41 10.3%	33 8.2%
Not moderate or severe cerebral palsy	289 72.6%	297 73.9%

13. Secondary Outcome

Title	Number of Participants With Severe Hearing Impairment (by Report)
Description	Number of infants with bilateral hearing impairment with or without amplification (by report)
Time Frame	At 22-26 months corrected age

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data who survived up to the two-year followup.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	328	327
Not severe hearing impairment	319 80.2%	313 77.9%
Severe hearing impairment	9 2.3%	14 3.5%

14. Secondary Outcome

Title	Number of Participants With no/Some Functional Vision
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data who survived up to the two-year followup.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	330	330
Not severe vision impairment	325 81.7%	321 79.9%
Severe vision impairment	5 1.3%	9 2.2%

15. Secondary Outcome

Title	Weight Growth Measure Following Extremely Preterm Birth
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data between 35 and 37 weeks at discharge.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	366	363
Mean (Standard Deviation) [Z-score]	-1.68 (1.01)	-1.65 (0.98)

16. Secondary Outcome

Title	Follow-up Weight Growth Measure Following Extremely Preterm Birth
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data between 18 and 30 months at follow-up.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	319	316
Mean (Standard Deviation) [Z-score]	-0.51 (1.04)	-0.44 (1.15)

17. Secondary Outcome

Title	Length Growth Measure Following Extremely Preterm Birth
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data between 35 and 37 weeks at discharge.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	340	340
Mean (Standard Deviation) [Z-score]	-2.33 (1.16)	-2.21 (1.14)

18. Secondary Outcome

Title	Follow-up Length Growth Measure Following Extremely Preterm Birth
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data between 18 and 30 months at follow-up.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	316	314
Mean (Standard Deviation) [Z-score]	-0.93 (1.17)	-0.94 (1.22)

19. Secondary Outcome

Title	Head Circumference Growth Measure Following Extremely Preterm Birth
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data between 35 and 37 weeks at discharge.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	353	354
Mean (Standard Deviation) [Z-score]	-1.68 (1.34)	-1.74 (1.17)

20. Secondary Outcome

Title	Follow-up Head Circumference Growth Measure Following Extremely Preterm Birth
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data between 18 and 30 months at follow-up.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	314	301
Mean (Standard Deviation) [Z-score]	-0.45 (1.41)	-0.35 (1.42)

21. Secondary Outcome

Title	Number of Participants With Bronchopulmonary Dysplasia (BPD) Grade 40 Weeks Postmenstrual Age
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data at hospital discharge.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	279	284
Invasive PPV	46 11.6%	38 9.5%
NC O2 greater than 2L or CPAP/NIPPV	73 18.3%	65 16.2%
Nasal cannula O2 less than or equal to 2L	124 31.2%	129 32.1%
No support, room air	36 9%	52 12.9%

22. Secondary Outcome

Title	Days of Mechanical Ventilation up to Status
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data who survived up to hospital discharge.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	361	362
Median (Inter-Quartile Range) [Days]	37	41

23. Secondary Outcome

Title	Duration of Oxygen Supplementation Among Survivors to 36 Weeks
Description	Number of days of oxygen supplementation from birth to 36 weeks post menstrual age
Time Frame	From birth to 36 weeks postmenstrual age

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data at hospital discharge.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	369	368
Median (Inter-Quartile Range) [Days]	74	73

24. Secondary Outcome

Title	Duration of Invasive Positive Pressure Ventilation (PPV) After Postnatal Day 14
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data who were extubated prior to hospital discharge.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	161	124
Median (Inter-Quartile Range) [Days]	29	27

25. Secondary Outcome

Title	Duration of Non-invasive Positive Pressure Ventilation (PPV) (Nasal IPPV/CPAP) After Postnatal Day 14
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data who were extubated prior to hospital discharge.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	161	124
Median (Inter-Quartile Range) [Days]	13	13

26. Secondary Outcome

Title	Number of Participants Who Received Inhaled Glucocorticoids During Study Period
Description	Number of infants who received Inhaled glucocorticoids during the study intervention period
Time Frame	From randomization to day 14 post randomization

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data at hospital discharge.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	396	399
Did not receive inhaled glucocorticoids during study period	345 86.7%	355 88.3%
Received inhaled glucocorticoids during study period	51 12.8%	44 10.9%

27. Secondary Outcome

Title	Number of Participants Who Received Other Systemic Glucocorticoids During Study Period
Description	Number of infants who received other systemic glucocorticoids during the study intervention period
Time Frame	From randomization to day 14 post randomization

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data at hospital discharge.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	396	399
Did not receive other systemic glucocorticoids during study period	342 85.9%	334 83.1%
Received other systemic glucocorticoids during study period	54 13.6%	65 16.2%

28. Secondary Outcome

Title	Number of Days Dexamethasone Given Before 36 Weeks PMA
Description	Number of days infant received dexamethasone anytime before 36 weeks postmenstrual age.
Time Frame	From birth to 36 weeks postmenstrual age

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data at hospital discharge.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	150	157
Median (Inter-Quartile Range) [Days]	10	10

29. Secondary Outcome

Title	Number of Participants With Patent Ductus Arteriosus (PDA) Treated With Medication or Surgery
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data at hospital discharge.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	398	402
Not PDA treated with medication or surgery	206 51.8%	209 52%
PDA treated with medication or surgery	192 48.2%	193 48%

30. Secondary Outcome

Title	Number of Participants Diagnosed With Necrotizing Enterocolitis (NEC)
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data at hospital discharge.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	398	402
Diagnosed with NEC	33 8.3%	46 11.4%
Not diagnosed with NEC	365 91.7%	356 88.6%

31. Secondary Outcome

Title	Number of Participants With Retinopathy of Prematurity (ROP) Stage 3 or Worse
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data at hospital discharge.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	382	376
Diagnosed with ROP stage 3 or worse	105 26.4%	116 28.9%
Not diagnosed with ROP stage 3 or worse	277 69.6%	260 64.7%

32. Secondary Outcome

Title	Number of Participants Receiving Therapy for Retinopathy of Prematurity (ROP)
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data at hospital discharge.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	379	376
Did not receive therapy for ROP	311 78.1%	293 72.9%
Received therapy for ROP	68 17.1%	83 20.6%

33. Secondary Outcome

Title	Number of Participants With Severe Intraventricular Hemorrhage (IVH)
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data at hospital discharge.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	397	402
Not severe IVH, grade 3 or 4	316 79.4%	331 82.3%
Severe IVH, grade 3 or 4	81 20.4%	71 17.7%

34. Secondary Outcome

Title	Number of Participants With Periventricular Leukomalacia
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data at hospital discharge.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	398	402
No periventricular leukomalacia	376 94.5%	378 94%
Periventricular leukomalacia	22 5.5%	24 6%

35. Secondary Outcome

Title	Number of Participants With Neurodevelopmental Impairment (NDI)
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data at the two-year followup.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	321	319
Neurodevelopmental impairment	189 47.5%	185 46%
No neurodevelopmental impairment	132 33.2%	134 33.3%

36. Secondary Outcome

Title	Number of Participants With a Bayley Scales of Infant Development (BSID) Cognitive Composite Score Less Than 85
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data at the two-year followup.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	318	318
Composite cognitive score greater or equal to 85	168 42.2%	176 43.8%
Composite cognitive score less than 85	150 37.7%	142 35.3%

37. Secondary Outcome

Title	Number of Participants With a Bayley Scales of Infant Development (BSID) Cognitive Composite Score Less Than 70
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data at the two-year followup.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	318	318
Composite cognitive score greater or equal to 70	259 65.1%	269 66.9%
Composite cognitive score less than 70	59 14.8%	49 12.2%

38. Secondary Outcome

Title	Number of Participants With a Bayley Scales of Infant Development (BSID) Motor Composite Score Less Than 85
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data at the two-year followup.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	310	310
Composite motor score greater or equal to 85	164 41.2%	158 39.3%
Composite motor score less than 85	146 36.7%	152 37.8%

39. Secondary Outcome

Title	Number of Participants With a Bayley Scales of Infant Development (BSID) Motor Composite Score Less Than 70
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data at the two-year followup.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	310	310
Composite motor score greater or equal to 70	241 60.6%	246 61.2%
Composite motor score less than 70	69 17.3%	64 15.9%

40. Secondary Outcome

Title	Number of Participants With Any Cerebral Palsy
Description	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

Outcome Measure Data

Analysis Population Description

The analysis population includes all randomized infants with available data at the two-year followup.

Arm/Group Title	Hydrocortisone	Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.	Saline placebo administered intravenously or orally if no intravenous line was available.
Measure Participants	330	330
Any cerebral palsy	84 21.1%	71 17.7%
No cerebral palsy	246 61.8%	259 64.4%

Adverse Events

Time Frame	Birth to 36 weeks PMA
Arm/Group Title	Hydrocortisone		Placebo
Arm/Group Description	Hydrocortisone sodium succinate administered intravenously or orally if no intravenous line was available, tapered over 10 days.		Saline placebo administered intravenously or orally if no intravenous line was available.
All Cause Mortality
	Hydrocortisone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	43/398 (10.8%)		46/402 (11.4%)
Serious Adverse Events
	Hydrocortisone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	84/398 (21.1%)		95/402 (23.6%)
Blood and lymphatic system disorders
Thrombocytopenia	1/398 (0.3%)		0/402 (0%)
Cardiac disorders
Tachycardia	1/398 (0.3%)		0/402 (0%)
Congenital, familial and genetic disorders
Adrenal insufficiency neonatal	5/398 (1.3%)		16/402 (4%)
Patent ductus arteriosus	1/398 (0.3%)		4/402 (1%)
Gastrointestinal disorders
Abdominal compartment syndrome	0/398 (0%)		1/402 (0.2%)
Intestinal perforation	9/398 (2.3%)		13/402 (3.2%)
Lip ulceration	1/398 (0.3%)		0/402 (0%)
Necrotizing enterocolitis neonatal	2/398 (0.5%)		5/402 (1.2%)
Hepatobiliary disorders
Liver injury	1/398 (0.3%)		0/402 (0%)
Infections and infestations
Nosocomial infection	32/398 (8%)		29/402 (7.2%)
Osteomyelitis	1/398 (0.3%)		0/402 (0%)
Pneumonia	6/398 (1.5%)		2/402 (0.5%)
Pneumonia (MRSA)	1/398 (0.3%)		0/402 (0%)
Sepsis neonatal	2/398 (0.5%)		3/402 (0.7%)
Septic shock	1/398 (0.3%)		1/402 (0.2%)
Ureaplasma infection	1/398 (0.3%)		0/402 (0%)
Urinary tract infection	2/398 (0.5%)		1/402 (0.2%)
Injury, poisoning and procedural complications
Extra-axial hemorrhage	0/398 (0%)		1/402 (0.2%)
Metabolism and nutrition disorders
Hyperglycaemia	28/398 (7%)		19/402 (4.7%)
Hyperkalemia	2/398 (0.5%)		1/402 (0.2%)
Hypoglycaemia	0/398 (0%)		1/402 (0.2%)
Hyponatremia	1/398 (0.3%)		4/402 (1%)
Metabolic acidosis	0/398 (0%)		2/402 (0.5%)
Musculoskeletal and connective tissue disorders
Rickets	0/398 (0%)		1/402 (0.2%)
Nervous system disorders
Hydrocephalus	0/398 (0%)		1/402 (0.2%)
Pregnancy, puerperium and perinatal conditions
Hydrops foetalis	0/398 (0%)		1/402 (0.2%)
Renal and urinary disorders
Acute kidney injury	1/398 (0.3%)		2/402 (0.5%)
Acute renal failure	0/398 (0%)		1/402 (0.2%)
Anuria	0/398 (0%)		1/402 (0.2%)
Oliguria	1/398 (0.3%)		0/402 (0%)
Renal failure	0/398 (0%)		2/402 (0.5%)
Respiratory, thoracic and mediastinal disorders
Pneumothorax	0/398 (0%)		1/402 (0.2%)
Respiratory failure	61/398 (15.3%)		61/402 (15.2%)
Vascular disorders
Hypertension	15/398 (3.8%)		4/402 (1%)
Hypotension	2/398 (0.5%)		2/402 (0.5%)
Other (Not Including Serious) Adverse Events
	Hydrocortisone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	106/398 (26.6%)		95/402 (23.6%)
Blood and lymphatic system disorders
Thrombocytopenia	0/398 (0%)		1/402 (0.2%)
Cardiac disorders
Supraventricular tachycardia	0/398 (0%)		2/402 (0.5%)
Tachycardia	1/398 (0.3%)		0/402 (0%)
Congenital, familial and genetic disorders
Adrenal insufficiency neonatal	22/398 (5.5%)		24/402 (6%)
Patent ductus arteriosus	1/398 (0.3%)		0/402 (0%)
Gastrointestinal disorders
Intestinal perforation	5/398 (1.3%)		5/402 (1.2%)
Necrotizing enterocolitis neonatal (Suspected)	0/398 (0%)		1/402 (0.2%)
Infections and infestations
Bacterial disease carrier	1/398 (0.3%)		0/402 (0%)
Nosocomial infection	18/398 (4.5%)		27/402 (6.7%)
Pneumonia	1/398 (0.3%)		3/402 (0.7%)
Pneumonia mycoplasmal	0/398 (0%)		1/402 (0.2%)
Sepsis neonatal	5/398 (1.3%)		7/402 (1.7%)
Tracheitis	2/398 (0.5%)		1/402 (0.2%)
Urinary tract infection	0/398 (0%)		3/402 (0.7%)
Wound infection (Neck)	1/398 (0.3%)		0/402 (0%)
Investigations
Alkaline phosphatase NOS increased	1/398 (0.3%)		0/402 (0%)
Metabolism and nutrition disorders
Hyperglycaemia	25/398 (6.3%)		12/402 (3%)
Hyperkalemia	5/398 (1.3%)		6/402 (1.5%)
Hypernatremia	0/398 (0%)		1/402 (0.2%)
Hypoglycaemia	0/398 (0%)		1/402 (0.2%)
Hyponatremia	4/398 (1%)		2/402 (0.5%)
Metabolic acidosis	0/398 (0%)		1/402 (0.2%)
Nervous system disorders
Hydrocephalus	0/398 (0%)		1/402 (0.2%)
Renal and urinary disorders
Oliguria	2/398 (0.5%)		0/402 (0%)
Prerenal failure	0/398 (0%)		1/402 (0.2%)
Respiratory, thoracic and mediastinal disorders
Respiratory failure	41/398 (10.3%)		48/402 (11.9%)
Vascular disorders
Hypertension	56/398 (14.1%)		29/402 (7.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Investigators must adhere to the Neonatal Research Network Publication Policies