Clinical trial NCT00167544: Randomized Trial of Hydrocortisone in Very Preterm High-Risk Infants
Official title: A Randomized Trial of Hydrocortisone in Very Preterm Infants at High Risk for Neurologic and Pulmonary Impairments
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Bronchopulmonary Dysplasia
Encephalomalacia
Premature Birth
Keywords: Bronchopulmonary Dysplasia
Encephalomalacia
Brain injury
Neurosensory impairment
Corticosteroids
Anti-Inflammatory Agents
Extremely Low Birth Weight (ELBW) infants
Premature Birth
Magnetic Resonance Imaging
Lead sponsor: Nationwide Children's Hospital
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2005-09-14
Enrollment: 64
Sex: ALL
Minimum age (years): 1
Maximum age (years): 3
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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.

Eligibility 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.

Primary outcomes:
measure: Total Cerebral Volume as Measured by Volumetric Brain MRI
timeFrame: 38 weeks postmenstrual age (PMA)
Secondary outcomes:
measure: Regional Brain Volumes
timeFrame: 38-weeks postmenstrual age
measure: Duration of Positive Pressure Support (Mechanical Ventilation or Continuous Positive Airway Pressure)
timeFrame: Up to 36 weeks PMA
measure: Duration of Oxygen Requirement
timeFrame: Up to 36 weeks PMA
measure: Survival Without Severe Bronchopulmonary Dysplasia (BPD)
timeFrame: 36 weeks postmenstrual age
Other outcomes:
Locations:
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
Study officials:
affiliation: The Research Institute at Nationwide Children's Hospital
name: Nehal A. Parikh, D.O., M.S.
role: PRINCIPAL_INVESTIGATOR
References:
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. doi: 10.1542/peds.2006-1354.
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.
citation: 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.
citation: 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.