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Hydrocortisone for BPD

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01353313
Recruitment Status : Active, not recruiting
First Posted : May 13, 2011
Last Update Posted : March 28, 2022
Sponsor:
Collaborators:
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)
Information provided by (Responsible Party):
NICHD Neonatal Research Network

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.

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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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 : August 11, 2011
Actual Primary Completion Date : September 21, 2020
Estimated Study Completion Date : January 2025


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





Primary Outcome Measures :
  1. Survival without moderate/severe physiologic bronchopulmonary dysplasia (BPD) [ Time Frame: At 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 >90%. A room air challenge was performed for infants estimated to be receiving <0.30 FiO2 by nasal cannula.

  2. Survival without moderate/severe neurodevelopmental impairment (NDI) [ Time Frame: At 22-26 moths 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 <85 (standardized mean 100, SD 15, range 55-145) or motor composite score <85 (standardized mean 100, range 45-155) (lower scores indicating greater impairment), Gross Motor Function Classification System (GMFCS) level ≥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 <20-200), or bilateral hearing impairment with or without amplification (by report).


Secondary Outcome Measures :
  1. Successful Extubation [ Time Frame: From time of randomization to day 14 post randomization ]
    Successful extubation during the intervention period, defined as remaining extubated for≥1 week, including ≥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 <0.40 to maintain a saturation of ≥88%, mean airway pressure <8 cm H2O, and hemodynamically stable in the opinion of the clinical team.

  2. Total deaths before discharge [ 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 ]
    Infant died before discharge home.

  3. Bronchopulmonary dysplasia (BPD) grade at 36 weeks postmenstrual age [ Time Frame: 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<=2L; 3) NC O2>2L or CPAP/NIPPV; 4) Invasive PPV

  4. Days of mechanical ventilation to 36 weeks postmenstrual age (PMA) [ Time Frame: From birth to 36 weeks postmenstrual age ]
    Number of days on mechanical ventilation (HFV/CV)

  5. Duration of oxygen supplementation 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 ]
    Number of days of oxygen supplementation from birth to discharge home

  6. Length of hospital stay (days) among survivors to discharge [ Time Frame: From birth up to one year ]
    Number of days infant stayed in hospitals

  7. Dexamethasone given before 36 weeks postmenstrual age (PMA) [ Time Frame: From birth to 36 weeks postmenstrual age ]
    Infant received dexamethasone anytime ≤ 36 weeks postmenstrual age.

  8. Severity of NDI [ Time Frame: At 22-26 months corrected age ]
    Number of infants with normal/mild, moderate, or severe/profound NDI

  9. Gross motor function ≥ level 2 [ Time Frame: At 22-26 months corrected age ]
    Number of infants with Gross Motor Function Classification System (GMFCS) level ≥II (on a scale from level I to V; I=normal and progressively higher levels indicate greater impairment)

  10. Moderate-severe cerebral palsy [ Time Frame: At 22-26 months corrected age ]
    Number of infants with moderate or severe grade of cerebral palsy

  11. Severe hearing impairment (by report) [ Time Frame: At 22-26 months corrected age ]
    Number of infants with bilateral hearing impairment with or without amplification (by report)

  12. No/some functional vision [ Time Frame: At 22-26 months corrected age ]
    Number of infants with severe vision impairment in both eyes (consistent with refraction <20-200)

  13. Weight growth measure following extremely preterm birth [ Time Frame: At 36 weeks PMA ]
    Growth curve Z-score for weight

  14. Follow-up weight growth measure following extremely preterm birth [ Time Frame: At 22-26 months corrected age ]
    Growth curve Z-score for follow-up weight

  15. Length growth measure following extremely preterm birth [ Time Frame: At 36 weeks PMA ]
    Growth curve Z-score for length

  16. Follow-up length growth measure following extremely preterm birth [ Time Frame: At 22-26 months corrected age ]
    Growth curve Z-score for follow-up length

  17. Head growth measure following extremely preterm birth [ Time Frame: At 36 weeks PMA ]
    Growth curve Z-score for head circumference

  18. Follow-up head growth measure following extremely preterm birth [ Time Frame: At 22-26 months corrected age ]
    Growth curve Z-score for follow-up head circumference


Other Outcome Measures:
  1. Bronchopulmonary dysplasia (BPD) grade 40 weeks postmenstrual age [ Time Frame: 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<=2L; 3) NC O2>2L or CPAP/NIPPV; 4) Invasive PPV

  2. Days of mechanical ventilation 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 ]
    Number of days on mechanical ventilation (HFV/CV)

  3. Duration of oxygen supplementation among survivors to 36 weeks [ Time Frame: From birth to 36 weeks postmenstrual age ]
    Number of days of oxygen supplementation from birth to 36 weeks post menstrual age

  4. Duration of invasive positive pressure ventilation (PPV) after postnatal day 14 [ Time Frame: From postnatal day 15 to 36 weeks post menstrual age or Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ]
    Number of days on invasive PPV after postnatal day 14

  5. Duration of non-invasive positive pressure ventilation (PPV) (nasal IPPV/CPAP) after postnatal day 14 [ Time Frame: From postnatal day 15 to 36 weeks post menstrual age or Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ]
    Number of days of non-invasive PPV after postnatal day 14

  6. Inhaled glucocorticoids during study period [ Time Frame: From randomization to day 14 post randomization ]
    Number of infants receiving Inhaled glucocorticoids during the study intervention period

  7. Other systemic glucocorticoids during study period [ Time Frame: From randomization to day 14 post randomization ]
    Number of infants receiving other systemic glucocorticoids during the study intervention period

  8. Number of days dexamethasone given before 36 weeks PMA [ Time Frame: From birth to 36 weeks postmenstrual age ]
    Number of days infant received dexamethasone anytime ≤ 36 weeks postmenstrual age.

  9. Patent Ductus Arteriosus (PDA) treated with medication or surgery [ Time Frame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ]
    Number of infants with a PDA that was treated with medicine or surgery

  10. Necrotizing Enterocolitis (NEC) [ Time Frame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ]
    Number of infants diagnosed with NEC

  11. Retinopathy of prematurity (ROP) stage 3 or worse [ Time Frame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ]
    Number of infants diagnosed with ROP stage 3 or worse

  12. Therapy for Retinopathy of prematurity (ROP) [ Time Frame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ]
    Number of infants receiving therapy for ROP

  13. Severe Intraventricular hemorrhage (IVH) [ Time Frame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ]
    Number of infants with severe IVH, grade 3 or 4.

  14. Periventricular leukomalacia [ Time Frame: From birth to Neonatal Research Network NRN infant status i.e., the first occurring of: discharge home, death, transfer, or 120 days following birth ]
    Number of infants with Periventricular leukomalacia

  15. Neurodevelopmental Impairment (NDI) [ Time Frame: 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 <85 (standardized mean 100, SD 15, range 55-145) or motor composite score <85 (standardized mean 100, range 45-155) (lower scores indicating greater impairment), Gross Motor Function Classification System (GMFCS) level ≥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 <20-200), or bilateral hearing impairment with or without amplification (by report).

  16. Bayley Scales of Infant Development (BSID) cognitive composite score <85 [ Time Frame: At 22-26 months corrected age ]
    Number of infants with a cognitive composite score <85. (standardized mean 100, SD 15, range 55-145)

  17. Bayley Scales of Infant Development (BSID) cognitive composite score <70 [ Time Frame: At 22-26 months corrected age ]
    Number of infants with a cognitive composite score <70. (standardized mean 100, SD 15, range 55-145)

  18. Bayley Scales of Infant Development (BSID) motor composite score <85 [ Time Frame: At 22-26 months corrected age ]
    Number of infants with a motor score <85. (standardized mean 100, range 45-155) (lower scores indicating greater impairment)

  19. Bayley Scales of Infant Development (BSID) motor composite score <70 [ Time Frame: At 22-26 months corrected age ]
    Number of infants with a motor composite score <70. (standardized mean 100, range 45-155) (lower scores indicating greater impairment)

  20. Cerebral Palsy [ Time Frame: At 22-26 months corrected age ]
    Number of infants with cerebral palsy



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   up to 30 Weeks   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01353313


Locations
Show Show 20 study locations
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)
Investigators
Layout table for investigator information
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
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: NICHD Neonatal Research Network
ClinicalTrials.gov Identifier: NCT01353313    
Other Study ID Numbers: NICHD-NRN-0045
U10HD034216 ( U.S. NIH Grant/Contract )
U10HD027904 ( U.S. NIH Grant/Contract )
U10HD021364 ( U.S. NIH Grant/Contract )
U10HD027853 ( U.S. NIH Grant/Contract )
U10HD040689 ( U.S. NIH Grant/Contract )
U10HD040492 ( U.S. NIH Grant/Contract )
U10HD027851 ( U.S. NIH Grant/Contract )
U10HD021373 ( U.S. NIH Grant/Contract )
U10HD027856 ( U.S. NIH Grant/Contract )
U10HD053109 ( U.S. NIH Grant/Contract )
U10HD036790 ( U.S. NIH Grant/Contract )
U10HD027880 ( U.S. NIH Grant/Contract )
U10HD053089 ( U.S. NIH Grant/Contract )
U10HD021385 ( U.S. NIH Grant/Contract )
U10HD068244 ( U.S. NIH Grant/Contract )
U10HD068263 ( U.S. NIH Grant/Contract )
U10HD068270 ( U.S. NIH Grant/Contract )
U10HD068278 ( U.S. NIH Grant/Contract )
U10HD068284 ( U.S. NIH Grant/Contract )
U24HL137729 ( U.S. NIH Grant/Contract )
1UG3HL137872 ( U.S. NIH Grant/Contract )
First Posted: May 13, 2011    Key Record Dates
Last Update Posted: March 28, 2022
Last Verified: March 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NIH has had a long-standing policy to share and make available to the public the results and accomplishments of the activities that it funds. The NRN plans to share de-identified data after final publication in an NIH supported data repository such as the NICHD Data and Specimen Hub (https://dash.nichd.nih.gov)

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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:
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Bronchopulmonary Dysplasia
Birth Weight
Body Weight
Ventilator-Induced Lung Injury
Lung Injury
Lung Diseases
Respiratory Tract Diseases
Infant, Premature, Diseases
Infant, Newborn, Diseases
Hydrocortisone
Anti-Inflammatory Agents