Necrotizing Enterocolitis
Conditions
Keywords
necrotizing enterocolitis, NEC, premature, hydrocortisone, steroids, anti-inflammatory
Brief summary
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
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.
Interventions
DRUGhydrocortisone
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and subjects will continue to receive study drug until all doses have been given (total of 18 doses) or consent is withdrawn.
DRUGplacebo
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.
Sponsors
University of Chicago
Endeavor Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
0 Days to 6 Months
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CRP Level | 3 days | C-reactive protein is a non-specific marker of inflammation, noted to be elevated in infants diagnosed with NEC. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Spontaneous Intestinal Perforation | at 36 weeks corrected gestational age | Whether or not infants had perforation. |
| Need for Gastrointestinal Surgery | at 36 weeks corrected gestational age | Whether or not the infants required GI surgery by 36 weeks CGA |
| Incidence of Sepsis | at 40 weeks corrected gestational age | Whether or not enrolled subjects had sepsis before 40 weeks CGA |
| Time on Parenteral Nutrition | at 40 weeks corrected gestational age | Total time on parenteral nutrition |
| Gastrointestinal (GI) Failure (Defined as Not Being on Full Enteral Feeds of 120kcal/kg/Day at 36 Weeks Corrected Age) | 36 weeks corrected gestational age | GI failure |
| Length of Stay | at 40 weeks corrected gestational age | 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. |
| Growth Velocity | at 40 weeks CGA | Growth velocity after NEC diagnosis, in g/kg/day. |
| Mortality | at 40 weeks corrected gestational age | — |
| Time to Full Enteral Feeds | at 40 weeks corrected gestational age | 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Hydrocortisone 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. | 0 |
| Placebo 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. | 1 |
| Total | 1 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | change in diagnosis | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total |
|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 1 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants |
| Region of Enrollment United States | 1 participants | 1 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 0 | 0 / 1 |
| serious Total, serious adverse events | 0 / 0 | 0 / 1 |
Outcome results
Primary
CRP Level
C-reactive protein is a non-specific marker of inflammation, noted to be elevated in infants diagnosed with NEC.
Time frame: 3 days
Population: This study was terminated due to low enrollment. We had a drop in our incidence of NEC, so there were very few eligible infants. One subject that was enrolled was soon thereafter thought NOT to have NEC, so that subject never received study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | CRP Level | 25.3 mg/L |
Primary
CRP Level
C-reactive protein (CRP) is a non-specific measure of inflammation, usually elevated in infants diagnosed with NEC
Time frame: 7 days
Population: This study was terminated due to low enrollment. We had a drop in our incidence of NEC, so there were very few eligible infants. One subject that was enrolled was soon thereafter thought NOT to have NEC, so that subject never received study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | CRP Level | 6.7 mg/L |
Secondary
Gastrointestinal (GI) Failure (Defined as Not Being on Full Enteral Feeds of 120kcal/kg/Day at 36 Weeks Corrected Age)
GI failure
Time frame: 36 weeks corrected gestational age
Population: The one enrolled infant did not have GI failure at 36 weeks CGA.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Gastrointestinal (GI) Failure (Defined as Not Being on Full Enteral Feeds of 120kcal/kg/Day at 36 Weeks Corrected Age) | 0 Participants |
Secondary
Growth Velocity
Growth velocity after NEC diagnosis, in g/kg/day.
Time frame: at 40 weeks CGA
Population: We only enrolled one subject into the placebo group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Growth Velocity | 14.4 grams/kg/d |
Secondary
Incidence of Sepsis
Whether or not enrolled subjects had sepsis before 40 weeks CGA
Time frame: at 40 weeks corrected gestational age
Population: We only enrolled one subject (placebo group). She did have fungal sepsis).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Incidence of Sepsis | 1 Participants |
Secondary
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.
Time frame: at 40 weeks corrected gestational age
Population: only one subject enrolled into placebo group
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Length of Stay | 141 days |
Secondary
Mortality
Time frame: at 40 weeks corrected gestational age
Population: Only one subject was enrolled into the placebo group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Mortality | 0 Participants |
Secondary
Need for Gastrointestinal Surgery
Whether or not the infants required GI surgery by 36 weeks CGA
Time frame: at 36 weeks corrected gestational age
Population: We only enrolled one subject (placebo group)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Need for Gastrointestinal Surgery | 0 Participants |
Secondary
Spontaneous Intestinal Perforation
Whether or not infants had perforation.
Time frame: at 36 weeks corrected gestational age
Population: Only 1 infant enrolled (placebo group)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Spontaneous Intestinal Perforation | 0 Participants |
Secondary
Time on Parenteral Nutrition
Total time on parenteral nutrition
Time frame: at 40 weeks corrected gestational age
Population: Only one subject was enrolled (placebo group)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time on Parenteral Nutrition | 39 days |
Secondary
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
Time frame: at 40 weeks corrected gestational age
Population: We only enrolled one subject into the placebo group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Time to Full Enteral Feeds | 35 days |