Cholestasis Prevention: Efficacy of IV Fish Oil

Parenteral nutrition (PN) solutions are life saving in patients with surgical gastrointestinal diseases. However, the use of PN in pediatric populations, especially premature infants, is frequently associated with liver injury that may ultimately result in hepatic failure. In studies conducted in a murine model, we observed that intravenous fat emulsions (IFE) comprised of omega-3 fatty acids were able to prevent the development of cholestasis, a common precursor of PN-associated liver disease, as well as reverse preexisting PNALD through a combination of factors, including improved triglyceride clearance coupled with anti-inflammatory properties. In a case series treating patients with hepatic cholestasis, serum bilirubin levels decreased markedly after the parenteral administration of an omega-3 fatty acid based fat emulsion (Omegaven®). Patients tolerated this therapy and no adverse reactions attributed to its use were observed. Based on results of these previous studies, we propose to conduct a randomized trial aiming to gain preliminary evidence of efficacy of an omega-3 fatty acid based IFE in preventing PNALD in children with intestinal failure

Study Overview

• Status: Completed
• Conditions: Cholestasis; Parenteral Nutrition
• Intervention / Treatment: Drug: Omegaven; Drug: Intralipid

Detailed Description

We propose to conduct a randomized controlled clinical trial to determine whether the use of an omega-3 fatty acid based IFE in infants with surgical gastrointestinal disease will improve clinical outcomes compared to infants treated with standard IFE up to 6 months post randomization. Neonates and infants < 3 months old (postnatally) with surgical gastrointestinal disease (defined as congenital or acquired gastrointestinal disease requiring PN for more than 21 days) will be eligible for enrollment. Patients who meet all inclusion and exclusion criteria will be randomized to receive PN with either Intralipid® or Omegaven®. The appearance of both IFEs is indistinguishable, so patients, families and the medical care team will be blinded to treatment group allocation. Aside from the IFE type, the clinical care of both groups of infants will remain unchanged, including standard use of feeding advancement protocols, and treatment of underlying gastrointestinal and other diseases.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Childrens's Hospital Boston

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 3 months (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria (all of the following):

1. Congenital or acquired gastrointestinal disease requiring surgical intervention [such as Midgut volvulus, Gastroschisis-(with known or suspected atresia(s), perforation(s) requiring a jejunostomy, or bowel resections > 20cm), Omphalocele, Jejunal atresia or NEC-(no peritoneal drains) or duodenal atresia] ; and
2. Expected dependence on parenteral nutrition for full or partial nutritional support for an anticipated duration of therapy of at least 21 days; Subjects will be judged by their clinical team to require PN support a minimum of 21 days based on the following criteria: inability to tolerate enteral feedings, lack of audible bowel sounds, contraindications to initiation of enteral feedings (e.g., grossly bloody stools or other sign of intestinal ischemia, hypotension, bilious emesis, or clinical or radiographic evidence of bowel obstruction); and
3. Neonates and infants < 3 months of age (postnatally); and
4. Gestational age > 28 weeks; and
5. Baseline direct bilirubin less than 1.0 mg/dL (normal); and
6. Weight > 1 kg

Exclusion criteria(any one of the following):

1. Exposure to soybean oil fat emulsion for greater than three weeks (>21 days) at time of enrollment
2. Known or suspected intolerance or allergy to any of the components of the study IFE, including fish, soy or egg protein
3. Inability to obtain written informed consent prior to the baseline labs
4. The patient is enrolled in any other clinical trial involving an investigational agent (unless approved by the designated physicians on the multidisciplinary team)
5. Intention to transfer care to another patient facility within 3 months of baseline labs
6. Any serum triglyceride level greater than 400 mg/dL at baseline
7. History of severe hemolytic disorders or INR greater than 1.5 at baseline (INR cutoff of greater than 2 for babies less than 1 week of age)
8. History of shock requiring vasopressors (dopamine equal or less than 20 micrograms/kilogram/minute is allowed; all other use of vasopressors is excluded)
9. Preexisting liver disease, regardless of etiology
10. Hemodynamically unstable as judged by PI
11. Renal failure (creatinine greater than 0.4 mg/dL unless less than 1 month of age-then at the PI's discretion)
12. Patient previously had STEP (Serial Transverse Enteroplasty Procedure)
13. Patient is currently on ECMO or nitric oxide
14. GGTP > 80 mg/L at baseline
15. Weight < 1 kg at time of enrollment
16. Gestational age < 28 weeks at time of enrollment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Omegaven; Omegaven is a fish based intravenous fat emulsion	Drug: Omegaven; Omegaven is a fish based intravenous fat emulsion
ACTIVE_COMPARATOR: Intralipid	Drug: Intralipid; Intralipid is a plant based intravenous fat emulsion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Presence vs. absence of PN-associated cholestasis (PNAC)	The definition of "Presence vs. Absence of PNAC" will vary with the post conceptual age of the child. In infants > 40 weeks post conceptual age, we will define PN-associated cholestasis as four consecutive measurements (> 6 days apart) of serum direct bilirubin > 2.0mg/dL obtained over a 30 day period in the absence of other demonstrable etiologies of cholestasis. Due to hepatic immaturity, for infants < 40 weeks post conceptual age, PN associated cholestasis will be defined as four consecutive measurements (> 6 days apart) of serum direct bilirubin > 2.0mg/dL obtained over a 42 day period.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fatty acid profiles	(i.e., Mead acid levels, triene:tetraene ratios, total omega-3 and omega-6 fatty acid levels, arachidonic acid levels)	6 months
Weight and height gain		6 months
Liver function tests	(i.e. serum triglycerides, cholesterol, ALT, AST and total and direct bilirubin levels)	6 months
Death from PNALD liver or liver/gastrointestinal tract transplant.		1 year
Duration of parenteral nutrition	(i.e. enteral feeding tolerance, including days to reach full enteral feeding (approximately 100-125kcal/kg/d + 10%) after randomization and the number of episodes of feeding intolerance (defined as an interruption of enteral feedings for > 12 hrs) , number of infants requiring TPN providing > 10% of total daily fluid volume at 12 weeks after randomization, and duration of TPN providing > 10% of total daily fluid intake)	6 months
Frequency of blood stream infections		6 months
Inflammatory markers (C-reactive protein), cytokine levels		6 months
Incidence and severity of ROP		6 months
Neurodevelopment Assessments	Neurodevelopment will be assessed at 6, 12, and 24 months (corrected) using Bayley Scales of Infant Development III(mean total, cognitive, language, and motor scaled score; and frequency of each score <70). The MSD parent questionnaire will be mailed at 12 and 24 months (corrected); and the Parent Report of Children's Abilities - Revised (PARCA-R) parent questionnaire will be mailed at 24 months (coorected).	6, 12, & 24 months (corrected for gestational age)

Collaborators and Investigators

• Sponsor: Boston Children's Hospital

Publications and helpful links

General Publications

• Nehra D, Fallon EM, Potemkin AK, Voss SD, Mitchell PD, Valim C, Belfort MB, Bellinger DC, Duggan C, Gura KM, Puder M. A comparison of 2 intravenous lipid emulsions: interim analysis of a randomized controlled trial. JPEN J Parenter Enteral Nutr. 2014 Aug;38(6):693-701. doi: 10.1177/0148607113492549. Epub 2013 Jun 14.

Study record dates

Study Major Dates

• Study Start: July 1, 2007
• Primary Completion (ACTUAL): December 1, 2011
• Study Completion (ACTUAL): December 1, 2011

Study Registration Dates

• First Submitted: August 6, 2007
• First Submitted That Met QC Criteria: August 7, 2007
• First Posted (ESTIMATE): August 8, 2007

Study Record Updates

• Last Update Posted (ACTUAL): December 3, 2020
• Last Update Submitted That Met QC Criteria: December 1, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: short bowel syndrome; cholestasis; PN; gastrointestinal disease in infants
• Additional Relevant MeSH Terms: Digestive System Diseases; Biliary Tract Diseases; Bile Duct Diseases; Cholestasis; Pharmaceutical Solutions; Parenteral Nutrition Solutions; Fat Emulsions, Intravenous; Soybean oil, phospholipid emulsion
• Other Study ID Numbers: 06-03-0105; 1R01FD003436-01 (FDA)