A Safety and Efficacy Study to Determine if Giving Intravenous Fish Oil Helps Children With Liver Disease (FO)

Omegaven and Parenteral Nutrition Associated Cholestasis

The purpose of the study is to investigate if intravenous fish oil, commercially available as Omegaven, safely and effectively reverses parenteral nutrition associated cholestasis in children.

Study Overview

• Status: Terminated
• Conditions: Cholestasis
• Intervention / Treatment: Drug: Omegaven

Detailed Description

Infants dependent on parenteral nutrition for greater than 1 year who develop parenteral nutrition associated cholestasis will universally face mortality unless they receive a timely liver and/or small bowel transplant. Although transplant survival has improved in recent years, survival is not guaranteed, and transplant care remains costly. Alternative nutritional and pharmacological strategies are imperative to improve the clinical outcomes of infants with intestinal failure and parenteral nutrition associated cholestasis. In both animal and human studies, intravenous fish oil, a lipid emulsion rich in omega-3 fatty acids and Vitamin E, and lacking phytosterols, has been shown to ameliorate parenteral nutrition associated cholestasis and improve morbidity and mortality. The purpose of this pilot study is to investigate if Omegaven, a commercially available intravenous fish oil, at 1 g/kg/d, will safely reverse liver disease in 80 subjects with parenteral nutrition associated cholestasis. Subjects can initially receive a maximum of 6 months (24 weeks) of intravenous fish oil. If the subject re-develops liver disease and still satisfies inclusion/exclusion criteria, the intervention can be restarted. Study subjects will be compared to a historical cohort of children with Short Bowel Syndrome and parenteral nutrition associated cholestasis who have been receiving standard intravenous soybean oil for > 60 days. The fish oil cohort will be followed for a total of 5 years to determine if transplant-free mortality is reduced.

• Study Type: Interventional
• Enrollment (Actual): 62
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California, Los Angeles

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 weeks to 18 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Clinical evidence of parenteral nutrition associated cholestasis
• Direct bilirubin greater or equal to 2 mg/dL on 2 consecutive measurements
• Expected parenteral nutrition course greater than 30 days
• Acquired or congenital gastrointestinal disease
• > 2 weeks of age and < 18 years of age
• > 60% calories from parenteral nutrition
• Failed standard therapies to prevent progression of liver disease (Actigal, cyclic parenteral nutrition, avoidance of overfeeding, reduction/removal of copper from parenteral nutrition if elevated my laboratory analysis, advancement of enteral feeds)

Exclusion Criteria:

• Inborn errors of metabolism
• Extracorporeal Membrane Oxygenation
• Seafood, egg, or Omegaven allergy
• Documented case of liver disease other than Parenteral Nutrition Associated Cholestasis
• Hemorrhagic disorder
• Anticoagulant therapy
• Hemodynamically unstable or in shock
• Comatose state
• Stroke, pulmonary embolism, recent myocardial infarction
• Diabetes
• Fatal chromosomal disorder
• Enrollment in any other clinical trial involving an investigational agent
• Patient, parent, or legal guardians unable or unwilling to give consent
• Patient expected to be weaned from parenteral nutrition in 30 days
• unable to tolerate necessary monitoring
• Patient requiring aspirin or toradel or motrin
• Patient requiring dialysis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Omegaven; 0.5 g/kg/d IV x 2 days, then 1 g/kg/d IV for 24 weeks or until parenteral nutrition discontinuation, death or transplant, whichever comes first. Subjects are eligible to restart Omegaven should they re-satisfy inclusion/exclusion criteria.	Drug: Omegaven; 0.5 g/kg/d intravenous every day for 2 days, then 1 g/kg/d intravenous everyday

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Reversal of Parenteral Nutrition Associated Cholestasis	weeks	24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Death	expiration	24 weeks, transplant, or discontinuation of Parenteral Nutrition (whichever comes first)
Number of Participants Who Underwent a Transplant	includes isolated liver or multi-visceral transplant including liver graft	24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first)
Time to Full Enteral Feeds	discontinuation of parenteral nutrition	24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first)
Growth Z-scores	Weight Z-scores at the end of the study. Formula used: (weight at end of study-average weight of reference population)/standard deviation of weight of reference population. The Z-score indicates the number of standard deviations away from the mean. A weight Z-score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. A weight Z-score </= -2 indicates an underweight or malnourished status, while a weight Z-score >/= 2 indicates an overweight or obese status.	24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first)
Platelet Counts at the End of the Study - Risk of Bleeding	platelet counts at the end of the study	24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first)
Number of Participants With Essential Fatty Acid Deficiency	triene:tetraene ratio less than 0.2	24 weeks, death, transplant, or discontinuation of Parenteral Nutrition (whichever comes first)
Markers of Inflammation	Serum Cytokines - interleukin-8	24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first)
Markers of Sterol Metabolism	Serum Phytosterols - stigmasterol	24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first)
Markers of Bile Acid Metabolism	Serum Bile acids - total chenodeoxycholic acid	24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first)
Markers of Fatty Acid Metabolism	Erythrocyte fatty acid - Docosahexaenoic Acid	24 weeks, death, or discontinuation of Parenteral Nutrition (whichever comes first)

Collaborators and Investigators

• Sponsor: University of California, Los Angeles

Publications and helpful links

General Publications

• Calkins KL, Dunn JC, Shew SB, Reyen L, Farmer DG, Devaskar SU, Venick RS. Pediatric intestinal failure-associated liver disease is reversed with 6 months of intravenous fish oil. JPEN J Parenter Enteral Nutr. 2014 Aug;38(6):682-92. doi: 10.1177/0148607113495416. Epub 2013 Jul 26.
• Calkins KL, DeBarber A, Steiner RD, Flores MJ, Grogan TR, Henning SM, Reyen L, Venick RS. Intravenous Fish Oil and Pediatric Intestinal Failure-Associated Liver Disease: Changes in Plasma Phytosterols, Cytokines, and Bile Acids and Erythrocyte Fatty Acids. JPEN J Parenter Enteral Nutr. 2018 Mar;42(3):633-641. doi: 10.1177/0148607117709196. Epub 2017 Dec 18.
• Wang C, Venick RS, Shew SB, Dunn JCY, Reyen L, Gou R, Calkins KL. Long-Term Outcomes in Children With Intestinal Failure-Associated Liver Disease Treated With 6 Months of Intravenous Fish Oil Followed by Resumption of Intravenous Soybean Oil. JPEN J Parenter Enteral Nutr. 2019 Aug;43(6):708-716. doi: 10.1002/jpen.1463. Epub 2018 Nov 8.
• Ong ML, Venick RS, Shew SB, Dunn JCY, Reyen L, Grogan T, Calkins KL. Intravenous Fish Oil and Serum Fatty Acid Profiles in Pediatric Patients With Intestinal Failure-Associated Liver Disease. JPEN J Parenter Enteral Nutr. 2019 Aug;43(6):717-725. doi: 10.1002/jpen.1532. Epub 2019 Mar 22.
• Calkins KL, Thamotharan S, Ghosh S, Dai Y, Devaskar SU. MicroRNA 122 Reflects Liver Injury in Children with Intestinal Failure-Associated Liver Disease Treated with Intravenous Fish Oil. J Nutr. 2020 May 1;150(5):1144-1150. doi: 10.1093/jn/nxaa001.

Study record dates

Study Major Dates

• Study Start (ACTUAL): August 1, 2009
• Primary Completion (ACTUAL): January 12, 2019
• Study Completion (ACTUAL): February 12, 2019

Study Registration Dates

• First Submitted: August 31, 2009
• First Submitted That Met QC Criteria: August 31, 2009
• First Posted (ESTIMATE): September 1, 2009

Study Record Updates

• Last Update Posted (ACTUAL): February 26, 2020
• Last Update Submitted That Met QC Criteria: February 11, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: children; liver; fish oil; parenteral nutrition; omegaven
• Additional Relevant MeSH Terms: Digestive System Diseases; Biliary Tract Diseases; Bile Duct Diseases; Cholestasis
• Other Study ID Numbers: 09-02-079-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No