Randomized Trial of Hydrocortisone in Very Preterm High-Risk Infants

Premature Birth Clinical Trial

Official title:

A Randomized Trial of Hydrocortisone in Very Preterm Infants at High Risk for Neurologic and Pulmonary Impairments

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00167544
• Other study ID #: K23NS048152
• Secondary ID: K23NS048152HSC-M
• Status: Completed
• Phase: Phase 2
• First received: September 9, 2005
• Last updated: July 29, 2013
• Start date: November 2005
• Est. completion date: November 2012

Study information

• Verified date: July 2013
• Source: Nationwide Children's Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 64
• Est. completion date: November 2012
• Est. primary completion date: January 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 3 Weeks

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Bronchopulmonary Dysplasia
• Encephalomalacia
• Premature Birth

Intervention

Drug:
• Hydrocortisone
Hydrocortisone 3 mg/kg/d divided q 12h IV/PO tapered over 7 days
• Placebo
Saline

Locations

Country	Name	City	State
United States	Nationwide Children's Hospital	Columbus	Ohio

Sponsors (3)

Lead Sponsor	Collaborator
Nationwide Children's Hospital	National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

References & Publications (3)

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Total Cerebral Volume as Measured by Volumetric Brain MRI	Total cerebral volume included all brain gray matter and white matter, including cerebellum.	38 weeks postmenstrual age (PMA)	Yes
Secondary	Regional Brain Volumes	Cerebral white matter volume	38-weeks postmenstrual age	Yes
Secondary	Duration of Positive Pressure Support (Mechanical Ventilation or Continuous Positive Airway Pressure)		Up to 36 weeks PMA	No
Secondary	Duration of Oxygen Requirement		Up to 36 weeks PMA	No
Secondary	Survival Without Severe Bronchopulmonary Dysplasia (BPD)	Using the NIH Consensus definition (Jobe A, 2001)	36 weeks postmenstrual age	No

External Links

•   Patient information page - Bronchopulmonary Dysplasia