Comparison of Smoflipid to Soy-based Lipid Reduction for Cholestasis Prevention in Surgical Neonates

Phase 3

Completed

Conditions: Cholestasis of Parenteral Nutrition

Interventions: Drug: Smoflipid 20% Lipid Emulsion for Injection
Drug: Intralipid, 20% Intravenous Emulsion

Registration Number: NCT03387579

Lead Sponsor: Indiana University

Brief Summary: Intestinal failure associated liver disease is a cholestatic liver disease associated with prolonged need for parenteral nutrition that can lead to such significant complications as liver failure. In the neonatal population, infants with history of intestinal resection and short bowel syndrome are at increased risk for this disease. The investigators plan to compare two possible lipid dosing preventative strategies including a composite, fish oil lipid and soy-based lipid reduction.

Detailed Description: Intestinal failure associated liver disease (IFALD) is a cholestatic liver disease associated with prolonged need for parenteral nutrition. This disease can lead to such serious complications as liver failure and need for transplantation. In the neonatal population, short bowel syndrome, due to intestinal resection, is the most common cause of intestinal failure. While the exact cause is yet to be determined, it is felt the lipid component of parenteral nutrition is a large contributor to the development of this disease. Currently, there is no standard preventative strategy to attempt to decrease the risk of IFALD in the high risk, post-surgical neonatal population. The investigators aim to complete a randomized trial comparing two possible preventative strategies. One group will receive a composite lipid containing fish oil (Smoflipid) and the other group will receive soy-based lipid at reduced dosing.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 24

Inclusion Criteria

Neonates with anticipated need for parenteral nutrition (based on primary physicians opinion) for greater than or equal to four weeks and one of the following diagnoses:

Anatomic: Neonate with intestinal atresia, omphalocele, gastroschisis, or volvulus with or without intestinal resection.
Ischemic/perforation: Neonates with spontaneous intestinal perforation or necrotizing enterocolitis requiring surgical intervention.

Exclusion Criteria

Current weight less than 750 grams
AST or ALT greater than 5 times the upper limit of normal within 2 weeks of enrollment
Direct bilirubin greater than 2 mg/dL on any consecutive measurements 5 - 7 days apart within 2 weeks of enrollment
Severe coagulopathy with INR greater than 95th percentile for age (>1.7 at less than 5 days of age, > 1.5 older than five days of age)
Culture confirmed sepsis with positive blood, urine, or CSF culture within 2 weeks of enrollment
Renal failure requiring dialysis
Cyanotic heart disease requiring prostaglandin therapy
Hypertriglyceridemia (greater than 250mg/dL) at time of enrollment

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Smoflipid 20%	Smoflipid 20% Lipid Emulsion for Injection	Patients randomized to this arm will receive the composite fish oil lipid, Smoflipid, at standard dosing up to 3 g/kg/day. Patients will be started on a dose of 1 g/kg/day and titrated up to maximum dose. As enteral nutrition is advanced the lipid dose will be weaned per study protocol and dietary recommendations.
Intralipid 20% Reduction	Intralipid, 20% Intravenous Emulsion	Patients randomized to this arm will receive soy-based lipid (Intralipid) at a dose of 1 g/kg/day throughout their enrollment in the study.
Intralipid 20% Historic	Intralipid, 20% Intravenous Emulsion	Patients who retrospectively received soy-based lipid (Intralipid) at standard dosing of 2-3 g/kg/day were eligible for inclusion. Patients in this group were matched to prospective patients based on diagnosis, gestational age, and length of lipid therapy.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Cholestasis	Patients were monitored during time enrolled in study for a maximum of up to 12 weeks or 84 days.	Cholestasis was defined as a direct bilirubin \> 2 mg/dL on two measurements 5 to 7 days apart.

Secondary Outcome Measures

Name	Time	Method
Weight Velocity	Patient weight was recorded at enrollment, weekly during time enrolled, and at end of study for up to a maximum of 12 weeks. End and enrollment weights were used to calculate velocity.	Weight velocity was calculated as the difference in weight from end to start of study divided by number of days enrolled in study.
Length Velocity	Length was measured at enrollment, weekly during time enrolled in study, and end of study up to a maximum of 12 weeks. End and enrollment measurements were used for velocity.	Length velocity was defined as the difference in length from end of study compared to enrollment divided by the number of days enrolled in study.
Average Total Calorie Intake	Daily calorie intake was recorded and averaged on a weekly basis for duration of study enrollment up to max of 12 weeks.	Total calorie intake, including parenteral and enteral sources, were averaged on a weekly basis.
Triglyceride Level Over Time	Serum triglyceride levels monitored at enrollment and weekly during time enrolled in study for a maximum of 12 weeks.	All enrolled patients had serum triglyceride levels monitored at enrollment and weekly. The triglyceride level changes was calculated using values at the end of study compared to enrollment with mean and standard deviation calculated for each treatment group.
Three Year Development: Gross Motor	three year chronological age 3 years and 0 days to 3 years and 364 days	During the third year of chronological age an Ages and Stages questionnaire (ASQ) was completed by the parents. For each section the range of score possible is 0-60. Higher scores indicate improved outcome, there are three possible scoring categories on schedule (normal), monitoring zone, below cutoff. Score thresholds by possible screens include: 36 months on schedule 50-60; monitoring 40-45; below cutoff \<40. 42 months on schedule 50-60; monitoring 40-45; below cutoff \<40. 48 months on schedule 45-60; monitoring 35-40; below cutoff \<35.
Three Year Development: Personal Social	three year chronological age (3 years and 0 days to 3 years and 364 days)	During the third year of chronological age an Ages and Stages questionnaire (ASQ) was completed by the parents. For each section the range of score possible is 0-60. Higher scores indicate improved outcomes with three score categories possible including on schedule (normal), monitoring zone, and below cutoff. These thresholds vary based on outcome measure and age of screen completed. Screen used depends on chronological age at screen. Score thresholds for each age include: 36 months: 45-60 on schedule; 35-40 monitoring; \<35 below cutoff. 42 months: 45-60 on schedule; 35-40 monitoring; \<35 below cutoff. 48 months: 40-60 on schedule; 30-40 monitoring; \<30 below cutoff.
Head Circumference (OFC) Velocity	OFC was measured at enrollment, weekly, and end of study. Enrollment and end of study measurements used for velocity.	OFC velocity was calculated as difference end and start of study divided by number of days enrolled in study.
Gamma Glutamyl Transferase (GGT) Over Time	GGT was measured at enrollment and every 2 weeks while enrolled in the study for a maximum of up to 12 weeks.	GGT was documented at baseline and regularly intervals with level compared over time between groups. GGT was compared by treatment group for levels at end of study and enrollment.
Number of Patients With Bronchopulmonary Dysplasia (BPD) or Chronic Lung Disease	All patient had diagnosis of BPD documented from admission at level 4 NICU.	The rate of BPD was documented and compared between groups. BPD was diagnosed based on need for respiratory support at 28 days of age. All levels of severity were included.
Three Year Development- Communication	ASQ was completed during the third year of life from 3 years 0 days to 3 years 364 days of chronologic age.	During the third year of chronological age an Ages and Stages questionnaire (ASQ) was completed by the parents. For each section the range of score possible is 0-60. Higher scores show improved outcomes. Scores are separated into on schedule, monitoring zone, and below cutoff. These thresholds vary by aged screened. Possible screens used for this age group include 36 months, 42 months, and 48 months dependent on exact chronologic age screen completed. At 36 months communication 45-60 is on schedule; 35-40 monitoring, and \<35 below cutoff. For 42 months on schedule 40-60; monitoring 30-35; below cutoff \<35. For 48 months on schedule 45-60; monitoring 35-40; below cutoff \<35.
Number of Patients With Retinopathy of Prematurity	Diagnosis was based on diagnosis during time of initial hospitalization to level 4 NICU.	The rate of retinopathy of prematurity (ROP) was compared between groups. ROP was diagnosed based on ophthalmologist examination with all stages included.
Three Year Development: Fine Motor	three year chronological age (3 years and 0 days to 3 years and 364 days)	During the third year of chronological age an Ages and Stages questionnaire (ASQ) was completed by the parents. For each section the range of score possible is 0-60. Higher scores show improved outcomes with three scoring categories: on schedule (normal), monitoring zone, and below cutoff. These thresholds vary by each category and screening age. Based on the possible screens for chronological age the score categories are: 36 months: 35-60 on schedule; 20-30 monitoring; \<20 below cutoff. 42 months: 35-60 on schedule; 20-30 monitoring; \<20 below cutoff. 48 months: 35-60 on schedule; 20-30 monitoring; \<20 below cutoff.
Three Year Development: Problem Solving	three year chronological age (3 years and 0 days to 3 years and 364 days)	During the third year of chronological age an Ages and Stages questionnaire (ASQ) was completed by the parents. For each section the range of score possible is 0-60. Higher scores indicate improved outcomes with three possible score categories: on schedule (normal), monitoring zone, and below cutoff. Category thresholds vary by outcome category and age of screen. There are three possible screens that were used for this population, chosen based on chronologic age. The score categories based on age are: 36 months: 45-60 on schedule; 35-40 monitoring; \<35 below cutoff. 42 months: 40-60 on schdule; 30-35 monitoring; \<30 below cutoff. 48 months: 45-60 on schedule; 35-40 monitoring; \<35 below cutoff
Number of Patients With Enteral Autonomy at End of Study	Enteral autonomy was recorded at the study end point for each individual patient. This end point was at time of stopping study lipid, discharge from hospital, or maximum of 12 weeks.	Percentage of patients with enteral autonomy at time of leaving or stopping study was calculated. Enteral autonomy was defined as relying on enteral nutrition only for nutrition intake with no need for parenteral nutrition supplementation.
Number of Patients With Essential Fatty Acid Deficiency (EFAD)	Essential fatty acid levels were measured every 4 weeks during enrollment for a maximum of up to 12 weeks.	Essential fatty acid deficiency was defined as a triene to tetraene ratio greater than 0.05.
AST Change Over Time	AST was recorded at enrollment and every 2 weeks while enrolled in the study up to a maximum of 12 weeks.	The change of AST over time was calculated and compared between groups. AST change was calculated as AST end - AST enrollment.
ALT Change Over Time	ALT measured at enrollment and every 2 weeks for max 12 weeks.	The rate of change of ALT over time was compared between groups using mixed model analysis. Change of ALT was calculated as ALT at end of study compared to ALT at enrollment.
Alkaline Phosphatase Change Over Time	Alkaline phosphatase was measured at enrollment and every 2 weeks for max of 12 weeks.	Alkaline phosphatase was recorded at enrollment and every 2 weeks. The change in alkaline phosphatase was calculated as alkaline phosphatase at end minus enrollment.
NICU Length of Stay	Length of stay will be calculated based on documenting each patient's admission date and date leaving the NICU.	The length of stay at the level 4 NICU was compared between groups.

Trial Locations

Locations (1): Riley Hospital for Children at IU Health
🇺🇸
Indianapolis, Indiana, United States
Riley Hospital for Children at IU Health
🇺🇸Indianapolis, Indiana, United States