Hydrocortisone for BPD

Study Description

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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 four 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.

Study Design

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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
Study Start Date :	September 2011
Estimated Primary Completion Date :	January 2020
Estimated Study Completion Date :	January 2025

Arms and Interventions

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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

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Primary Outcome Measures :

1. Efficacy [ Time Frame: Birth to 26 months corrected age ]
   Improvement in survival without physiologically defined moderate to severe BPD.
2. Safety [ Time Frame: Birth to 26 months corrected age ]
   Survival without moderate or severe neurodevelopmental impairment at 18 - 22 months corrected age

Secondary Outcome Measures :

1. Morbidity and Growth [ Time Frame: Birth to 26 months corrected age ]
2. Successful Extubation [ Time Frame: 36 Weeks Post Menstrual Age ]
3. Use of open-label dexamethasone [ Time Frame: 36 Weeks Post Menstrual Age ]
4. Respiratory status at 40 weeks [ Time Frame: 40 weeks Postmenstrual Age ]

Eligibility Criteria

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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

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Kristi L Watterberg, MD	505-272-8609
Contact: Rosemary D Higgins, MD	(301) 496-5575

Locations

United States, Alabama
University of Alabama at Birmingham	Recruiting
Birmingham, Alabama, United States, 35233
Contact: Waldemar A. Carlo, MD
Principal Investigator: Waldemar A. Carlo, MD
United States, California
University of California - Los Angeles	Active, not recruiting
Los Angeles, California, United States, 90025
Stanford University	Recruiting
Palo Alto, California, United States, 94304
Contact: Krisa P. Van Meurs, MD
Principal Investigator: Krisa P. Van Meurs, MD
United States, Georgia
Emory University	Recruiting
Atlanta, Georgia, United States, 30303
Contact: David P Carlton, MD
Principal Investigator: David P Carlton, MD
United States, Indiana
Indiana University	Active, not recruiting
Indianapolis, Indiana, United States, 46202
United States, Iowa
University of Iowa	Recruiting
Iowa City, Iowa, United States, 52242
Contact: Edward F. Bell, MD
Principal Investigator: Edward F. Bell, MD
United States, Michigan
Wayne State University	Active, not recruiting
Detroit, Michigan, United States, 48201
United States, Missouri
Children's Mercy Hospital	Active, not recruiting
Kansas City, Missouri, United States, 64108
United States, New Mexico
University of New Mexico	Recruiting
Albuquerque, New Mexico, United States, 87131
Contact: Kristi L. Watterberg, MD
Principal Investigator: Kristi L. Watterberg, MD
United States, New York
University of Rochester	Recruiting
Rochester, New York, United States, 14642
Contact: Carl T D'Angio, MD
Principal Investigator: Carl T D'Angio, MD
United States, North Carolina
RTI International	Active, not recruiting
Durham, North Carolina, United States, 27705
Duke University	Recruiting
Durham, North Carolina, United States, 27710
Contact: C. Michael Cotten, MD
Sub-Investigator: C. Michael Cotten, MD MHS
United States, Ohio
Cincinnati Children's Medical Center	Recruiting
Cincinnati, Ohio, United States, 45267
Contact: Brenda Poindiexter, MD
Principal Investigator: Brenda Poindexter, MD
Case Western Reserve University, Rainbow Babies and Children's Hospital	Recruiting
Cleveland, Ohio, United States, 44106
Contact: Michele C. Walsh, MD MS
Principal Investigator: Michele C. Walsh, MD MS
Research Institute at Nationwide Children's Hospital	Recruiting
Columbus, Ohio, United States, 43205
Contact: Pablo Sanchez, MD
Principal Investigator: Pablo Sanchez, MD
United States, Pennsylvania
Univeristy of Pennsylvania	Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Eric Eichenwald, MD
Principal Investigator: Eric Eicenwald, MD
United States, Rhode Island
Brown University, Women & Infants Hospital of Rhode Island	Recruiting
Providence, Rhode Island, United States, 02905
Contact: Abbot R. Laptook, MD
Principal Investigator: Abbot R. Laptook, MD
United States, Texas
University of Texas Southwestern Medical Center at Dallas	Recruiting
Dallas, Texas, United States, 75235
Contact: Myra Wyckoff, MD
Principal Investigator: Myra Wyckoff, MD
University of Texas Health Science Center at Houston	Recruiting
Houston, Texas, United States, 77030
Contact: Jon E Tyson, MD MPH
Principal Investigator: Jon E. Tyson, MD MPH
United States, Utah
University of Utah	Recruiting
Salt Lake City, Utah, United States, 84108
Contact: Bradley Yoder, MD
Principal Investigator: Bradley A. Yoder, MD

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

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

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

NICHD Neonatal Research Network site 

NICHD Pregnancy &amp; Perinatology Branch 

Responsible Party:	NICHD Neonatal Research Network
ClinicalTrials.gov Identifier:	NCT01353313 History of Changes
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
Last Update Posted:	December 15, 2017
Last Verified:	December 2017
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)

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:

Lung Diseases; Respiratory Tract Diseases; Infant, Premature, Diseases; Infant, Newborn, Diseases; Birth Weight; Bronchopulmonary Dysplasia; Body Weight; Signs and Symptoms; Ventilator-Induced Lung Injury; Lung Injury; Hydrocortisone 17-butyrate 21-propionate	Hydrocortisone acetate; Cortisol succinate; Hydrocortisone; Benzyl Alcohol; Anti-Inflammatory Agents; Anesthetics, Local; Anesthetics; Central Nervous System Depressants; Physiological Effects of Drugs; Sensory System Agents; Peripheral Nervous System Agents