Anti-inflammatory Treatment at the Onset of Necrotizing Enterocolitis (NEC) in Preterm Infants

Study Overview
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Brief Summary
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Despite modern medical advances, necrotizing enterocolitis (NEC) remains a significant problem in neonatal intensive care units (ICUs). Although research has shown NEC to be an inflammatory necrosis of the bowels, to date no study has examined the effect of anti-inflammatory therapy on this dreaded disease once it is diagnosed. The investigators propose a multi-center, randomized, placebo-controlled, double-blinded pilot study to examine the effect of hydrocortisone in infants diagnosed with stages II and III NEC. The investigators will follow C-reactive protein (CRP) levels as a marker of systemic inflammation for the primary outcome in this study.

Detailed Description
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Given the extensive inflammatory response inherent to NEC, anti-inflammatory treatment may be of benefit, to both reduce inflammation and as a potential therapy to improve outcome. To date, there is no specific therapy for NEC that has been found to improve outcome, but corticosteroids have yet to be investigated in that capacity. Therefore, we propose to examine the effect of hydrocortisone for treatment of NEC in a randomized, blinded, placebo-controlled pilot study, focusing on a primary outcome of C-reactive protein levels at 3 and 7 days of therapy as a measure of inflammation. In addition, we will follow several secondary outcome measures to determine the possibility of improved outcome in those infants assigned to hydrocortisone. The investigators hypothesize that infants diagnosed with NEC who receive hydrocortisone will have significantly lower C-reactive protein levels at 3 and 7 days of treatment versus infants who receive placebo.

Official Title
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Anti-inflammatory Treatment at the Onset of NEC in Preterm Infants- a Pilot Study

Conditions
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Necrotizing Enterocolitis

Intervention / Treatment
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* Drug: hydrocortisone
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Infant born at gestational age less than 34 weeks Birth weight less than 2500 grams Diagnosis of stage II or III NEC made by attending neonatologist, neonatology fellow, or pediatric hospitalist Legally authorized representative is able to provide written informed consent prior to the performance of an protocol-specified evaluations or procedures Consent can be obtained and study drug can be administered within 6 hours of diagnosis Exclusion Criteria: congenital gastrointestinal anomaly subject is already receiving parenteral steroid therapy or subject has received parenteral steroids within one week prior to study entry subject has received indomethacin therapy within 48 hours prior to being diagnosed with NEC

Ages Eligible for Study
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Minimum Age: 0 Days
Maximum Age: 6 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: hydrocortisone<br>Subjects in hydrocortisone group will receive 3mg/kg/day divided every 8 hours via intravenous (IV) route for 3 days, followed by 2mg/kg/day divided every 8 hours IV for 1 day, followed by 1.5mg/kg/day divided every 8 hours IV for 1 day, followed by 1mg/kg/day divided every 12 hours for 1 day, followed by 0.5mg/kg/day in single dose for one day. Subjects in placebo group will receive equal volume of placebo on the same dosing schedule. The first dose of study drug will be given within 6 hours of diagnosis of NEC, once informed consent is obtained, and subjects will continue to receive study drug until all doses have been given (total of 18 doses) or consent is withdrawn. | Drug: hydrocortisone<br>* Subjects in hydrocortisone group will receive 3mg/kg/day divided every 8 hours via IV route for 3 days, followed by 2mg/kg/day divided every 8 hours IV for 1 day, followed by 1.5mg/kg/day divided every 8 hours IV for 1 day, followed by 1mg/kg/day divided every 12 hours for 1 day, followed by 0.5mg/kg/day in single dose for one day. The first dose of study drug will be given within 6 hours of diagnosis of NEC, once informed consent is obtained, and subjects will continue to receive study drug until all doses have been given (total of 18 doses) or consent is withdrawn.<br>|
| Placebo Comparator: Placebo<br>Subjects in placebo group will receive equal volume of placebo (as compared to hydrocortisone arm) on the same dosing schedule. The first dose of study drug will be given within 6 hours of diagnosis of NEC, once informed consent is obtained, and subjects will continue to receive study drug until all doses have been given (total of 18 doses) or consent is withdrawn. | Drug: placebo<br>* Subjects in placebo group will receive a volume of placebo equal to the hydrocortisone group, on the same dosing schedule, with doses given every 8 hours via IV route for 3 days, followed by placebo every 8 hours IV for 1 day, followed by placebo every 8 hours IV for 1 day, followed by placebo every 12 hours for 1 day, followed by placebo in single dose for one day. The first dose of study drug will be given within 6 hours of diagnosis of NEC, once informed consent is obtained, and subjects will continue to receive study drug until all doses have been given (total of 18 doses) or consent is withdrawn.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CRP Level | C-reactive protein is a non-specific marker of inflammation, noted to be elevated in infants diagnosed with NEC. | 3 days | 
| CRP Level | C-reactive protein (CRP) is a non-specific measure of inflammation, usually elevated in infants diagnosed with NEC | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gastrointestinal (GI) Failure (Defined as Not Being on Full Enteral Feeds of 120kcal/kg/Day at 36 Weeks Corrected Age) | GI failure | 36 weeks corrected gestational age | 
| Spontaneous Intestinal Perforation | Whether or not infants had perforation. | at 36 weeks corrected gestational age | 
| Need for Gastrointestinal Surgery | Whether or not the infants required GI surgery by 36 weeks CGA | at 36 weeks corrected gestational age | 
| Incidence of Sepsis | Whether or not enrolled subjects had sepsis before 40 weeks CGA | at 40 weeks corrected gestational age | 
| Time on Parenteral Nutrition | Total time on parenteral nutrition | at 40 weeks corrected gestational age | 
| Time to Full Enteral Feeds | this will be assessed as the time needed to achieve full enteral feeds following the diagnosis of NEC. On average, it will be assessed at 40 weeks CGA, near the time of discharge, but there is a subset of infants who will not yet have achieved full enteral feeds at that time, so it may need to be assessed later than 40 weeks CGA | at 40 weeks corrected gestational age | 
| Length of Stay | this will be assessed at the time of discharge, around 40 weeks CGA on average. A subset of infants may be discharged later than 40 weeks corrected gestational age (CGA), however, so these infants will need to have length of stay assessed later than 40 weeks CGA. | at 40 weeks corrected gestational age | 
| Growth Velocity | Growth velocity after NEC diagnosis, in g/kg/day. | at 40 weeks CGA | 
| Mortality |  | at 40 weeks corrected gestational age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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necrotizing enterocolitis, NEC, premature, hydrocortisone, steroids, anti-inflammatory