Randomized Trial of Hydrocortisone in Very Preterm High-Risk Infants

• ClinicalTrials.gov Identifier: NCT00167544
• Recruitment Status: Completed
• First Posted: September 14, 2005
• Results First Posted: August 30, 2013
• Last Update Posted: August 30, 2013
• Sponsor: Nationwide Children's Hospital
• Collaborators: National Institutes of Health (NIH); National Institute of Neurological Disorders and Stroke (NINDS)
• Information provided by (Responsible Party): Nehal Parikh, Nationwide Children's Hospital

Study Description

Brief Summary:

The purpose of this study is to determine whether treatment of very preterm infants at high-risk for lung and brain injury with low dose hydrocortisone results in improved pulmonary and neurologic outcomes.

Condition or disease	Intervention/treatment	Phase
Bronchopulmonary Dysplasia; Encephalomalacia; Premature Birth	Drug: Hydrocortisone; Drug: Placebo	Phase 2

Detailed Description:

Hypothesis: Among extremely low birth weight infants (ELBW; BW ≤ 1000 g) at high risk for bronchopulmonary dysplasia (BPD) and neurologic impairments, those infants randomized to seven days of hydrocortisone will demonstrate increased total cerebral tissue volumes as compared to infants randomized to placebo.

Specific Aims: 1) To perform a pilot blinded randomized controlled trial of a 7-day regimen of low dose hydrocortisone in ELBW infants at high risk for BPD and neurosensory impairments and assess its effect on cerebral tissue volumes. 2) Evaluate and report 2 year neurodevelopmental outcomes.

Background and Significance: Bronchopulmonary dysplasia is a disease of arrested lung development and lung inflammation. It is primarily seen in ELBW infants. Neurological delay, including cerebral palsy and mental retardation, affect up to 40%-50% of surviving ELBW infants. BPD is an important risk factor for such neurological delay. Postnatal administration of corticosteroids to ventilated preterm neonates results in a reduced risk of developing BPD. Postnatal corticosteroids however have shown harmful effects on the brain and can lead to increased rates of cerebral palsy and learning problems. This effect has primarily been seen with dexamethasone when high doses were given in the first week of life. Beyond the first week of life, there is insufficient information on the effects of steroids on the brain. Steroids other than dexamethasone, in much lower doses have been shown to improve short term lung function with minimal short-term side effects. A review study of all steroid trials for BPD shows that when given to a high risk group of infants (> 50% risk of BPD) steroids protect the brain and reduce rates of cerebral palsy. The American and Canadian Pediatric societies and respected researchers have commented on the urgent need for more trials of other corticosteroids at lower doses started after the first week of life to evaluate their short and long-term pulmonary and neurological benefits and risks.

Research Design and Methods:

1. Inclusion & Exclusion Criteria: See below.
2. Procedures: Consented eligible patients will be randomly assigned to receive hydrocortisone in a tapering schedule over 7 days or placebo (comparison group). Study drug will be given every 12 hours IV with only study pharmacist aware of assignment. The patient's anatomic brain MRI (routinely done on all ELBW infants at 38 weeks post-menstrual age) will be further processed by the masked study investigators to derive total and regional brain volumes. Administration of indomethacin or dexamethasone to enrolled infants will be closely monitored and regulated throughout the trial period. Indomethacin use during study period is contraindicated. Dexamethasone (or other steroid) use will be restricted to ELBW infants on high ventilator settings (RIS > 10) after 28 days of life. All other procedures will be per routine care. Blinded developmental follow-up at two years, already currently performed for all ELBW infants at MHCH, will be analyzed and reported for all study infants.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 64 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: A Randomized Trial of Hydrocortisone in Very Preterm Infants at High Risk for Neurologic and Pulmonary Impairments
• Study Start Date: November 2005
• Actual Primary Completion Date: January 2009
• Actual Study Completion Date: November 2012

Arms and Interventions

Arm	Intervention/treatment
Experimental: 1; 1. Tapering dose of hydrocortisone every 12 h over 7 day period	Drug: Hydrocortisone; Hydrocortisone 3 mg/kg/d divided q 12h IV/PO tapered over 7 days
Placebo Comparator: 2; 2. Identical-appearing saline placebo	Drug: Placebo; Saline

Outcome Measures

Primary Outcome Measures :

1. Total Cerebral Volume as Measured by Volumetric Brain MRI [ Time Frame: 38 weeks postmenstrual age (PMA) ]
   Total cerebral volume included all brain gray matter and white matter, including cerebellum.

Secondary Outcome Measures :

1. Regional Brain Volumes [ Time Frame: 38-weeks postmenstrual age ]
   Cerebral white matter volume
2. Duration of Positive Pressure Support (Mechanical Ventilation or Continuous Positive Airway Pressure) [ Time Frame: Up to 36 weeks PMA ]
3. Duration of Oxygen Requirement [ Time Frame: Up to 36 weeks PMA ]
4. Survival Without Severe Bronchopulmonary Dysplasia (BPD) [ Time Frame: 36 weeks postmenstrual age ]
   Using the NIH Consensus definition (Jobe A, 2001)

Eligibility Criteria

• Ages Eligible for Study: 1 Week to 3 Weeks (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Patient in the Memorial Hermann Children's Hospital (MHCH) neonatal intensive care unit with a birth weight ≤ 1000 grams.
• Ventilator-dependent between 10 and 21 days of age.
• Respiratory index score (RIS: mean airway pressure x fraction of inspired oxygen) of ≥ 2.0 that is increasing or stable for the previous 24 hours or a RIS ≥ 3.0 if improvement noted in the past 24 hours.

Exclusion Criteria:

• Prior postnatal steroid treatment.
• Evidence of sepsis or necrotizing enterocolitis.
• Known major congenital anomalies of the cardiopulmonary or central nervous system.
• Infants being treated with indomethacin or those likely to require treatment in the next 7 days as judged by the treating physician.
• Inability or unwillingness of parent or legal guardian/representative to give written informed consent.
• Gestational age < 23 weeks.

Contacts and Locations

Locations

United States, Ohio

Nationwide Children's Hospital

Columbus, Ohio, United States, 432025

Sponsors and Collaborators

Nationwide Children's Hospital

National Institutes of Health (NIH)

National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

• Principal Investigator: Nehal A. Parikh, D.O., M.S.; The Research Institute at Nationwide Children's Hospital

More Information

Additional Information:

Patient information page - Bronchopulmonary Dysplasia 

Publications of Results:

Parikh NA, Kennedy KA, Lasky RE, McDavid GE, Tyson JE. Pilot randomized trial of hydrocortisone in ventilator-dependent extremely preterm infants: effects on regional brain volumes. J Pediatr. 2013 Apr;162(4):685-690.e1. doi: 10.1016/j.jpeds.2012.09.054. Epub 2012 Nov 8.

Other Publications:

Parikh NA, Lasky RE, Kennedy KA, Moya FR, Hochhauser L, Romo S, Tyson JE. Postnatal dexamethasone therapy and cerebral tissue volumes in extremely low birth weight infants. Pediatrics. 2007 Feb;119(2):265-72. doi: 10.1542/peds.2006-1354.

Yu X, Zhang Y, Lasky RE, Datta S, Parikh NA, Narayana PA. Comprehensive brain MRI segmentation in high risk preterm newborns. PLoS One. 2010 Nov 8;5(11):e13874. doi: 10.1371/journal.pone.0013874.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Parikh NA, Kennedy KA, Lasky RE, Tyson JE. Neurodevelopmental Outcomes of Extremely Preterm Infants Randomized to Stress Dose Hydrocortisone. PLoS One. 2015 Sep 16;10(9):e0137051. doi: 10.1371/journal.pone.0137051. eCollection 2015.

• Responsible Party: Nehal Parikh, Associate Professor of Pediatrics, Nationwide Children's Hospital
• ClinicalTrials.gov Identifier: NCT00167544
• Other Study ID Numbers: K23NS048152 ( U.S. NIH Grant/Contract ); K23NS048152 ( U.S. NIH Grant/Contract ); HSC-MS-05-0218
• First Posted: September 14, 2005
• Results First Posted: August 30, 2013
• Last Update Posted: August 30, 2013
• Last Verified: July 2013

Keywords provided by Nehal Parikh, Nationwide Children's Hospital:

Bronchopulmonary Dysplasia; Encephalomalacia; Brain injury; Neurosensory impairment; Corticosteroids; Anti-Inflammatory Agents; Extremely Low Birth Weight (ELBW) infants; Premature Birth; Magnetic Resonance Imaging

Additional relevant MeSH terms:

Bronchopulmonary Dysplasia; Encephalomalacia; Premature Birth; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Ventilator-Induced Lung Injury; Lung Injury; Lung Diseases; Respiratory Tract Diseases; Infant, Premature, Diseases; Infant, Newborn, Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hydrocortisone; Anti-Inflammatory Agents