Clinical trial NCT01353313: Hydrocortisone for BPD
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Infant, Newborn
Infant, Small for Gestational Age
Infant, Very Low Birth Weight
Infant, Premature
Bronchopulmonary Dysplasia
Keywords: NICHD Neonatal Research Network
Extremely Low Birth Weight (ELBW)
Very Low Birth Weight (VLBW)
Prematurity
Mechanical ventilation
Intubation
Neurodevelopmental impairment
Lead sponsor: NICHD Neonatal Research Network
Sponsor class: NETWORK
Collaborators: name: National Center for Research Resources (NCRR)
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: National Heart, Lung, and Blood Institute (NHLBI)
name: National Center for Advancing Translational Sciences (NCATS)
First posted: 2011-05-13
Enrollment: 800
Sex: ALL
Maximum age (years): 30
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Survival Without Moderate/Severe Physiologic Bronchopulmonary Dysplasia (BPD)
timeFrame: From day of randomization to 36 weeks post menstrual age
measure: Survival Without Moderate/Severe Neurodevelopmental Impairment (NDI)
timeFrame: From day of randomization to 22-26 months corrected age
Secondary outcomes:
measure: Number of Participants With Successful Extubation
timeFrame: From day of randomization to day 14 post randomization
measure: Total Deaths Before Discharge
timeFrame: 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
measure: Number of Participants With Bronchopulmonary Dysplasia (BPD) Grade at 36 Weeks Postmenstrual Age
timeFrame: At 36 weeks postmenstrual age
measure: Days of Mechanical Ventilation to 36 Weeks Postmenstrual Age (PMA)
timeFrame: From birth to 36 weeks postmenstrual age
measure: Duration of Oxygen Supplementation up to Status
timeFrame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
measure: Length of Hospital Stay in Days Among Survivors to Discharge
timeFrame: From birth up to one year
measure: Number of Participants With Dexamethasone Given Before 36 Weeks Postmenstrual Age (PMA)
timeFrame: From birth to 36 weeks postmenstrual age
measure: Number of Participants With Normal/Mild, Moderate or Severe/Profound NDI
timeFrame: At 22-26 months corrected age
measure: Number of Participants With Gross Motor Function Greater Than or Equal to Level 2
timeFrame: At 22-26 months corrected age
measure: Number of Participants With Moderate-severe Cerebral Palsy
timeFrame: At 22-26 months corrected age
measure: Number of Participants With Severe Hearing Impairment (by Report)
timeFrame: At 22-26 months corrected age
measure: Number of Participants With no/Some Functional Vision
timeFrame: At 22-26 months corrected age
measure: Weight Growth Measure Following Extremely Preterm Birth
timeFrame: At 36 weeks post-menstrual age
measure: Follow-up Weight Growth Measure Following Extremely Preterm Birth
timeFrame: At 22-26 months corrected age
measure: Length Growth Measure Following Extremely Preterm Birth
timeFrame: At 36 weeks post-menstrual age
measure: Follow-up Length Growth Measure Following Extremely Preterm Birth
timeFrame: At 22-26 months corrected age
measure: Head Circumference Growth Measure Following Extremely Preterm Birth
timeFrame: At 36 weeks post-menstrual age
measure: Follow-up Head Circumference Growth Measure Following Extremely Preterm Birth
timeFrame: At 22-26 months corrected age
measure: Number of Participants With Bronchopulmonary Dysplasia (BPD) Grade 40 Weeks Postmenstrual Age
timeFrame: At 40 weeks post menstrual age
measure: Days of Mechanical Ventilation up to Status
timeFrame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
measure: Duration of Oxygen Supplementation Among Survivors to 36 Weeks
timeFrame: From birth to 36 weeks postmenstrual age
measure: Duration of Invasive Positive Pressure Ventilation (PPV) After Postnatal Day 14
timeFrame: 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
measure: Duration of Non-invasive Positive Pressure Ventilation (PPV) (Nasal IPPV/CPAP) After Postnatal Day 14
timeFrame: 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
measure: Number of Participants Who Received Inhaled Glucocorticoids During Study Period
timeFrame: From randomization to day 14 post randomization
measure: Number of Participants Who Received Other Systemic Glucocorticoids During Study Period
timeFrame: From randomization to day 14 post randomization
measure: Number of Days Dexamethasone Given Before 36 Weeks PMA
timeFrame: From birth to 36 weeks postmenstrual age
measure: Number of Participants With Patent Ductus Arteriosus (PDA) Treated With Medication or Surgery
timeFrame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
measure: Number of Participants Diagnosed With Necrotizing Enterocolitis (NEC)
timeFrame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
measure: Number of Participants With Retinopathy of Prematurity (ROP) Stage 3 or Worse
timeFrame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
measure: Number of Participants Receiving Therapy for Retinopathy of Prematurity (ROP)
timeFrame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
measure: Number of Participants With Severe Intraventricular Hemorrhage (IVH)
timeFrame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
measure: Number of Participants With Periventricular Leukomalacia
timeFrame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth
measure: Number of Participants With Neurodevelopmental Impairment (NDI)
timeFrame: At 22-26 months corrected age
measure: Number of Participants With a Bayley Scales of Infant Development (BSID) Cognitive Composite Score Less Than 85
timeFrame: At 22-26 months corrected age
measure: Number of Participants With a Bayley Scales of Infant Development (BSID) Cognitive Composite Score Less Than 70
timeFrame: At 22-26 months corrected age
measure: Number of Participants With a Bayley Scales of Infant Development (BSID) Motor Composite Score Less Than 85
timeFrame: At 22-26 months corrected age
measure: Number of Participants With a Bayley Scales of Infant Development (BSID) Motor Composite Score Less Than 70
timeFrame: At 22-26 months corrected age
measure: Number of Participants With Any Cerebral Palsy
timeFrame: At 22-26 months corrected age
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: University of California - Los Angeles
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Durham
country: United States
facility: RTI International
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Case Western Reserve University, Rainbow Babies and Children's Hospital
state: Ohio
city: Columbus
country: United States
facility: Research Institute at Nationwide Children's Hospital
state: Ohio
city: Philadelphia
country: United States
facility: Univeristy of Pennsylvania
state: Pennsylvania
city: Providence
country: United States
facility: Brown University, Women & Infants Hospital of Rhode Island
state: Rhode Island
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center at Dallas
state: Texas
city: Houston
country: United States
facility: University of Texas Health Science Center at Houston
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
Study officials:
affiliation: Case Western Reserve University, Rainbow Babies and Children's Hospital
name: Michele C Walsh, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Wayne State University
name: Seetha Shankaran, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Brown University, Women & Infants Hospital of Rhode Island
name: Abbot R Laptook, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Duke University
name: C. Michael Cotten, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Emory University
name: David Carlton, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Indiana University
name: Greg Sokol, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: RTI International
name: Abhik Das, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Stanford University
name: Krisa P Van Meurs, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Hospital Medical Center, Cincinnati
name: Brenda P Poindexter, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Alabama at Birmingham
name: Waldemar A Carlo, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Iowa
name: Edward F Bell, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of New Mexico
name: Kristi L Watterberg, MD
role: STUDY_CHAIR
affiliation: University of Texas, Southwestern Medical Center at Dallas
name: Myra Wyckoff, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The University of Texas Health Science Center, Houston
name: Jon E Tyson, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pennsylvania
name: Eric Eichenwald, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Rochester
name: Carl T D'Angio, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, Los Angeles
name: Uday Devaskar, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Research Institute at Nationwide Children's Hospital
name: Pablo J Sanchez, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Children's Mercy Hospital Kansas City
name: William Truog, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Utah
name: Bradley Yoder, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Watterberg KL, Walsh MC, Li L, Chawla S, D'Angio CT, Goldberg RN, Hintz SR, Laughon MM, Yoder BA, Kennedy KA, McDavid GE, Backstrom-Lacy C, Das A, Crawford MM, Keszler M, Sokol GM, Poindexter BB, Ambalavanan N, Hibbs AM, Truog WE, Schmidt B, Wyckoff MH, Khan AM, Garg M, Chess PR, Reynolds AM, Moallem M, Bell EF, Meyer LR, Patel RM, Van Meurs KP, Cotten CM, McGowan EC, Hines AC, Merhar S, Peralta-Carcelen M, Wilson-Costello DE, Kilbride HW, DeMauro SB, Heyne RJ, Mosquera RA, Natarajan G, Purdy IB, Lowe JR, Maitre NL, Harmon HM, Hogden LA, Adams-Chapman I, Winter S, Malcolm WF, Higgins RD; Eunice Kennedy Shriver NICHD Neonatal Research Network. Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia. N Engl J Med. 2022 Mar 24;386(12):1121-1131. doi: 10.1056/NEJMoa2114897.